research article on physical exercise

• Research article
• Open access
• Published: 16 November 2020

Exercise/physical activity and health outcomes: an overview of Cochrane systematic reviews

• Pawel Posadzki 1 , 2 ,
• Dawid Pieper   ORCID: orcid.org/0000-0002-0715-5182 3 ,
• Ram Bajpai 4 ,
• Hubert Makaruk 5 ,
• Nadja Könsgen 3 ,
• Annika Lena Neuhaus 3 &
• Monika Semwal 6  

BMC Public Health volume  20 , Article number:  1724 ( 2020 ) Cite this article

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Sedentary lifestyle is a major risk factor for noncommunicable diseases such as cardiovascular diseases, cancer and diabetes. It has been estimated that approximately 3.2 million deaths each year are attributable to insufficient levels of physical activity. We evaluated the available evidence from Cochrane systematic reviews (CSRs) on the effectiveness of exercise/physical activity for various health outcomes.

Overview and meta-analysis. The Cochrane Library was searched from 01.01.2000 to issue 1, 2019. No language restrictions were imposed. Only CSRs of randomised controlled trials (RCTs) were included. Both healthy individuals, those at risk of a disease, and medically compromised patients of any age and gender were eligible. We evaluated any type of exercise or physical activity interventions; against any types of controls; and measuring any type of health-related outcome measures. The AMSTAR-2 tool for assessing the methodological quality of the included studies was utilised.

Hundred and fifty CSRs met the inclusion criteria. There were 54 different conditions. Majority of CSRs were of high methodological quality. Hundred and thirty CSRs employed meta-analytic techniques and 20 did not. Limitations for studies were the most common reasons for downgrading the quality of the evidence. Based on 10 CSRs and 187 RCTs with 27,671 participants, there was a 13% reduction in mortality rates risk ratio (RR) 0.87 [95% confidence intervals (CI) 0.78 to 0.96]; I 2  = 26.6%, [prediction interval (PI) 0.70, 1.07], median effect size (MES) = 0.93 [interquartile range (IQR) 0.81, 1.00]. Data from 15 CSRs and 408 RCTs with 32,984 participants showed a small improvement in quality of life (QOL) standardised mean difference (SMD) 0.18 [95% CI 0.08, 0.28]; I 2  = 74.3%; PI -0.18, 0.53], MES = 0.20 [IQR 0.07, 0.39]. Subgroup analyses by the type of condition showed that the magnitude of effect size was the largest among patients with mental health conditions.

There is a plethora of CSRs evaluating the effectiveness of physical activity/exercise. The evidence suggests that physical activity/exercise reduces mortality rates and improves QOL with minimal or no safety concerns.

Trial registration

Registered in PROSPERO ( CRD42019120295 ) on 10th January 2019.

Peer Review reports

The World Health Organization (WHO) defines physical activity “as any bodily movement produced by skeletal muscles that requires energy expenditure” [ 1 ]. Therefore, physical activity is not only limited to sports but also includes walking, running, swimming, gymnastics, dance, ball games, and martial arts, for example. In the last years, several organizations have published or updated their guidelines on physical activity. For example, the Physical Activity Guidelines for Americans, 2nd edition, provides information and guidance on the types and amounts of physical activity that provide substantial health benefits [ 2 ]. The evidence about the health benefits of regular physical activity is well established and so are the risks of sedentary behaviour [ 2 ]. Exercise is dose dependent, meaning that people who achieve cumulative levels several times higher than the current recommended minimum level have a significant reduction in the risk of breast cancer, colon cancer, diabetes, ischemic heart disease, and ischemic stroke events [ 3 ]. Benefits of physical activity have been reported for numerous outcomes such as mortality [ 4 , 5 ], cognitive and physical decline [ 5 , 6 , 7 ], glycaemic control [ 8 , 9 ], pain and disability [ 10 , 11 ], muscle and bone strength [ 12 ], depressive symptoms [ 13 ], and functional mobility and well-being [ 14 , 15 ]. Overall benefits of exercise apply to all bodily systems including immunological [ 16 ], musculoskeletal [ 17 ], respiratory [ 18 ], and hormonal [ 19 ]. Specifically for the cardiovascular system, exercise increases fatty acid oxidation, cardiac output, vascular smooth muscle relaxation, endothelial nitric oxide synthase expression and nitric oxide availability, improves plasma lipid profiles [ 15 ] while at the same time reducing resting heart rate and blood pressure, aortic valve calcification, and vascular resistance [ 20 ].

However, the degree of all the above-highlighted benefits vary considerably depending on individual fitness levels, types of populations, age groups and the intensity of different physical activities/exercises [ 21 ]. The majority of guidelines in different countries recommend a goal of 150 min/week of moderate-intensity aerobic physical activity (or equivalent of 75 min of vigorous-intensity) [ 22 ] with differences for cardiovascular disease [ 23 ] or obesity prevention [ 24 ] or age groups [ 25 ].

There is a plethora of systematic reviews published by the Cochrane Library critically evaluating the effectiveness of physical activity/exercise for various health outcomes. Cochrane systematic reviews (CSRs) are known to be a source of high-quality evidence. Thus, it is not only timely but relevant to evaluate the current knowledge, and determine the quality of the evidence-base, and the magnitude of the effect sizes given the negative lifestyle changes and rising physical inactivity-related burden of diseases. This overview will identify the breadth and scope to which CSRs have appraised the evidence for exercise on health outcomes; and this will help in directing future guidelines and identifying current gaps in the literature.

The objectives of this research were to a. answer the following research questions: in children, adolescents and adults (both healthy and medically compromised) what are the effects (and adverse effects) of exercise/physical activity in improving various health outcomes (e.g., pain, function, quality of life) reported in CSRs; b. estimate the magnitude of the effects by pooling the results quantitatively; c. evaluate the strength and quality of the existing evidence; and d. create recommendations for future researchers, patients, and clinicians.

Our overview was registered with PROSPERO (CRD42019120295) on 10th January 2019. The Cochrane Handbook for Systematic Reviews of interventions and Preferred Reporting Items for Overviews of Reviews were adhered to while writing and reporting this overview [ 26 , 27 ].

Search strategy and selection criteria

We followed the practical guidance for conducting overviews of reviews of health care interventions [ 28 ] and searched the Cochrane Database of Systematic Reviews (CDSR), 2019, Issue 1, on the Cochrane Library for relevant papers using the search strategy: (health) and (exercise or activity or physical). The decision to seek CSRs only was based on three main aspects. First, high quality (CSRs are considered to be the ‘gold methodological standard’) [ 29 , 30 , 31 ]. Second, data saturation (enough high-quality evidence to reach meaningful conclusions based on CSRs only). Third, including non-CSRs would have heavily increased the issue of overlapping reviews (also affecting data robustness and credibility of conclusions). One reviewer carried out the searches. The study screening and selection process were performed independently by two reviewers. We imported all identified references into reference manager software EndNote (X8). Any disagreements were resolved by discussion between the authors with third overview author acting as an arbiter, if necessary.

We included CSRs of randomised controlled trials (RCTs) involving both healthy individuals and medically compromised patients of any age and gender. Only CSRs assessing exercise or physical activity as a stand-alone intervention were included. This included interventions that could initially be taught by a professional or involve ongoing supervision (the WHO definition). Complex interventions e.g., assessing both exercise/physical activity and behavioural changes were excluded if the health effects of the interventions could not have been attributed to exercise distinctly.

Any types of controls were admissible. Reviews evaluating any type of health-related outcome measures were deemed eligible. However, we excluded protocols or/and CSRs that have been withdrawn from the Cochrane Library as well as reviews with no included studies.

Data analysis

Three authors (HM, ALN, NK) independently extracted relevant information from all the included studies using a custom-made data collection form. The methodological quality of SRs included was independently evaluated by same reviewers using the AMSTAR-2 tool [ 32 ]. Any disagreements on data extraction or CSR quality were resolved by discussion. The entire dataset was validated by three authors (PP, MS, DP) and any discrepant opinions were settled through discussions.

The results of CSRs are presented in a narrative fashion using descriptive tables. Where feasible, we presented outcome measures across CSRs. Data from the subset of homogeneous outcomes were pooled quantitatively using the approach previously described by Bellou et al. and Posadzki et al. [ 33 , 34 ]. For mortality and quality of life (QOL) outcomes, the number of participants and RCTs involved in the meta-analysis, summary effect sizes [with 95% confidence intervals (CI)] using random-effects model were calculated. For binary outcomes, we considered relative risks (RRs) as surrogate measures of the corresponding odds ratio (OR) or risk ratio/hazard ratio (HR). To stabilise the variance and normalise the distributions, we transformed RRs into their natural logarithms before pooling the data (a variation was allowed, however, it did not change interpretation of results) [ 35 ]. The standard error (SE) of the natural logarithm of RR was derived from the corresponding CIs, which was either provided in the study or calculated with standard formulas [ 36 ]. Binary outcomes reported as risk difference (RD) were also meta-analysed if two more estimates were available. For continuous outcomes, we only meta-analysed estimates that were available as standardised mean difference (SMD), and estimates reported with mean differences (MD) for QOL were presented separately in a supplementary Table  9 . To estimate the overall effect size, each study was weighted by the reciprocal of its variance. Random-effects meta-analysis, using DerSimonian and Laird method [ 37 ] was applied to individual CSR estimates to obtain a pooled summary estimate for RR or SMD. The 95% prediction interval (PI) was also calculated (where ≥3 studies were available), which further accounts for between-study heterogeneity and estimates the uncertainty around the effect that would be anticipated in a new study evaluating that same association. I -squared statistic was used to measure between study heterogeneity; and its various thresholds (small, substantial and considerable) were interpreted considering the size and direction of effects and the p -value from Cochran’s Q test ( p  < 0.1 considered as significance) [ 38 ]. Wherever possible, we calculated the median effect size (with interquartile range [IQR]) of each CSR to interpret the direction and magnitude of the effect size. Sub-group analyses are planned for type and intensity of the intervention; age group; gender; type and/or severity of the condition, risk of bias in RCTs, and the overall quality of the evidence (Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria). To assess overlap we calculated the corrected covered area (CCA) [ 39 ]. All statistical analyses were conducted on Stata statistical software version 15.2 (StataCorp LLC, College Station, Texas, USA).

The searches generated 280 potentially relevant CRSs. After removing of duplicates and screening, a total of 150 CSRs met our eligibility criteria [ 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 , 144 , 145 , 146 , 147 , 148 , 149 , 150 , 151 , 152 , 153 , 154 , 155 , 156 , 157 , 158 , 159 , 160 , 161 , 162 , 163 , 164 , 165 , 166 , 167 , 168 , 169 , 170 , 171 , 172 , 173 , 174 , 175 , 176 , 177 , 178 , 179 , 180 , 181 , 182 , 183 , 184 , 185 , 186 , 187 , 188 , 189 ] (Fig.  1 ). Reviews were published between September 2002 and December 2018. A total of 130 CSRs employed meta-analytic techniques and 20 did not. The total number of RCTs in the CSRs amounted to 2888; with 485,110 participants (mean = 3234, SD = 13,272). The age ranged from 3 to 87 and gender distribution was inestimable. The main characteristics of included reviews are summarised in supplementary Table  1 . Supplementary Table  2 summarises the effects of physical activity/exercise on health outcomes. Conclusions from CSRs are listed in supplementary Table  3 . Adverse effects are listed in supplementary Table  4 . Supplementary Table  5 presents summary of withdrawals/non-adherence. The methodological quality of CSRs is presented in supplementary Table  6 . Supplementary Table  7 summarises studies assessed at low risk of bias (by the authors of CSRs). GRADE-ings of the review’s main comparison are listed in supplementary Table  8 .

Study selection process

There were 54 separate populations/conditions, considerable range of interventions and comparators, co-interventions, and outcome measures. For detailed description of interventions, please refer to the supplementary tables . Most commonly measured outcomes were - function 112 (75%), QOL 83 (55%), AEs 70 (47%), pain 41 (27%), mortality 28 (19%), strength 30 (20%), costs 47 (31%), disability 14 (9%), and mental health in 35 (23%) CSRs.

There was a 13% reduction in mortality rates risk ratio (RR) 0.87 [95% CI 0.78 to 0.96]; I 2  = 26.6%, [PI 0.70, 1.07], median effect size (MES) = 0.93 [interquartile range (IQR) 0.81, 1.00]; 10 CSRs, 187 RCTs, 27,671 participants) following exercise when compared with various controls (Table 1 ). This reduction was smaller in ‘other groups’ of patients when compared to cardiovascular diseases (CVD) patients - RR 0.97 [95% CI 0.65, 1.45] versus 0.85 [0.76, 0.96] respectively. The effects of exercise were not intensity or frequency dependent. Sessions more than 3 times per week exerted a smaller reduction in mortality as compared with sessions of less than 3 times per week RR 0.87 [95% CI 0.78, 0.98] versus 0.63 [0.39, 1.00]. Subgroup analyses by risk of bias (ROB) in RCTs showed that RCTs at low ROB exerted smaller reductions in mortality when compared to RCTs at an unclear or high ROB, RR 0.90 [95% CI 0.78, 1.02] versus 0.72 [0.42, 1.22] versus 0.86 [0.69, 1.06] respectively. CSRs with moderate quality of evidence (GRADE), showed slightly smaller reductions in mortality when compared with CSRs that relied on very low to low quality evidence RR 0.88 [95% CI 0.79, 0.98] versus 0.70 [0.47, 1.04].

Exercise also showed an improvement in QOL, standardised mean difference (SMD) 0.18 [95% CI 0.08, 0.28]; I 2  = 74.3%; PI -0.18, 0.53], MES = 0.20 [IQR 0.07, 0.39]; 15 CSRs, 408 RCTs, 32,984 participants) when compared with various controls (Table 2 ). These improvements were greater observed for health related QOL when compared to overall QOL SMD 0.30 [95% CI 0.21, 0.39] vs 0.06 [− 0.08, 0.20] respectively. Again, the effects of exercise were duration and frequency dependent. For instance, sessions of more than 90 mins exerted a greater improvement in QOL as compared with sessions up to 90 min SMD 0.24 [95% CI 0.11, 0.37] versus 0.22 [− 0.30, 0.74]. Subgroup analyses by the type of condition showed that the magnitude of effect was the largest among patients with mental health conditions, followed by CVD and cancer. Physical activity exerted negative effects on QOL in patients with respiratory conditions (2 CSRs, 20 RCTs with 601 patients; SMD -0.97 [95% CI -1.43, 0.57]; I 2  = 87.8%; MES = -0.46 [IQR-0.97, 0.05]). Subgroup analyses by risk of bias (ROB) in RCTs showed that RCTs at low or unclear ROB exerted greater improvements in QOL when compared to RCTs at a high ROB SMD 0.21 [95% CI 0.10, 0.31] versus 0.17 [0.03, 0.31]. Analogically, CSRs with moderate to high quality of evidence showed slightly greater improvements in QOL when compared with CSRs that relied on very low to low quality evidence SMD 0.19 [95% CI 0.05, 0.33] versus 0.15 [− 0.02, 0.32]. Please also see supplementary Table  9 more studies reporting QOL outcomes as mean difference (not quantitatively synthesised herein).

Adverse events (AEs) were reported in 100 (66.6%) CSRs; and not reported in 50 (33.3%). The number of AEs ranged from 0 to 84 in the CSRs. The number was inestimable in 83 (55.3%) CSRs. Ten (6.6%) reported no occurrence of AEs. Mild AEs were reported in 28 (18.6%) CSRs, moderate in 9 (6%) and serious/severe in 20 (13.3%). There were 10 deaths and in majority of instances, the causality was not attributed to exercise. For this outcome, we were unable to pool the data as effect sizes were too heterogeneous (Table 3 ).

In 38 CSRs, the total number of trials reporting withdrawals/non-adherence was inestimable. There were different ways of reporting it such as adherence or attrition (high in 23.3% of CSRs) as well as various effect estimates including %, range, total numbers, MD, RD, RR, OR, mean and SD. The overall pooled estimates are reported in Table 3 .

Of all 16 domains of the AMSTAR-2 tool, 1876 (78.1%) scored ‘yes’, 76 (3.1%) ‘partial yes’; 375 (15.6%) ‘no’, and ‘not applicable’ in 25 (1%) CSRs. Ninety-six CSRs (64%) were scored as ‘no’ on reporting sources of funding for the studies followed by 88 (58.6%) failing to explain the selection of study designs for inclusion. One CSR (0.6%) each were judged as ‘no’ for reporting any potential sources of conflict of interest, including any funding for conducting the review as well for performing study selection in duplicate.

In 102 (68%) CSRs, there was predominantly a high risk of bias in RCTs. In 9 (6%) studies, this was reported as a range, e.g., low or unclear or low to high. Two CSRs used different terminology i.e., moderate methodological quality; and the risk of bias was inestimable in one CSR. Sixteen (10.6%) CSRs did not identify any studies (RCTs) at low risk of random sequence generation, 28 (18.6%) allocation concealment, 28 (18.6%) performance bias, 84 (54%) detection bias, 35 (23.3%) attrition bias, 18 (12%) reporting bias, and 29 (19.3%) other bias.

In 114 (76%) CSRs, limitation of studies was the main reason for downgrading the quality of the evidence followed by imprecision in 98 (65.3%) and inconsistency in 68 (45.3%). Publication bias was the least frequent reason for downgrading in 26 (17.3%) CSRs. Ninety-one (60.7%) CSRs reached equivocal conclusions, 49 (32.7%) reviews reached positive conclusions and 10 (6.7%) reached negative conclusions (as judged by the authors of CSRs).

In this systematic review of CSRs, we found a large body of evidence on the beneficial effects of physical activity/exercise on health outcomes in a wide range of heterogeneous populations. Our data shows a 13% reduction in mortality rates among 27,671 participants, and a small improvement in QOL and health-related QOL following various modes of physical activity/exercises. This means that both healthy individuals and medically compromised patients can significantly improve function, physical and mental health; or reduce pain and disability by exercising more [ 190 ]. In line with previous findings [ 191 , 192 , 193 , 194 ], where a dose-specific reduction in mortality has been found, our data shows a greater reduction in mortality in studies with longer follow-up (> 12 months) as compared to those with shorter follow-up (< 12 months). Interestingly, we found a consistent pattern in the findings, the higher the quality of evidence and the lower the risk of bias in primary studies, the smaller reductions in mortality. This pattern is observational in nature and cannot be over-generalised; however this might mean less certainty in the estimates measured. Furthermore, we found that the magnitude of the effect size was the largest among patients with mental health conditions. A possible mechanism of action may involve elevated levels of brain-derived neurotrophic factor or beta-endorphins [ 195 ].

We found the issue of poor reporting or underreporting of adherence/withdrawals in over a quarter of CSRs (25.3%). This is crucial both for improving the accuracy of the estimates at the RCT level as well as maintaining high levels of physical activity and associated health benefits at the population level.

Even the most promising interventions are not entirely risk-free; and some minor AEs such as post-exercise pain and soreness or discomfort related to physical activity/exercise have been reported. These were typically transient; resolved within a few days; and comparable between exercise and various control groups. However worryingly, the issue of poor reporting or underreporting of AEs has been observed in one third of the CSRs. Transparent reporting of AEs is crucial for identifying patients at risk and mitigating any potential negative or unintended consequences of the interventions.

High risk of bias of the RCTs evaluated was evident in more than two thirds of the CSRs. For example, more than half of reviews identified high risk of detection bias as a major source of bias suggesting that lack of blinding is still an issue in trials of behavioural interventions. Other shortcomings included insufficiently described randomisation and allocation concealment methods and often poor outcome reporting. This highlights the methodological challenges in RCTs of exercise and the need to counterbalance those with the underlying aim of strengthening internal and external validity of these trials.

Overall, high risk of bias in the primary trials was the main reason for downgrading the quality of the evidence using the GRADE criteria. Imprecision was frequently an issue, meaning the effective sample size was often small; studies were underpowered to detect the between-group differences. Pooling too heterogeneous results often resulted in inconsistent findings and inability to draw any meaningful conclusions. Indirectness and publication bias were lesser common reasons for downgrading. However, with regards to the latter, the generally accepted minimum number of 10 studies needed for quantitatively estimate the funnel plot asymmetry was not present in 69 (46%) CSRs.

Strengths of this research are the inclusion of large number of ‘gold standard’ systematic reviews, robust screening, data extractions and critical methodological appraisal. Nevertheless, some weaknesses need to be highlighted when interpreting findings of this overview. For instance, some of these CSRs analysed the same primary studies (RCTs) but, arrived at slightly different conclusions. Using, the Pieper et al. [ 39 ] formula, the amount of overlap ranged from 0.01% for AEs to 0.2% for adherence, which indicates slight overlap. All CSRs are vulnerable to publication bias [ 196 ] - hence the conclusions generated by them may be false-positive. Also, exercise was sometimes part of a complex intervention; and the effects of physical activity could not be distinguished from co-interventions. Often there were confounding effects of diet, educational, behavioural or lifestyle interventions; selection, and measurement bias were inevitably inherited in this overview too. Also, including CSRs only might lead to selection bias; and excluding reviews published before 2000 might limit the overall completeness and applicability of the evidence. A future update should consider these limitations, and in particular also including non-CSRs.

Conclusions

Trialists must improve the quality of primary studies. At the same time, strict compliance with the reporting standards should be enforced. Authors of CSRs should better explain eligibility criteria and report sources of funding for the primary studies. There are still insufficient physical activity trends worldwide amongst all age groups; and scalable interventions aimed at increasing physical activity levels should be prioritized [ 197 ]. Hence, policymakers and practitioners need to design and implement comprehensive and coordinated strategies aimed at targeting physical activity programs/interventions, health promotion and disease prevention campaigns at local, regional, national, and international levels [ 198 ].

Availability of data and materials

Data sharing is not applicable to this article as no raw data were analysed during the current study. All information in this article is based on published systematic reviews.

Abbreviations

Adverse events

Cardiovascular diseases

Cochrane Database of Systematic Reviews

Cochrane systematic reviews

Confidence interval

Grading of Recommendations Assessment, Development and Evaluation

Hazard ratio

Interquartile range

Mean difference

Prediction interval

Quality of life

Randomised controlled trials

Relative risk

Risk difference

Risk of bias

Standard error

Standardised mean difference

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PP wrote the protocol, ran the searches, validated, analysed and synthesised data, wrote and revised the drafts. HM, NK and ALN screened and extracted data. MS and DP validated and analysed the data. RB ran statistical analyses. All authors contributed to writing and reviewing the manuscript. PP is the guarantor. The authors read and approved the final manuscript.

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Supplementary Table 1. Main characteristics of included Cochrane systematic reviews evaluating the effects of physical activity/exercise on health outcomes ( n  = 150). Supplementary Table 2. Additional information from Cochrane systematic reviews of the effects of physical activity/exercise on health outcomes ( n  = 150). Supplementary Table 3. Conclusions from Cochrane systematic reviews “quote”. Supplementary Table 4 . AEs reported in Cochrane systematic reviews. Supplementary Table 5. Summary of withdrawals/non-adherence. Supplementary Table 6. Methodological quality assessment of the included Cochrane reviews with AMSTAR-2. Supplementary Table 7. Number of studies assessed as low risk of bias per domain. Supplementary Table 8. GRADE for the review’s main comparison. Supplementary Table 9. Studies reporting quality of life outcomes as mean difference.

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Posadzki, P., Pieper, D., Bajpai, R. et al. Exercise/physical activity and health outcomes: an overview of Cochrane systematic reviews. BMC Public Health 20 , 1724 (2020). https://doi.org/10.1186/s12889-020-09855-3

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The beneficial effects of physical exercise in the brain and related pathophysiological mechanisms in neurodegenerative diseases

• Yan Liu 1 , 2 ,
• Tim Yan 1 ,
• John Man-Tak Chu 1 , 2 ,
• Ying Chen 1 , 2 ,
• Sophie Dunnett 1 ,
• Yuen-Shan Ho 3 ,
• Gordon Tin-Chun Wong 2 &
• Raymond Chuen-Chung Chang   ORCID: orcid.org/0000-0001-8538-7993 1 , 4  

Laboratory Investigation volume  99 ,  pages 943–957 ( 2019 ) Cite this article

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Growing evidence has shown the beneficial influence of exercise on humans. Apart from classic cardioprotection, numerous studies have demonstrated that different exercise regimes provide a substantial improvement in various brain functions. Although the underlying mechanism is yet to be determined, emerging evidence for neuroprotection has been established in both humans and experimental animals, with most of the valuable findings in the field of mental health, neurodegenerative diseases, and acquired brain injuries. This review will discuss the recent findings of how exercise could ameliorate brain function in neuropathological states, demonstrated by either clinical or laboratory animal studies. Simultaneously, state-of-the-art molecular mechanisms underlying the exercise-induced neuroprotective effects and comparison between different types of exercise will be discussed in detail. A majority of reports show that physical exercise is associated with enhanced cognition throughout different populations and remains as a fascinating area in scientific research because of its universal protective effects in different brain domain functions. This article is to review what we know about how physical exercise modulates the pathophysiological mechanisms of neurodegeneration.

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Introduction.

Physical activity is a crucial element throughout human life. The evolutionary theory suggests that humans need basal physical activities for survival [ 1 ]. In the US, approximately 26% of premature deaths can be attributed to physical inactivity [ 2 ]. In recent decades, there are compelling lines of evidence which support that exercise not only protects against cardiovascular diseases, but also reduces the risks of several cancers and metabolic dysfunction [ 3 ]. In the central nervous system (CNS), the protective effects of both short term and long term physical exercise on neurodegeneration and cerebrovascular diseases have attracted many researchers’ attention. For instance, acute aerobic exercise (AE) modulates neurotransmitter release and modulates neural circuitry [ 4 ]. Endurance AE is also known to ameliorate symptoms of major depression, prevent neuronal dysfunction, and slow down the progression of different diseases [ 5 , 6 ]. Both preclinical animal models and human patients with neurodegeneration have shown convincing evidence that exercise improves cognitive performance [ 7 , 8 ]. Moreover, with the advancement of molecular techniques, researchers have discovered and identified the involvement of several molecular pathways involved in exercise-related beneficial effects [ 9 ].

On the other hand, although solid evidence has demonstrated the neuroprotective effects of exercise, whether different neuroprotective mechanisms are involved in each specific type of exercise remains one of the debated topics in the exercise medicine field. The answer to this debate is important to determine since exercise can be divided into different types, depending on the purpose of the training regime [ 10 ]. It remains controversial whether the therapeutic efficacy of a specific type of exercise surpasses another type of exercise, and needs further investigation.

In this review, we will present the updated findings on the beneficial effects of physical exercise in brain disorders and neurodegeneration. More importantly, we will also summarize the novel underlying molecular mechanisms about the neuroprotective actions of exercises from recent research, mainly laboratory studies. Finally, we will briefly introduce and compare different types of exercise which have been explored for their potential value in treating brain disorders.

Beneficial effects of physical exercise in different brain disorders

Mental disorders.

Mental disorders are common health problems characterized by abnormal emotions, perceptions, behaviors, and relationships with others [ 11 ]. Among adults in the US, one year and lifetime morbidities of major depressive disorder (MDD) in 2011 (10.4% and 20.6%, respectively) were nearly doubled when compared with 2001 (5.3% and 13.2%, respectively) [ 12 ]. In 2017, an estimated 18.9% of adults in the US experienced any mental illness (AMI) within the past year, while about 23.8% of the adults having AMI suffered from serious mental illness [ 13 ]. Accumulating studies have indicated that mental disorders are becoming one of the most common causes of disability and death worldwide [ 13 ]. Medications like antidepressants are available for moderate to severe mental disorders, but are not recommended for mild mental disorders and should be used with caution while dealing with patients under 18 years old due to a poor risk-benefit ratio [ 14 ].

Many studies suggested physical exercise as an effective nonpharmacologic treatment for different psychiatric problems like depression, anxiety, and dementia, either alone or as an adjunctive therapy for antidepressants/psychotropic drugs [ 15 ]. However, most of these studies had small sample sizes and included few types, frequencies, and durations of exercise. Moreover, the dose–response relationship between exercise and mental health remains unclear. In a recent cross-sectional study of a representative sample including more than one million people aged above 18, which was the largest study of its kind to date [ 5 ], the authors showed that individuals in the exercise group had 1.49 fewer days of bad self-reported mental health in the past month than individuals in the control group. Furthermore, they demonstrated that all kinds of physical exercise were associated with better mental health. The largest associations were seen for popular team sports, cycling, as well as aerobic and gym activities. This research also indicated that the best duration and frequency of exercise were 45 min and 3–5 times per week, respectively.

Among patients who have taken antidepressants, about 60% of them have reported adverse effects, which include negative events in sex life, work or study, and social life [ 16 ]. Another common problem in depression treatment is drug and/or psychotherapy resistance. Treatment-resistant depression (TRD) is a complex condition hardly reaching full remission, with very few “next choice” treatments. Mota-Pereira and colleagues showed that a 3-month walking exercise program improved all depression and functioning parameters in TRD patients. In addition, 26% of these patients met the criteria of remission [ 17 ], suggesting that moderate-intensity exercise might be a helpful and effective adjuvant therapy for TRD. Similar findings are reported with schizophrenia, which is a major psychiatric disease that affects approximately 24 million people worldwide [ 18 ]. Antipsychotic drugs are effective when dealing with the positive symptoms in schizophrenia, but can induce many side effects, such as weight gain and metabolic syndromes [ 19 ]. Furthermore, negative symptoms, which are highly associated with the functional outcome of schizophrenia patients, show poor response to antipsychotic drugs [ 20 ]. Interestingly, physical exercise has not only been demonstrated to reduce overall symptoms in schizophrenia, but also was found to be more effective in dealing with negative symptoms than positive symptoms [ 21 ]. These benefits suggest that physical exercise could be a therapy to decrease the negative symptoms in patients with schizophrenia.

Neurodegenerative diseases

Over the last decade, with a continually aging population, age-related neurodegenerative diseases are dramatically becoming more prevalent and represent one of the major health problems in society. The etiology of neurodegenerative diseases is multifactorial and complex, including not only genetic predispositions, but also environmental and endogenous factors. Nutritional deficiencies, hypertension, diabetes, hypercholesterolemia, obesity, and inflammation are associated with the onset and the deterioration of neurodegenerative diseases [ 22 ]. Physical exercise has been suggested as one of the best lifestyle interventions for both healthy aging and patients with neurodegenerative diseases including Alzheimer’s disease (AD) and Parkinson’s disease (PD).

AD is a progressive neurodegenerative disease affecting about 40 million people globally, and the number of patients is expected to triple by 2050 [ 23 ]. At present, AD patients are commonly treated with combined pharmacological treatment and supportive therapy, such as counseling and social care, to slow down the progression of the disease, and no disease-modifying treatment exists yet. There are promising findings in clinical studies that demonstrate physical exercise as an effective treatment to AD patients, which may even be a disease-modifying therapeutic approach [ 6 , 24 ]. The beneficial effects of physical exercise include stimulating the release of neurotrophic factors, anti-inflammatory effects, and induction of angiogenesis [ 6 ]. Furthermore, accumulating evidence shows that exercise is associated with decreased deposition of Aβ [ 24 , 25 ] and improvement of tau pathology [ 26 ] in the brain. However, it might be too early to reach any definite conclusion as the quality of current studies varies with sample size and definite diagnosis of disease; also the type, duration, and frequencies of physical exercise were different during these studies. High-quality studies with a large sample size are needed to illustrate the relationship between exercise and the pathology of AD.

PD is a mobility-related neurodegenerative disease directly related to the degradation of the nigrostriatal pathway, in which the extent of degeneration predicts increased disability and mortality in patients [ 27 ]. Previous studies suggested that exercise ameliorated a variety of symptoms in PD patients, including not only executive dysfunction, but also psychiatric problems and cognitive impairment [ 28 ]. A recent clinical trial, which was designed to investigate the dose-response of treadmill exercise to PD, showed that only high-intensity exercise successfully improved motor symptoms of PD patients [ 29 ]. Therefore, the intensity of exercise is an important factor to optimize its effect on symptom remission and disease progression in PD. Moreover, animal studies demonstrated that exercise could rescue the loss of dopaminergic neurons and fibers, as well as decrease the expression of α-synuclein in the nigrostriatal region [ 30 , 31 ], which emphasized the therapeutic potential of exercise as a disease-modifying treatment for PD.

Acquired brain injuries

Acquired brain injuries (ABI) include traumatic brain injury (TBI) and stroke. More than ten million people suffer from TBI annually worldwide, which lead to temporary brain dysfunction or permanent mood, physical, and cognitive deficits. Only a few noninvasive interventions have been shown to be beneficial to the brain after TBI, among which, physical rehabilitation is one of the most promising strategies to promote functional recovery after TBI [ 32 ]. Clinical studies suggested that exercise could improve fatigue and enhance recovery of cognitive functions in patients who have suffered from TBI [ 33 , 34 ]. On the other hand, animal experiments suggested that treadmill exercise might be an important mediator to enhance the survival of Purkinje neurons, to help overcome TBI-induced apoptotic neuronal death, and to suppress the formation of reactive astrocytes [ 35 ]. In addition, the effects of exercise preconditioning on TBI might be associated with increased expression of neuroprotective genes and proteins including vascular endothelial growth factor (VEGF) and erythropoietin in the brain [ 36 ].

Stroke is the second leading cause of death and adult disability worldwide, affecting approximately 15 million individuals annually. Approximately 50 to 75% of all stroke survivors have residual physical or cognitive impairments [ 37 ]. Evidence suggests that patients with cardiovascular disease, diabetes, dyslipidemia, obesity, and physical inactivity are at an increased risk for stroke [ 38 ]. Therefore, the application of exercise in the prevention of stroke is more like an etiological treatment, through the improvement of a variety of conditions and diseases. The typical beneficial effects of exercise include lower body weight, better control of hypertension, glucose tolerance, decreased LDL cholesterol level, and an overall reduction in the risk of cardiovascular diseases and diabetes mellitus [ 39 ]. A clinical study showed that highly active individuals exhibit a 21% lower risk of ischemic stroke and a 34% lower risk of hemorrhagic stroke [ 40 ]. The benefits of exercise have also been demonstrated in post-stroke intervention. Physical training after stroke improves walking speed, balance, optimal recovery and promotes the earlier return to an independent life [ 41 ].

Pathophysiological mechanisms

Neurotrophic factors.

The induction of neurotrophic factors is considered as a central mechanism that mediates the benefits of physical exercise on brain functions. Exercise has been shown to be associated with the expression of neurotrophic factors including brain-derived neurotrophic factor (BDNF), insulin-like growth factor 1 (IGF-1), and VEGF, thereby promoting neural plasticity and adult hippocampal neurogenesis [ 42 ].

BDNF is a neurotrophic growth factor that is essential to neuronal survival, growth, differentiation, as well as synaptic plasticity [ 43 , 44 ]. Notably, it has been found to be involved in adult neurogenesis and myelin repair [ 45 ]. BDNF is widely expressed in the CNS, with a particularly high concentration in the hippocampus and cortex, and has also been found in the peripheral nervous system as a proxy of cortical BDNF [ 44 ]. Furthermore, a decrease of BDNF in the periphery and CNS is found in many neurodegenerative and psychiatric diseases [ 46 ]. Exercise induced the upregulation of BDNF, both in circulation and in the brain, and the increased levels of BDNF were associated with improved cognitive function [ 42 , 46 , 47 ]. Although exercise increased the levels of BDNF mRNA and proteins in skeletal muscle, this muscle-derived BDNF was not released into circulation. Instead, the brain contributed 70–80% of the BDNF in circulation during exercise [ 48 ]. It is suggested that the increased expression of BDNF in the brain, especially in the hippocampus or dentate gyrus (DG), attenuates cognitive deterioration and improves memory formation.

The underlying mechanism of how exercise mediates the expression of BDNF in the brain remains unclear. Wrann and colleagues found that exercise increased BDNF expression in the hippocampus via the PGC-1α/FNDC5 pathway [ 49 ]. They demonstrated that endurance exercise induced the expression of the Fndc5 gene in the hippocampus, accompanied with the expression of peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α), which co-regulated the expression of neuronal fibronectin type III domain-containing protein 5 (FNDC5) with estrogen-related receptor α. In addition, overexpression of FNDC5 in the periphery increased the expression of BDNF in the hippocampus, indicating that the exercise-induced up-regulation of BDNF in the hippocampus was mediated via both the neuronal PGC-1α/FNDC5 pathway and the muscle-derived irisin (the secreted form of FNDC5) in serum. On the other hand, evidence also suggested that exercise induced an accumulation of metabolite-like ketone bodies in the hippocampus, which promoted the expression of BDNF by altering the Bdnf promoter [ 50 ]. Moreover, accumulating bodies of evidence showed that the effect of exercise on brain BDNF expression was regulated by multiple genetic factors including the Val66Met mutation [ 51 ], APOEε4 allele carriers [ 7 ] and methyl CpG binding protein 2 [ 45 ].

VEGF is a hypoxia-induced protein, which is expressed in different kinds of cells, such as smooth or skeletal muscle cells, endothelial cells, macrophages and glial cells [ 42 ]. VEGF plays a critical role in vasculogenesis and angiogenesis by promoting the formation of blood vessels and increased blood flow in both the peripheral nervous system and CNS [ 42 , 44 ]. Several reports showed that increased levels of brain-derived VEGF from exercise reduced ischemic injury and attenuated ischemia-induced cognitive deficits by promoting the proliferation of progenitor cells and neuronal differentiation in the ischemic penumbra [ 52 , 53 ].

Naturally, exercise can induce accumulation of lactate, thereby activating hydroxycarboxylic acid receptor 1 (HCAR1) and improving the activity of downstream pathways like ERK1/2 and Akt signaling, which are linked to the expression of VEGF as well as angiogenesis in the hippocampus [ 54 ]. A recent study indicated that exercise increased the levels of VEGF and angiogenesis in the brain through the lactate receptor HCAR1 [ 54 ]. In the ischemic brain, exercise-induced neurogenesis and angiogenesis rely on enhanced VEGF expression, resulting in the reduction of infarct volume and alleviation of cognitive decline. On the other hand, in a conditional skeletal myofiber-specific VEGF gene ablation mouse model, it was shown that muscle-derived VEGF induced by exercise increased the levels of VEGF in the hippocampus [ 55 ]. More interestingly, skeletal muscle-derived VEGF has been reported to enhance neurogenesis in the hippocampus [ 42 ]. One hypothesis for this phenomenon is that exercise-induced VEGF in the periphery can cross the blood-brain barrier (BBB) and mediate neurogenesis and angiogenesis in CNS, similar to the mechanisms of IGF-1. The BBB is formed by a monolayer of endothelial cells, supplemented with capillary pericytes and astrocyte perivascular end-feet. Tight junctions are also present to limit the paracellular flow of substances across the BBB [ 56 ]. The mechanism of how VEGF crosses the BBB remains an issue to be investigated, though it is expected that exercise could alter the physical status of endothelial cells, leading to increased BBB permeability [ 57 , 58 ].

IGFs are proteins that have highly similar sequences to insulin. Serum IGF-1 has emerged as a key growth factor to modulate synaptic plasticity, neurotransmission, and neurogenesis in the adult hippocampus [ 59 ]. It was demonstrated that a lack of serum IGF-1 caused cognitive impairment and depressive behavior [ 59 ], while diminished Igf-1 gene expression with aging was associated with cognitive decline [ 60 ]. It has been reported that muscle-derived IGF-1 enhanced muscle mitochondria functions and the levels of IGF-1 in the hippocampus [ 57 ]. The high BBB permeability of IGF-1 allows serum IGF-1, instead of other neurotrophic factors, to access the brain and increase uptake of IGF-1 in the brain; this underlying mechanism may be linked to the regulation of IGF binding proteins (IGF-BPs) and expression of IGF-1 receptors on the BBB [ 59 ]. Moreover, in some pathological statuses, exercise is able to attenuate neurodegeneration or neuropathological behaviors by altering cytokine production, which indirectly restores normal IGF-1 levels [ 61 ].

Neurotransmitters: serotonin and kynurenine metabolism

Cerebral serotonin (5-hydroxytryptamine, 5-HT) homeostasis has been implicated in mood and cognition, thereby fundamentally impacting the pathophysiology of brain disorders such as depression and cognitive dysfunctions. In accordance with the theory of 5-HT dysregulation in depression and anxiety, selective serotonin reuptake inhibitors (SSRIs) that primarily target the CNS 5-HT system are now the first-line treatment for MDD and anxiety disorders [ 62 ]. Furthermore, the pharmacological effects of SSRIs are indispensable for hippocampal neurogenesis.

Evidence from experiments in rats has demonstrated that exercise increased the levels of 5-HT in different brain regions, including the cerebellum, striatum, hippocampus, and frontal cortex [ 63 ]. It has been recently reported that central 5-HT is an essential positive modulator of neurogenesis that specifically functions in response to running stimuli. In addition, Kondo and colleagues demonstrated that the 5-HT3 receptor was essential for 5-HT action in hippocampal neurogenesis and antidepressant-like behavior induced by exercise, but is not responsible for enhancing learning and memory [ 64 ]. Hence, more work is required to demonstrate the precise mechanisms of action of 5-HT in cognitive function induced by exercise.

In human studies, physical exercise increases 5-HT concentrations in urine, whole blood (with mainly platelets storing 5-HT), as well as in serum (free 5-HT) [ 65 ]. Although it was believed that 5-HT could not cross the BBB, a recent study revealed the presence of the 5-HT transporter in vascular endothelial cells in the BBB [ 66 ]. In addition, evidence has indicated that central 5-HT levels were positively correlated with 5-HT levels in the periphery [ 67 ]. These findings suggest that peripheral 5-HT levels could be a rough indicator for central 5-HT concentrations. On the other hand, changes in 5-HT precursors, such as tryptophan, are also used as peripheral proxies of cerebral 5-HT metabolism. Unlike 5-HT, tryptophan can be transferred from the brain to the periphery across the BBB. Melancon and colleagues showed that physical exercise increases the availability of tryptophan to the brain during exercise in the elderly [ 68 ].

Other than acting as a peripheral predictor of cerebral 5-HT levels, tryptophan has drawn a lot of attention in recent studies on depression because of its major degradative products, kynurenines. 5-HT dysregulation is believed to play a major role in depression, and it has been long proposed that 5-HT deficiency was mainly due to the shift of tryptophan metabolism from 5-HT synthesis to kynurenines [ 69 ]. Furthermore, kynurenic acid (KYNA) is a main product of kynurenine metabolism, which has a higher affinity to α-7-nicotinic acetylcholine (α7nACh) receptors and N-methyl-D-aspartate (NMDA) receptors, acting as an antagonist on NMDA and α7nACh receptors. Since α7nACh receptors and NMDA receptors are essential for normal synaptic function and memory formation, the accumulation of KYNA might contribute to the cognitive impairment observed in depression and dementia [ 70 ]. Kynurenine is actively transported across the BBB, while its metabolites, such as KYNA and quinolinic acid, cannot enter the brain freely from circulation. Based on these important principles, Agudelo and colleagues found that exercise enhanced the peripheral breakdown of kynurenine to KYNA in skeletal muscle, thus reducing plasma kynurenine to protect the brain from stress-induced depression [ 71 ]. In this groundbreaking study, the authors proposed for the first time that exercise is beneficial to depression by targeting kynurenine breakdown in skeletal muscle to facilitate central kynurenine clearance, without needing to cross the BBB. More interestingly, as mentioned above, circulating kynurenine can be transported into the brain by the large amino transporter 1 (LAT1) in the BBB. A new study showed that peripheral administration of leucine, which has a high affinity for LAT1, prevented the entry of kynurenine into the brain and attenuated inflammation-induced depression-like behavior in mice [ 72 ].

The role of myokines in muscle-brain crosstalk

In recent years, skeletal muscle has been proposed to be a secretory organ. Accordingly, myokines are defined as cytokines and peptides that are secreted from skeletal muscle fibers and exert either autocrine, paracrine, or endocrine effects [ 73 ]. The secretion and release of myokines are mainly mediated by the muscle contraction-induced factors, also referred to as “the exercise factor”. Skeletal muscle accounts for about 40% of total body mass in humans, therefore, exercise can be a powerful way to impact systemic metabolism and functions in other organs by mediating the secretion of myokines [ 74 ]. Studies showed that exercise promoted the production of several hundred myokines in muscle; some of which, like PGC-1α, Irisin and Cathepsin B, have been shown to be important parts of the muscle-brain crosstalk. Furthermore, we also present some evidence suggesting fibroblast growth factor 21 (FGF-21) and SPARC as novel brain-beneficial myokines.

PGC-1α is dramatically up-regulated during physical exercise and is considered to be a major mediator of the beneficial effects of exercise to the brain [ 49 ]. Although initially reported as a transcriptional co-activator of oxidative metabolism and differentiation-induced mitochondrial biogenesis in brown fat [ 75 ], subsequent studies demonstrated the high expression levels of PGC-1α in cells including cardiac myocytes, neurons, and skeletal muscle cells, which have a relatively higher demand of energy [ 76 ]. One animal study has shown that activating the expression of PGC-1α by astrocytic nerve growth factor successfully restored the behavior deficits, sensorimotor disorders, and neuronal loss in a Huntington’s disease (HD) model [ 77 ], probably because it negatively regulated the activity of extrasynaptic NMDA receptors, thereby reducing excitotoxicity in the cortical neurons [ 78 ]. PGC-1α has also shown neuroprotective effects in a MPTP animal model of PD [ 27 ], depression and other neuropsychiatric disorders [ 71 , 74 ]. In addition, researchers found that PGC-1α played an important part in the formation and maintenance of neuronal dendritic spines and synapses in the hippocampus [ 79 ].

FNDC5 was identified as a PGC-1α-dependent myokine a few years ago [ 80 ]. During physical exercise, FNDC5 is cleaved and secreted from muscle into the circulation as irisin [ 81 ]. Irisin can act on subcutaneous fat, activating the thermogenic program and giving the white adipose tissue “brown fat”-like functions [ 80 ]. Recent studies have shown that the target of irisin is not limited to adipocytes since FNDC5 was also found throughout the brain to mediate cell differentiation [ 82 ]. Furthermore, studies have shown that the irisin in the brain was beneficial to neurons beyond neonatal development. Centrally administered irisin successfully reduced neuronal apoptosis and increased the expression of BDNF in a mouse model of stroke [ 83 ], and also produced antidepressive effects and modulated neuroplasticity-related genes in a mouse model of depression [ 84 ]. Interestingly, Wrann and colleagues found that peripheral delivery of FNDC5 by adenoviral vectors increased Bdnf expression in the hippocampus [ 49 ]. This study raised suspicions that irisin in the blood can actually go through the BBB or bind to receptors on endothelial cells [ 74 ], showing that peripheral irisin and centrally expressed irisin can have synergistic effects on the brain.

Cathepsin B (CTSB) is a lysosomal cysteine protease found all over the body [ 85 ]. It is currently under investigation for its potential use as a tumor marker as increased expression of this compound is observed in premalignant and malignant cells [ 86 ]. However, one recent study unearthed its alternative function as a myokine communicating with the nervous system. Increased CTSB levels were found in the plasma of rhesus monkeys and humans under exercise; as well as the gastrocnemius muscle and plasma in mice after running [ 87 ]. In the same study, CTSB was found to be able to cross the BBB and promote the induction of BDNF and doublecortin (DCX), which were responsible for neuronal survival and brain development [ 88 ], respectively. The P11 protein was suggested to be involved in CTSB-mediated DCX expression, while the pathway involved in CTSB-mediated BDNF expression remains unknown [ 87 ]. Although exercise was shown to increase CTSB transcripts in the brain directly, it is suggested that this direct stimulation is supplemented by peripheral CTSB myokine signaling [ 89 ].

FGF21 is a peptide hormone mainly produced by the liver, but is also expressed in skeletal muscles and adipose tissue. It is known to have beneficial metabolic effects like weight loss and improved glycaemia, which rely upon its role on the regulation of fatty acid oxidation and glucose metabolism [ 90 ]. Therefore, FGF21 is regarded as hepatokine and adipokine, acting as messengers of the liver and adipose tissue under dietary stimulation or metabolic stress [ 90 ]. It was demonstrated that the concentrations of FGF21 were increased in both skeletal muscles and serum after acute exercise [ 91 ]. FGF21 can cross the BBB. Although FGF21 was previously thought to be expressed only peripherally, it was also found in the CSF of both mice and humans [ 92 , 93 ]. FGF21 in the brain was shown to interact with the brain through its co-receptors, β-Klotho, and FGFR-1, thereby producing effects such as modulating sympathetic nerve output to brown fat, controlling circadian behavior and neuroprotection [ 90 , 94 ]. Furthermore, Kuroda and colleagues found that peripherally derived FGF21 leaked into the brain after injury and promoted remyelination in a mouse model of demyelination [ 95 ]. Hence, although very few studies have demonstrated the direct link between exercise-induced upregulation of FGF21 and the beneficial effects of exercise in the brain, FGF21 has great potential to be a novel myokine that helps to promote brain health.

Osteonectin, also known as SPARC, is a bone glycoprotein that mediates bone mineralization and mineral crystal formation. Its relationship with muscles remained hidden until a recent study revealed its alternative function as a myokine [ 96 ]. Increased secretion of SPARC was found in the gastrocnemius muscle after 60 min of exercise in a mouse model, while in vitro cell studies found out that increased SPARC translation was responsible for the increased secretion. These results were consistent with study in humans, as exercise was shown to increase SPARC in the circulation [ 96 ]. SPARC is also expressed in the brain and has many different functions. SPARC knock-out mice had increased levels of anxiety and depression, but the expression of SPARC in adult mouse hippocampus was found to reduce depressive behaviors in SPARC knock-out mice [ 97 ]. SPARC acts synergistically with BDNF to promote the outgrowth of retinal ganglion cells via Akt phosphorylation and BDNF-induced Erk1/2 phosphorylation [ 98 ]. Mature, ramified microglia also expressed SPARC, and knock-out of the gene resulted in altered microglial morphology, with increased branching and elongated microglial processes when compared to the control [ 99 ]. Although muscle-derived SPARC has not been shown to cross the BBB yet, the multitude of its effects on the brain, as well as its dependency on exercise for secretion, make SPARC a potential candidate for a myokine that could benefit the brain.

Anti-Inflammatory effects of exercise

Clinical studies demonstrated that persistent systemic inflammation is a common feature in many neurological disorders, including depression, AD, PD, and HD [ 100 ]. Chronic systemic inflammation predisposes individuals to insulin resistance, endothelial cell dysfunction, and atherosclerosis and exacerbates neuroinflammation, thereby contributing to neuropathological changes in the brain [ 101 ]. Exercise is advocated as a powerful anti-inflammatory therapy for depression and neurodegeneration diseases. Rethorst and colleagues found that a high level of TNF-α was linked to poor response to antidepressive effects of exercise in MDD [ 102 ]. Specifically, evidence suggested that exercise could protect the brain from inflammation, either by directly mediating inflammatory cytokines [ 8 ], or reducing pro-inflammatory adipokines through the muscle-adipose crosstalk [ 103 ], thereby rescuing the secretion of growth factors and promoting neural plasticity and neurogenesis. Furthermore, exercise has also been suggested to mediate the innate inflammatory response through the sympathetic nerves or the hypothalamic-pituitary-adrenal axis as a physiological stressor [ 104 ].

The direct effect of exercise on inflammation can be varied depending on the different pathophysiological conditions of individuals, since both pro-inflammatory cytokines and anti-inflammatory cytokines were increased immediately in the circulation after exercise [ 57 ]. Although there was previously a concern that exercise might aggravate symptoms of diseases like TBI, stroke, and multiple sclerosis by exaggerating inflammation [ 105 ], exercise has now been suggested as a protective intervention to improve symptoms and reduce overall inflammatory conditions of those diseases if performed during the appropriate time. Animal studies demonstrated that exercise could directly improve the immune condition of the brain by increasing the levels of IL-10 in the hippocampus of aged rats [ 106 ], and by reducing the levels of IL-1β in the brain of a β-amyloid-induced mouse model of AD [ 107 ]. Furthermore, physical exercise has also been shown to prevent brain inflammation in stroke [ 108 ]. Some data indicated that physical exercise could reduce the production of pro-inflammatory cytokines in the brain by promoting the clearance of Aβ [ 24 , 25 ], which has pro-inflammatory effects itself. In line with these studies, we demonstrated that 5-weeks of resistance training reduced the activation of microglia, which were important sources of pro-inflammatory cytokines, in the DG of both wild type and 3xTg male mice (Fig.  1 ). In addition, another study showed that exercise might protect against inflammation-induced neurological deficits in a TBI model by activating the HSP70/NF-κB/IL-6/synapsin I axis [ 109 ].

Five-weeks of RE reduced microglia activation in DG region of 10-month wild type and 3xTg mice. Representative stacked confocal images of IBA-1 Immunoreactivity in ( a – d ) low magnification, ×20 and ( e – h ) high magnification, ×40. (Scale bar: 20 mm)

One prominent effect of exercise on the body is reducing the number and improving the functions of adipocytes, which are important sources of peripheral inflammatory cytokines [ 110 , 111 ]. Recent data also demonstrated a direct anti-inflammatory effect of irisin by suppressing the production of several major pro-inflammatory cytokines including TNF-α, MCP-1, and IL-6 by adipocytes. In addition, the presence of irisin inhibited the activity of a well-known inflammatory transcription factor, nuclear factor kappa B [ 103 ]. More importantly, an adipocyte-secreted hormone, adiponectin, which is an insulin-sensitizing and anti-inflammatory factor, has been shown to be essential to the physical exercise-induced antidepressant effects and hippocampal neurogenesis in an adiponectin-deficient mouse model [ 111 ].

Mitochondrial-mediated mechanisms

Mitochondria are double-membrane bound organelles most widely known for their role in aerobic respiration [ 112 ]. However, with an increasing number of studies that are focused on this intracellular powerhouse, it has been revealed that ATP production is only one of the many functions. Notably, mitochondria have been found to play a role in exercise-induced neuronal benefits, which might occur through the mediation of mitochondrial biogenesis and mitophagy [ 113 ]. Mitophagy is the autophagic elimination of damaged mitochondria. It can aid the restoration of a healthy mitochondrial population by removing the stressed or damaged parts of the mitochondria [ 114 ]. Mitochondrial fusion and biogenesis could rescue mildly dysfunctional mitochondria, while mitochondrial fission and mitophagy could clear damaged mitochondria so that they would not interfere with healthy mitochondria. This interplay between mitochondrial biogenesis and mitophagy could maintain the health of mitochondria, contributing to the overall neuronal health together.

The SIRT1-PGC1-α axis is an important compensatory mechanism counteracting excessive mitochondrial fission and degradation that predominates neurodegenerative pathologies [ 115 ]. Several studies found that the SIRT1-PGC1-α axis was associated with exercise-induced mitochondria-mediated neuroprotection by increased mitochondrial biogenesis [ 116 , 117 ]. Silent information regulator T1 (SIRT1) is an enzyme that deacetylates peroxisome PGC-1α, which increases its transcriptional activity. Increased levels of SIRT1 and PGC1-α were found after moderate long-term exercise in rats [ 116 ] and mice [ 117 ], suggesting that exercise can upregulate the SIRT1-PGC1-α axis. Furthermore, these studies demonstrated various mitochondria-related beneficial effects of exercise in the brain, including increased mtDNA content [ 116 ], decreased p53 acetylation, increased activation of 5’AMP-activated protein kinase (AMPK), as well as a concomitant increase in the content of mitochondrial respiratory complexes [ 117 ]. The above evidence suggests that exercise-induced activation of SIRT1-PGC1-α can increase mitochondrial biogenesis and promote neuronal health.

Exercise can also provide protective effects for the brain by promoting mitophagy through mediating the AMPK-Ulk1 pathway. It was found that LC3-II (a marker for autophagy) was co-localized with mitochondria and the autophagic flux was increased following exhaustive treadmill running in mice [ 118 ]. Moreover, a recently published study demonstrated that AMPK phosphorylation of Ulk1 was essential for exercise-induced mitophagy [ 114 ].

Exosomes: a bridge between muscle and brain

Exosomes are “saucer-shaped” vesicles [ 119 ] first discovered within maturing mammalian reticulocytes in 1987, which have a phospholipid bilayer and measure between 30 and 100 nm [ 72 ]. They are formed intracellularly by the inward budding of endosomes, with the endosome surrounding them termed multivesicular bodies (MVB). MVB can then fuse with the plasma membrane to release the exosomes to extracellular space. Exosomes can be found in various body fluids, including plasma, saliva, urine, amniotic fluid, synovial fluid, pleural effusions, and malignant ascites [ 119 ]. It was demonstrated that exosomes can be secreted into the blood after exercise as signal transducers, communicating with target cells via surface interaction or membrane fusion, which in turn mediated the release of the exosomal contents into the target cells and activated downstream signaling [ 120 ].

Exosomes were suggested to be key players in enabling muscle-tissue crosstalk during exercise in a recently conducted study. Increased plasma levels of myokines, as well as proteins highly enriched in small extracellular vesicles, were observed in humans after an hour of cycle exercise [ 121 ]. Exosomes packed with hundreds of peptides were also found to be released from skeletal muscles in mice [ 122 ]. In a pilot study, an exosome marker, ALG-2-interacting protein X was found to be severely depleted right after acute endurance exercise, suggesting the presence of exosomes in muscles and their exercise-dependent release. Moreover, up to 75% of reported myokines were found to exist in exosomes [ 123 ], highlighting the possibility of exosomes mediating exercise-induced myokines release.

It is well known that the BBB is the most important insuperable barrier for many signal molecules from the periphery to interact with the brain. Molecules flowing freely within the plasma cannot pass through the BBB easily, but exosomes are capable of migrating across the BBB via the transcellular route [ 124 ]. Multiple pharmacological studies aimed at treating brain diseases like primary brain cancer [ 125 ] and PD [ 126 ] had employed the use of exosomes as a means to deliver drugs to the brain, while others merely demonstrated that exosomes could cross the BBB [ 124 ] or deliver genetic cargo like siRNA across the BBB [ 127 ]. Despite the diverse aims and designs of these studies, they have consistently demonstrated the successful migration of exosomes across the BBB.

As the above evidence suggests, exosomes carrying myokines are released during exercise. Moreover, exosomes also have a favorable interaction with the BBB. Taken together, these results lead us to believe that exosomes might have an important role in the muscle-brain crosstalk.

Brain changes during exercise-induced hippocampal neuronal activation

Regarding the previously discussed circulating myokine hypothesis, exercise exerted its effects by blood-borne muscle-derived factors. Recently, it was proposed that the direct neuronal stimulation to the brain during exercise might also be involved with the beneficial effects of exercise in the brain [ 128 ]. Neuronal activity could induce widespread changes in the structure and function of the brain, including the modulation of membrane receptors, neurotrophic factors, dendritic spines, and even blood vessel structure [ 129 ]. Many studies have shown that hippocampal neurogenesis was affected following electrical activity and neuronal activation [ 130 , 131 ]. Specifically, these studies not only showed that neurogenesis occurred in the presence of stimuli like Ca 2+ channel and NMDA activation, but also demonstrated that these stimuli alone are sufficient to promote differentiation and proliferation of neurons. Activation of the neurons in the hippocampus during exercise has been reported in different rodent models [ 129 , 132 ], and the specific form of neuronal activation has been demonstrated as an acute expression in immediate early genes (IEG) [ 132 , 133 ] changes in regional blood flow, increased firing rates of neurons in the hippocampus and simultaneous modulation of hippocampal theta oscillations (4–12 Hz) [ 134 ] and gamma oscillations (30–120 Hz) [ 133 ].

The direct relationship between the average running speed and the degree of neuronal activity has been demonstrated by the changes of the IEG, which reflect the extent of chronic activation since high levels of IEG correlate with increased gene expression and cell remodeling [ 135 ]. Induction of IEG was originally thought to occur when the animal explored a novel environment [ 136 ], but animal models of exercise have shown that chronic exercise induced a proportional increase in IEG-activated neurons [ 137 ]. Consistently, electrophysiological studies also showed a close relationship between the firing rates of hippocampal neurons and the instantaneous moving speed of rodents in animal models including voluntary wheel running [ 138 ], treadmills [ 139 ] and mazes [ 140 ]. Interestingly, another experiment, which compared active and passive movement, found that spatial movement without actual physical activity was not enough to excite hippocampal neurons [ 141 ]. This finding suggests that neuronal activation during exercise is mainly attributed to the amount of physical activity, instead of the novelty of experience or spatial navigation.

Exercise was also found to elicit synchronized hippocampal neuronal activations called theta waves, during both initiation of exercise and ongoing movement [ 134 ]. Theta rhythms are electrical waves ranging from 4 to 8 Hz, generated from hippocampal regions like CA1-3 and DG [ 128 ]. It is suggested that the inputs from the medial septum and nucleus of the diagonal band of Broca (MS-DBB) to the hippocampus are responsible for synchronizing hippocampal neuronal activity during theta oscillation [ 142 ], with modulations of the MS-DBB pathway coming from the posterior hypothalamic nucleus [ 143 ] and the vesicular glutamate transporter 2-positive neurons [ 139 ]. The activities of the MS-DBB axis, as well as the medial entorhinal cortex, are both shown to predict theta waves and the speed of locomotion [ 143 ].

The common and distinct pathophysiological changes induced by different types of exercise

As mentioned previously, great deals of studies have revealed the effects of physical exercise on cognition and related pathophysiological mechanisms. In general, there exists four types of exercise, which are AE (e.g., running, walking, and yard work), resistance exercises (RE, e.g., weightlifting and some types of gym training that use a resistance band or an individual’s own body weight), balance exercises (e.g., Tai Chi) and flexibility exercises (e.g., Yoga). Although most studies focus on AE, nearly all types of exercise have been demonstrated to reduce depression, enhance cognitive function, and promote the recovery from ABI [ 5 , 144 ]. Furthermore, the combination of different types of exercises led to greater benefits in brain functions [ 145 , 146 ].

It is suggested that different types of exercise induce similar physiological and structural changes in the brain. First of all, the levels of BDNF [ 147 , 148 ] and serotonin [ 149 , 150 ] in serum are increased in different types of exercise. Secondly, different types of exercise showed similar anti-inflammatory effects by promoting the induction of anti-inflammatory factors and inhibiting the expression of pro-inflammatory factors, thereby contributing to a healthy immunologic environment [ 150 , 151 ]. However, some types of exercise showed greater benefits than other types of exercise to the brain by modulating specific brain functions and pathophysiologic markers, despite the similar cognitive and neuroplastic outcomes with other types of exercise. A systematic review suggested that although both AE and RE improved visuospatial function in older humans, AE induced greater benefits in cognitive function and executive function than RE [ 146 ]. In addition, it was also demonstrated in a population-based analysis that AE showed a stronger anti-inflammatory effect compared to RE, despite the fact that they both reduced the levels of inflammatory markers [ 152 ].

Accumulating bodies of evidence from neuroimaging studies revealed that different types of exercise have divergent effects on the structure of the brain. It was reported that AE increased the volume of the right hippocampus and prevented the atrophy of the medial temporal lobe and anterior cingulate cortex [ 153 ]. Despite little research on other types of exercise, a six-month clinical trial showed that RE increased the volume of the hippocampus [ 154 ], while Tai Chi increased the grey matter volume [ 155 ] and yoga reduced the volume of the amygdala [ 156 ]. Taken together, these results suggest that different types of exercise might induce structural changes in diverse brain regions. However, the current findings are from limited studies that varied in frequency and duration of exercise, and most importantly, the condition of the participants. Therefore, more studies with larger sample sizes and involving similar populations should be conducted in the future to illustrate the diverse effects of different types of exercise on the structure of different brain regions.

Cassilhas and colleagues demonstrated that, in a rat model, both AE and RE improved hippocampus-dependent learning and memory function. They found that AE preferentially promoted the induction of BDNF, while RE preferentially increased the levels of IGF-1 in the hippocampus [ 157 ]. In addition, AE, rather than RE, induced neurogenesis in the DG of adult male rats [ 158 ]. In line with these results, it was found that AE and RE specifically induced different isoforms of PGC-1α, which has been mentioned above for its role as an important myokine. Specifically, PGC-1α can be differentially spliced and translated into different isoforms, including PGC-1α1 (the previously described PGC-1α), -α2, -α3 and -α4, performing functions like promoting mitochondrial biogenesis, fatty acid oxidation and angiogenesis [ 159 ]. The levels of PGC-1α4 are most dramatically increased during RE both in mouse and human muscle [ 160 ]. Interestingly, it was found that SIRT3 and PGC-1α (1) levels were increased following AE, but not RE [ 161 ], indicating that AE and RE promote the induction of PGC-1α1 and PGC-1α4, respectively. Furthermore, since AE was shown to increase BDNF expression in the hippocampus via the PGC-1α (1)/FNDC5 pathway [ 49 ], while PGC-1α4 is known to regulate genes in the IGF-1 pathways [ 159 ], these findings, which are consistent with the findings of Cassilhas and colleagues, suggest that AE and RE might benefit the brain via distinct pathways.

In conclusion, exercise will be one of the promising therapeutic strategies in preventing mental disorders, neurodegeneration, and ABI. Several molecular targets have been identified, which are critically involved in the different brain regions that could be beneficial for patients with mental disorders and neurodegenerative diseases. Exercise modulates neurotransmitter release, enhances neurogenesis, exerts anti-neuroinflammatory actions, triggers neurotrophic factor release, as well as modulates intracellular signaling to inhibit neuronal dysfunction and promote synaptic plasticity. In line with these exciting results, exercise training is shown to ameliorate different neuropathology in neurodegenerative patients. By discovering more molecular pathways which are specifically activated by exercise, potential biomarkers which reflect the advantage of exercise may be developed, and it may assist clinicians to tailor make exercise regimes for individual patients, including the type and intensity of exercise.

Nevertheless, there are still many obstacles and challenges along the research path regarding exercise in neuroprotection. As indicated in previous reports, exercise is a complicated behavior that involves the interactions between the brain and periphery. Multiple, rather than single pathways, are expected to be involved in the neuroprotective mechanisms. Future research should focus on the interaction between the periphery and brain, and how this interaction may influence subsequent neuronal dysfunction and neuropathology in the brain.

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Liu, Y., Yan, T., Chu, J.MT. et al. The beneficial effects of physical exercise in the brain and related pathophysiological mechanisms in neurodegenerative diseases. Lab Invest 99 , 943–957 (2019). https://doi.org/10.1038/s41374-019-0232-y

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Physical Fitness Linked to Better Mental Health in Young People

A new study bolsters existing research suggesting that exercise can protect against anxiety, depression and attention challenges.

By Matt Richtel

Physical fitness among children and adolescents may protect against developing depressive symptoms, anxiety and attention deficit hyperactivity disorder, according to a study published on Monday in JAMA Pediatrics.

The study also found that better performance in cardiovascular activities, strength and muscular endurance were each associated with greater protection against such mental health conditions. The researchers deemed this linkage “dose-dependent,” suggesting that a child or adolescent who is more fit may be accordingly less likely to experience the onset of a mental health disorder.

These findings come amid a surge of mental health diagnoses among children and adolescents, in the United States and abroad, that have prompted efforts to understand and curb the problem.

The new study, conducted by researchers in Taiwan, compared data from two large data sets: the Taiwan National Student Fitness Tests, which measures student fitness performance in schools, and the National Insurance Research Databases, which records medical claims, diagnoses prescriptions and other medical information. The researchers did not have access to the students’ names but were able to use the anonymized data to compare the students’ physical fitness and mental health results.

The risk of mental health disorder was weighted against three metrics for physical fitness: cardio fitness, as measured by a student’s time in an 800-meter run; muscle endurance, indicated by the number of situps performed; and muscle power, measured by the standing broad jump.

Improved performance in each activity was linked with a lower risk of mental health disorder. For instance, a 30-second decrease in 800-meter time was associated, in girls, with a lower risk of anxiety, depression and A.D.H.D. In boys, it was associated with lower anxiety and risk of the disorder.

An increase of five situps per minute was associated with lower anxiety and risk of the disorder in boys, and with decreased risk of depression and anxiety in girls.

“These findings suggest the potential of cardiorespiratory and muscular fitness as protective factors in mitigating the onset of mental health disorders among children and adolescents,” the researchers wrote in the journal article.

Physical and mental health were already assumed to be linked , they added, but previous research had relied largely on questionnaires and self-reports, whereas the new study drew from independent assessments and objective standards.

The Big Picture

The surgeon general, Dr. Vivek H. Murthy, has called mental health “the defining public health crisis of our time,” and he has made adolescent mental health central to his mission. In 2021 he issued a rare public advisory on the topic. Statistics at the time revealed alarming trends: From 2001 to 2019, the suicide rate for Americans ages 10 to 19 rose 40 percent, and emergency visits related to self-harm rose 88 percent.

Some policymakers and researchers have blamed the sharp increase on the heavy use of social media, but research has been limited and the findings sometimes contradictory. Other experts theorize that heavy screen use has affected adolescent mental health by displacing sleep, exercise and in-person activity, all of which are considered vital to healthy development. The new study appeared to support the link between physical fitness and mental health.

“The finding underscores the need for further research into targeted physical fitness programs,” its authors concluded. Such programs, they added, “hold significant potential as primary preventative interventions against mental disorders in children and adolescents.”

Matt Richtel is a health and science reporter for The Times, based in Boulder, Colo. More about Matt Richtel

Understanding A.D.H.D.

The challenges faced by those with attention deficit hyperactivity disorder can be daunting. but people who are diagnosed with it can still thrive..

Millions of children in the United States have received a diagnosis of A.D.H.D . Here is how their families can support them .

The condition is also being recognized more in adults . These are some of the behaviors  that might be associated with adult A.D.H.D.

Since a nationwide Adderall shortage started, some people with A.D.H.D. have said their medication no longer helps with their symptoms. But there could be other factors at play .

Everyone has bouts of distraction and forgetfulness. Here is when psychiatrists diagnose it as something clinical .

The disorder can put a strain on relationships. But there are ways to cope .

Though meditation can be beneficial to those with A.D.H.D., sitting still and focusing on breathing can be hard for them. These tips can help .

Physical Activity Is Good for the Mind and the Body

Health and Well-Being Matter is the monthly blog of the Director of the Office of Disease Prevention and Health Promotion.

Everyone has their own way to “recharge” their sense of well-being — something that makes them feel good physically, emotionally, and spiritually even if they aren’t consciously aware of it. Personally, I know that few things can improve my day as quickly as a walk around the block or even just getting up from my desk and doing some push-ups. A hike through the woods is ideal when I can make it happen. But that’s me. It’s not simply that I enjoy these activities but also that they literally make me feel better and clear my mind.

Mental health and physical health are closely connected. No kidding — what’s good for the body is often good for the mind. Knowing what you can do physically that has this effect for you will change your day and your life.

Physical activity has many well-established mental health benefits. These are published in the Physical Activity Guidelines for Americans and include improved brain health and cognitive function (the ability to think, if you will), a reduced risk of anxiety and depression, and improved sleep and overall quality of life. Although not a cure-all, increasing physical activity directly contributes to improved mental health and better overall health and well-being.

Learning how to routinely manage stress and getting screened for depression are simply good prevention practices. Awareness is especially critical at this time of year when disruptions to healthy habits and choices can be more likely and more jarring. Shorter days and colder temperatures have a way of interrupting routines — as do the holidays, with both their joys and their stresses. When the plentiful sunshine and clear skies of temperate months give way to unpredictable weather, less daylight, and festive gatherings, it may happen unconsciously or seem natural to be distracted from being as physically active. However, that tendency is precisely why it’s so important that we are ever more mindful of our physical and emotional health — and how we can maintain both — during this time of year.

Roughly half of all people in the United States will be diagnosed with a mental health disorder at some point in their lifetime, with anxiety and anxiety disorders being the most common. Major depression, another of the most common mental health disorders, is also a leading cause of disability for middle-aged adults. Compounding all of this, mental health disorders like depression and anxiety can affect people’s ability to take part in health-promoting behaviors, including physical activity. In addition, physical health problems can contribute to mental health problems and make it harder for people to get treatment for mental health disorders.

The COVID-19 pandemic has brought the need to take care of our physical and emotional health to light even more so these past 2 years. Recently, the U.S. Surgeon General highlighted how the pandemic has exacerbated the mental health crisis in youth .

The good news is that even small amounts of physical activity can immediately reduce symptoms of anxiety in adults and older adults. Depression has also shown to be responsive to physical activity. Research suggests that increased physical activity, of any kind, can improve depression symptoms experienced by people across the lifespan. Engaging in regular physical activity has also been shown to reduce the risk of developing depression in children and adults.

Though the seasons and our life circumstances may change, our basic needs do not. Just as we shift from shorts to coats or fresh summer fruits and vegetables to heartier fall food choices, so too must we shift our seasonal approach to how we stay physically active. Some of that is simply adapting to conditions: bundling up for a walk, wearing the appropriate shoes, or playing in the snow with the kids instead of playing soccer in the grass.

Sometimes there’s a bit more creativity involved. Often this means finding ways to simplify activity or make it more accessible. For example, it may not be possible to get to the gym or even take a walk due to weather or any number of reasons. In those instances, other options include adding new types of movement — such as impromptu dance parties at home — or doing a few household chores (yes, it all counts as physical activity).

During the COVID-19 pandemic, I built a makeshift gym in my garage as an alternative to driving back and forth to the gym several miles from home. That has not only saved me time and money but also afforded me the opportunity to get 15 to 45 minutes of muscle-strengthening physical activity in at odd times of the day.

For more ideas on how to get active — on any day — or for help finding the motivation to get started, check out this Move Your Way® video .

The point to remember is that no matter the approach, the Physical Activity Guidelines recommend that adults get at least 150 minutes of moderate-intensity aerobic activity (anything that gets your heart beating faster) each week and at least 2 days per week of muscle-strengthening activity (anything that makes your muscles work harder than usual). Youth need 60 minutes or more of physical activity each day. Preschool-aged children ages 3 to 5 years need to be active throughout the day — with adult caregivers encouraging active play — to enhance growth and development. Striving toward these goals and then continuing to get physical activity, in some shape or form, contributes to better health outcomes both immediately and over the long term.

For youth, sports offer additional avenues to more physical activity and improved mental health. Youth who participate in sports may enjoy psychosocial health benefits beyond the benefits they gain from other forms of leisure-time physical activity. Psychological health benefits include higher levels of perceived competence, confidence, and self-esteem — not to mention the benefits of team building, leadership, and resilience, which are important skills to apply on the field and throughout life. Research has also shown that youth sports participants have a reduced risk of suicide and suicidal thoughts and tendencies. Additionally, team sports participation during adolescence may lead to better mental health outcomes in adulthood (e.g., less anxiety and depression) for people exposed to adverse childhood experiences. In addition to the physical and mental health benefits, sports can be just plain fun.

Physical activity’s implications for significant positive effects on mental health and social well-being are enormous, impacting every facet of life. In fact, because of this national imperative, the presidential executive order that re-established the President’s Council on Sports, Fitness & Nutrition explicitly seeks to “expand national awareness of the importance of mental health as it pertains to physical fitness and nutrition.” While physical activity is not a substitute for mental health treatment when needed and it’s not the answer to certain mental health challenges, it does play a significant role in our emotional and cognitive well-being.

No matter how we choose to be active during the holiday season — or any season — every effort to move counts toward achieving recommended physical activity goals and will have positive impacts on both the mind and the body. Along with preventing diabetes, high blood pressure, obesity, and the additional risks associated with these comorbidities, physical activity’s positive effect on mental health is yet another important reason to be active and Move Your Way .

As for me… I think it’s time for a walk. Happy and healthy holidays, everyone!

Yours in health, Paul

Paul Reed, MD Rear Admiral, U.S. Public Health Service Deputy Assistant Secretary for Health Director, Office of Disease Prevention and Health Promotion

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Endurance exercise affects all tissues of the body, even those not normally associated with movement

NIH-funded project in rats also finds widespread differences between male and female organisms.

A large research project in young adult rats has found that that all bodily tissues tested respond to exercise training, amounting to over 35,000 biological molecules that respond and adapt to endurance exercise over time, including tissues from organs not usually associated with exercise. Researchers also found differences in responses between male and female rats that were more widespread than anticipated, highlighting the importance of including animals of both sexes in pre-clinical research. The effort, funded by the National Institutes of Health (NIH), used data from thousands of analyses of 19 tissue types and identified molecular changes in genes, proteins, and metabolites, which are substances essential to the metabolism of a particular organism or to a particular metabolic process. The findings are published in a group of papers in Nature.

While molecular changes were seen in all tissues, the way in which each tissue responded was unique. For example, effects on the functions of mitochondria, which are cellular hubs for energy production and metabolism, were observed across the body yet the specific changes observed differed depending on the tissue. For example, researchers found that mitochondria in the adrenal gland responded substantially to endurance training, including a change in regulation of nearly half the mitochondria-associated genes. This was surprising as adrenal glands had not been explored in detail for their role in exercise previously.

Additionally, differences were found in molecular responses to endurance exercise between young male and female rats in most tissues tested, including the brain, adrenal gland, lung, and fat tissue. Scientists uncovered striking differences in responses between the sexes in white fat tissue, findings that may play a role in researching how exercise interventions could be recommended for men or women experiencing conditions such as obesity. The differences between the exercise responses of the sexes in humans or animals have not been well characterized, and these findings emphasize the need for inclusion of both sexes in future exercise research to fully understand its role in health.

By tracking exercise’s impact on biological molecules in humans and rats, scientists are creating a map of molecular changes in the body following exercise. Studies in rats allow for a wider range of tissue types to be analyzed compared to human studies, and the resulting knowledge will allow a variety of hypotheses to be explored and guide the researchers in their analysis of the human data.

Researchers are currently conducting an exercise study in humans that will enhance our understand of why the body responds to exercise and how much the response varies for people of different ages, sexes, body compositions, and fitness levels. In the long-term, these insights could make it possible for clinicians to recommend specific, personalized exercise regimens to their patients to treat or prevent a variety of ailments and health conditions.

NIH’s Molecular Transducers of Physical Activity Consortium (MoTrPAC) , launched in 2016 to uncover how exercise improves and maintains our health at the molecular level, is funded by the  NIH Common Fund  and overseen in collaboration with the  National Institute on Aging  , the  National Institute of Arthritis and Musculoskeletal and Skin Diseases , and the  National Institute of Diabetes and Digestive and Kidney Diseases . For a list of current projects, visit https://commonfund.nih.gov/MolecularTransducers/fundedresearch . For more information on adult and pediatric clinical studies, visit clinicaltrials.gov  under NCT03960827 and NCT04151199 or visit the recruitment webpage to learn more about how you can participate.

The data produced through this research project is publicly available for further analysis and direct download to encourage more hypotheses from the biomedical community.

Concepcion Nierras, Ph.D., Office of the Director, Office of Strategic Coordination

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Article Contents

Cardiovascular and associated metabolic disease.

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Physical activity and health: current issues and research needs

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Adrianne E Hardman, Physical activity and health: current issues and research needs, International Journal of Epidemiology , Volume 30, Issue 5, October 2001, Pages 1193–1197, https://doi.org/10.1093/ije/30.5.1193

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A substantial body of evidence now demonstrates the burden of ill-health attributable to sedentary living. This is most compelling for coronary heart disease (CHD) and, combined with the high prevalence of inactivity, 1 provides the rationale for Professor Morris's claim that exercise is 'today's best buy in public health'. 2 Besides a reduced risk of CHD, evidence is secure for many other health gains from physical activity; these include a reduced risk of stroke, 3, 4 type II diabetes, 5, 6 colon cancer, 7, 8 and hip fracture. 9, 10 There is evidence enough to justify the further development of public health policies to promote physical activity. The difficulty is with the specifics of what to promote and prescribe.

This paper is concerned with future contributions by research to an evidence-based rationale for exercise recommendations—both to the public at large and to individuals. It is clear that physically active people have a lower disease risk than sedentary individuals but the components of activity which determine particular health gains are poorly understood. Thus the 'dose-response' relationships for physical activity are the subject of current research interest. Intuitively, these will not be the same for different health outcomes and this is one reason why further study of the associated mechanisms is important. Understanding the underlying mechanisms will clarify the relative importance of intensity, frequency, duration and mode of exercise for specified health gains. It will also help us to distinguish the effects of exercise per se from those of co-existing behaviours and to identify stages of life during which levels of particular types of activity are critical for given health outcomes. This paper presents a personal view of research needs.

How important is intensity?

The rate of energy expenditure (in oxygen uptake units) of common physical activities is expressed in METS. One MET is equivalent to the resting metabolic rate, assumed to be 3.5 ml oxygen per kg of body mass per minute.

Oxygen uptake reserve is obtained by subtracting one MET (3.5 ml . kg .–1 min –1 ) from the maximal oxygen uptake.

Its importance in the epidemiology of physical activity is evidenced by data from British civil servants. 12 Whereas only frequent vigorous exercise (defined as liable to entail peaks of energy expenditure of ≥7.5 kcal.min –1 [31.5 kJ.min –1 ]) was associated with protection against heart attack in men aged 45–54 at entry, there was a dose-response relationship for a lesser degree of such exercise (either <2 sessions per week or not so intense, e.g. 'fairly brisk' walking for >30 min. per day) among older men aged 55–64 at entry. Thus, for example, older men reporting moderately intense activity such as 'much stair climbing' (not judged sufficiently vigorous to be included in the 'vigorous aerobic' cluster of activities) showed a coronary rate which was significantly lower than that in less active men. Protection among younger men was limited to those reporting frequent vigorous aerobic exercise. This finding suggests that the key features of cardio-protective exercise include its intensity relative to individual capacity. V • O 2 max declines, on average, by about 10% per decade in middle-aged and older people, 13 so exercise of a given MET value represents a higher relative intensity for older people. Where the number of individuals surveyed permit, one approach 14 may be to express the MET value of the activity in relation to age-related average values for oxygen uptake reserve.

Frequency of exercise

Recent recommendations 15, 16 are for exercise on '… most, preferably all, days of the week', underlining the importance of frequent exercise. This notion reflects increasing recognition of the acute effects of exercise, i.e. altered physiological or metabolic responses lasting between several hours and a few days after a session of exercise. These include a decrease in blood pressure, 17 improved insulin sensitivity 18 and decreases in plasma triglycerides. 19 The time-courses over which they disappear are poorly understood, however. Some information is available, for example the attenuation of the postprandial rise in plasma triglycerides following a standard high-fat meal has been reported to disappear within 60 hours of an exercise session. 20 Improved insulin sensitivity may persist for a little longer. 21 More information is required, however, as the duration of these effects dictates the frequency with which exercise sessions must be taken if favourable postprandial responses are to be maintained. Similarly, the determinants of the magnitude of acute effects of exercise need to be elucidated. Theoretically, this may be enhanced by training 22 because training permits more frequent and longer exercise sessions to be accomplished without fatigue. To the author's knowledge, this proposition has seldom been tested. 23

Pattern of exercise

Epidemiological studies have found an inverse relationship between the total energy expended in leisure time physical activity and health outcomes. These include a lower risk of all-cause mortality, 24 cardiovascular morbidity and mortality, 24, 25 type II diabetes, 6 hypertension, 26 and site-specific cancers. 27, 28 Some activities contributing to high totals of energy expenditure seem likely to have been performed at least partly on an intermittent basis, for example walking, 29 climbing stairs, 25, 30 gardening, 29 and repair work. 24 Survey evidence therefore suggests that several short sessions of moderate physical activity during the day influence health outcomes in a positive manner, at least when they contribute to a high total energy expenditure.

Scientific evidence for the efficacy of this pattern of exercise as a means of eliciting chronic (training) effects is limited however, both in the number of randomly controlled trials (three to the author's knowledge) and scope (the only common outcome measure was fitness). 31 Evidence is limited to scientific studies with outcome measures primarily of fitness and/or fatness. Only one study reported the effect of exercise pattern on acute health-related responses. This found similar reductions in plasma triglycerides with three, 10-minute bouts of brisk walking at intervals during the day and one, 30-minute bout in sedentary people consuming normal meals. 32

Further research is clearly required before the principle of accumulating exercise in short bouts throughout the day can be endorsed with confidence.

Energy expenditure and energy turnover

The product of intensity, frequency and duration of exercise—sometimes described as the total 'volume' of exercise (a difficult term)—yields the total gross energy expenditure. Some evidence points to this as an important determinant of health gains. In addition to the surveys referred to above, this includes the finding from the US Runners' Health Study that running mileage was six times more important in predicting high density lipoprotein cholesterol concentration than running speed. 33 This was not the case for associations with blood pressure or waist circumference, however, where running speed was the more important determinant. 33 Total energy expenditure may also be the main determinant of some acute effects of exercise. Two examples are relevant. First, the increase in glucose disposal rate was similar following exercise at 50% or 75% V • O 2 max when the total energy expended was held constant. 34 Second, the attenuation of postprandial plasma triglycerides by prior exercise was strikingly similar following a long bout of low intensity exercise and a shorter bout of moderate exercise expending the same energy. 35 This topic, again under-researched, is related to that of the accumulation of exercise (referred to above) because that enshrines the notion that the total energy expenditure is all-important.

Of course, in free-living people, an increased level of physical activity is invariably associated with an increase in energy intake so that energy turnover is increased. Speculatively, a higher energy turnover may constitute a metabolically desirable state because of effects on the pathways concerned with the disposition, storage and degradation of muscle energy substrates. Evidence for the health gains from such a state include the finding that men who were classified as obese by body mass index (BMI) but who had a high level of physical fitness had lower cardiovascular and total mortality rates than lean men who were unfit. 36 Similarly, although both high BMI and a high energy intake were associated with increased risk of colon cancer among inactive people, this was not the case among physically active individuals. 8 This finding suggests that a high energy intake does not confer increased risk of this cancer in the presence of a high expenditure.

The suggestion that a high energy turnover is metabolically advantageous is not new. The term 'metabolic fitness' was introduced by Després and Lamarche, 37 on the basis of a series of studies showing that change to plasma lipoprotein lipids and body fatness were achieved through high-volume, low intensity training in the absence of increases in V • O 2 max. Efforts to test this hypothesis through comparing the effects of 'lifestyle' activity with those of traditional exercise programmes have recently been reported 38– 40 but information is needed for a variety of health outcomes in different populations.

Over the last decade, epidemiological data on physical activity (a behaviour) has been complemented by findings based on physical fitness (a set of attributes related to the ability to perform exercise). These studies show a dose-response relationship so that, although men in the highest fitness groups consistently show the lowest coronary attack and total mortality rates, moderate levels of fitness also confer a statistically significant and clinically important reduction in risk. 41, 42 Physical fitness, because it is probably a more objective measure than physical activity is an attractive outcome measure. Its use could be extended of course if it could be measured satisfactorily outside the laboratory. A low-cost, rapid, non-intimidating method for this would allow large surveys with the statistical power to detect, for example, effects in sub-groups and effects of specific activities. Walking tests such as the UKK Institute's 2 km protocol 43 are attractive for both practical and theoretical reasons. Performance on these tests measures not only functional capacity (V • O 2 max, the most frequently used laboratory measure), but also endurance. This is defined as the capability to sustain aerobic exercise using a high proportion of V • O 2 max. Endurance is more sensitive to changes in physical activity level than V • O 2 max and, because it derives largely from metabolic adaptations in muscle, may be a more important determinant of related health gains.

As mentioned, epidemiological studies show associations between fitness and a variety of health outcomes. The need to elucidate the relationships between the 'dose' and pattern of activity and the health outcome has been mentioned above. Fitness (particularly endurance) is labile and so rather easily changed through short-term interventions. It therefore offers a means of studying these dose-response relations indirectly (but inexpensively), serving a link between the behaviour and health outcomes.

Most epidemiological studies have classified physical activities according to estimated energy expenditure—either totals or threshold rates. Recommendations to the public (whether direct or via health professionals), however, need to promote activities rather than energy expenditures. Walking is an obvious example. It is popular, inexpensive and carries a low risk of injury. It is often the most commonly reported activity, particularly among women 44 and older men. 12 Some landmark studies, including those by Professor Morris's group, 12 have published separate analyses for walking. 25 In British civil servants brisk walking accounted for over half of the exercise which was protective against heart attack in 55–64-year-old men. 12 Protection from attack among fairly brisk walkers was not significantly affected by controlling for participation in sports and cycling or for a lot of other CHD predictive factors. In recent years more data has become available, however. In the US Nurses Health Study, for example, walking was inversely associated with coronary events; women in the highest quintile group for walking (≥3 h per week at a brisk pace) had a multivariate relative risk of 0.65 (95% CI : 0.47–0.91). 45 Similarly, healthy older men in the Honolulu Heart Study who walked >1.5 miles per day had half the coronary risk of those who walked <0.25 miles per day. 46 Walking has also been reported to be associated with a lower risk of type II diabetes 47 (independently of participation in vigorous activity).

These observations are consistent with reports that moderate levels of fitness, associated with a reduction in all-cause mortality, are attainable through brisk or fast walking. 48, 49 Bearing in mind that sedentary people seldom exert themselves at more than 30–35% of V • O 2 max, 50 such walking is sufficiently vigorous to improve fitness in a majority of people whose health is at risk because of their inactivity.

Walking is especially suitable for older people and the functional gains it elicits will likely improve quality of life. It is plainly acceptable for them, and carries a low risk of injury. In 13 weeks of training by walking, only one injury was sustained among 57 healthy men and women their 70s. 51 Among older people, regular walking has been associated with lower rates of hospitalization, 52 lower plasma triglycerides and higher bone mineral density. 53

Because it is accessible to all but the very frail, more information on the specific benefits from walking—according to pace and distance—is sorely needed.

Studies of the associations between physical activity habits and disease outcomes must be complemented by research into the underlying mechanisms. Not only does this increase confidence that such associations may be causal but it helps us to understand the relative importance of the different components of exercise as mediators of specified health gains. For cardiovascular disease much is known of the potential contribution from exercise-induced changes to blood lipids, with recent information about considerable effects on the dynamic postprandial phase. Other mechanisms must be involved, however, because patients with CHD get improved myocardial perfusion (and decreased risk of further episodes) without net regression. 54

Recent findings suggest effects on the acute phases of the disease. (This would be concordant with observations that only continuing, current exercise confers a lower risk; past exercise has no effect. 12, 55 ) These include improved flow-mediated dilatation. 56 There may be links here with lipoprotein metabolism because flow-mediated dilatation is impaired by high plasma triglycerides, in proportion to concentration. 57

Mechanisms need elucidating in other areas, for instance skeletal health. Is the lower risk of hip fracture among physically active older women due to a decreased risk of falling and/or to an effect on bone mineral density? Is physical activity level particularly important during the years when bone formation predominates? The relationship between physical activity and a reduced risk of colon cancer is among the most consistent finding in the epidemiological literature. Is the mechanism systemic (reduced growth-promoting milieu) or local (increased colonic peristalsis)? Women who regularly engage in exercise may have a lower risk of breast cancer. 58 Speculation on potential mechanisms has involved endocrine factors and/or improved weight maintenance. Depending on the answers to such questions, some forms and regimens of exercise may be more effective than others in the achievement of particular objectives.

Physical inactivity is a waste of human potential for health and well-being and its high prevalence is a cause for concern. Its potential contribution to positive health (not merely the absence of disease but associated with a capacity to enjoy life and to withstand challenges 16 ) is considerable. So much is known—yet we need to understand much more. The effective 'dose' of exercise needed to elicit effects likely to be of clinical importance must be defined and this information translated into practical advice readily understood by the population at risk. Ten years after Professor Morris's plea for 'physiology and epidemiology to get together', 12 the need for co-operative efforts from these disciplines is even more urgent.

'Thank you'

I thank Professor Morris for posing thought-provoking questions and for stimulating discussion of these. His contributions—to research, to the National Fitness Survey for England, and to the development of public health policies—are valued by so many. It continues to be an education and a privilege to work with him.

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Scientists work out the effects of exercise at the cellular level

The health benefits of exercise are well known but new research shows that the body's response to exercise is more complex and far-reaching than previously thought. In a study on rats, a team of scientists from across the United States has found that physical activity causes many cellular and molecular changes in all 19 of the organs they studied in the animals.

Exercise lowers the risk of many diseases, but scientists still don't fully understand how exercise changes the body on a molecular level. Most studies have focused on a single organ, sex, or time point, and only include one or two data types.

To take a more comprehensive look at the biology of exercise, scientists with the Molecular Transducers of Physical Activity Consortium (MoTrPAC) used an array of techniques in the lab to analyze molecular changes in rats as they were put through the paces of weeks of intense exercise. Their findings appear in Nature .

The team studied a range of tissues from the animals, such as the heart, brain, and lungs. They found that each of the organs they looked at changed with exercise, helping the body to regulate the immune system, respond to stress, and control pathways connected to inflammatory liver disease, heart disease, and tissue injury.

The data provide potential clues into many different human health conditions; for example, the researchers found a possible explanation for why the liver becomes less fatty during exercise, which could help in the development of new treatments for non-alcoholic fatty liver disease.

The team hopes that their findings could one day be used to tailor exercise to an individual's health status or to develop treatments that mimic the effects of physical activity for people who are unable to exercise. They have already started studies on people to track the molecular effects of exercise.

Launched in 2016, MoTrPAC draws together scientists from the Broad Institute of MIT and Harvard, Stanford University, the National Institutes of Health, and other institutions to shed light on the biological processes that underlie the health benefits of exercise. The Broad project was originally conceived of by Steve Carr, senior director of Broad's Proteomics Platform; Clary Clish, senior director of Broad's Metabolomics Platform; Robert Gerszten, a senior associate member at the Broad and chief of cardiovascular medicine at Beth Israel Deaconess Medical Center; and Christopher Newgard, a professor of nutrition at Duke University.

Co-first authors on the study include Pierre Jean-Beltran, a postdoctoral researcher in Carr's group at Broad when the study began, as well as David Amar and Nicole Gay of Stanford. Courtney Dennis and Julian Avila, both researchers in Clish's group, were also co-authors on the manuscript.

"It took a village of scientists with distinct scientific backgrounds to generate and integrate the massive amount of high quality data produced," said Carr, a co-senior author of the study. "This is the first whole-organism map looking at the effects of training in multiple different organs. The resource produced will be enormously valuable, and has already produced many potentially novel biological insights for further exploration."

The team has made all of the animal data available in an online public repository. Other scientists can use this site to download, for example, information about the proteins changing in abundance in the lungs of female rats after eight weeks of regular exercise on a treadmill, or the RNA response to exercise in all organs of male and female rats over time.

Whole-body analysis

Conducting such a large and detailed study required a lot of planning. "The amount of coordination that all of the labs involved in this study had to do was phenomenal," said Clish.

In partnership with Sue Bodine at the Carver College of Medicine at the University of Iowa, whose group collected tissue samples from animals after up to eight weeks of training, other members of the MoTrPAC team divided the samples up so that each lab -- Carr's team analyzing proteins, Clish's studying metabolites, and others -- would examine virtually identical samples.

"A lot of large-scale studies only focus on one or two data types," said Natalie Clark, a computational scientist in Carr's group. "But here we have a breadth of many different experiments on the same tissues, and that's given us a global overview of how all of these different molecular layers contribute to exercise response."

In all, the teams performed nearly 10,000 assays to make about 15 million measurements on blood and 18 solid tissues. They found that exercise impacted thousands of molecules, with the most extreme changes in the adrenal gland, which produces hormones that regulate many important processes such as immunity, metabolism, and blood pressure. The researchers uncovered sex differences in several organs, particularly related to the immune response over time. Most immune-signaling molecules unique to females showed changes in levels between one and two weeks of training, whereas those in males showed differences between four and eight weeks.

Some responses were consistent across sexes and organs. For example, the researchers found that heat-shock proteins, which are produced by cells in response to stress, were regulated in the same ways across different tissues. But other insights were tissue-specific. To their surprise, Carr's team found an increase in acetylation of mitochondrial proteins involved in energy production, and in a phosphorylation signal that regulates energy storage, both in the liver that changed during exercise. These changes could help the liver become less fatty and less prone to disease with exercise, and could give researchers a target for future treatments of non-alcoholic fatty liver disease.

"Even though the liver is not directly involved in exercise, it still undergoes changes that could improve health. No one speculated that we'd see these acetylation and phosphorylation changes in the liver after exercise training," said Jean-Beltran. "This highlights why we deploy all of these different molecular modalities -- exercise is a very complex process, and this is just the tip of the iceberg."

"Two or three generations of research associates matured on this consortium project and learned what it means to carefully design a study and process samples," added Hasmik Keshishian, a senior group leader in Carr's group and co-author of the study. "Now we are seeing the results of our work: biologically insightful findings that are yielding from the high quality data we and others have generated.That's really fulfilling."

Other MoTrPAC papers published today include deeper dives into the response of fat and mitochondria in different tissues to exercise. Additional MoTrPAC studies are underway to study the effects of exercise on young adult and older rats, and the short-term effects of 30-minute bouts of physical activity. The consortium has also begun human studies, and are recruiting about 1,500 individuals of diverse ages, sexes, ancestries, and activity levels for a clinical trial to study the effects of both endurance and resistance exercise in children and adults.

• Liver Disease
• Staying Healthy
• Diseases and Conditions
• Men's Health
• Chronic Illness
• Healthy Aging
• Today's Healthcare
• Physical exercise
• Anaerobic exercise
• Aerobic exercise
• Neural development
• Health science
• Weight training

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Materials provided by Broad Institute of MIT and Harvard . Original written by Allessandra DiCorato. Note: Content may be edited for style and length.

Journal Reference :

• David Amar, Nicole R. Gay, Pierre M. Jean-Beltran, Dam Bae, Surendra Dasari, Courtney Dennis, Charles R. Evans, David A. Gaul, Olga Ilkayeva, Anna A. Ivanova, Maureen T. Kachman, Hasmik Keshishian, Ian R. Lanza, Ana C. Lira, Michael J. Muehlbauer, Venugopalan D. Nair, Paul D. Piehowski, Jessica L. Rooney, Kevin S. Smith, Cynthia L. Stowe, Bingqing Zhao, Natalie M. Clark, David Jimenez-Morales, Malene E. Lindholm, Gina M. Many, James A. Sanford, Gregory R. Smith, Nikolai G. Vetr, Tiantian Zhang, Jose J. Almagro Armenteros, Julian Avila-Pacheco, Nasim Bararpour, Yongchao Ge, Zhenxin Hou, Shruti Marwaha, David M. Presby, Archana Natarajan Raja, Evan M. Savage, Alec Steep, Yifei Sun, Si Wu, Jimmy Zhen, Sue C. Bodine, Karyn A. Esser, Laurie J. Goodyear, Simon Schenk, Stephen B. Montgomery, Facundo M. Fernández, Stuart C. Sealfon, Michael P. Snyder, Joshua N. Adkins, Euan Ashley, Charles F. Burant, Steven A. Carr, Clary B. Clish, Gary Cutter, Robert E. Gerszten, William E. Kraus, Jun Z. Li, Michael E. Miller, K. Sreekumaran Nair, Christopher Newgard, Eric A. Ortlund, Wei-Jun Qian, Russell Tracy, Martin J. Walsh, Matthew T. Wheeler, Karen P. Dalton, Trevor Hastie, Steven G. Hershman, Mihir Samdarshi, Christopher Teng, Rob Tibshirani, Elaine Cornell, Nicole Gagne, Sandy May, Brian Bouverat, Christiaan Leeuwenburgh, Ching-ju Lu, Marco Pahor, Fang-Chi Hsu, Scott Rushing, Michael P. Walkup, Barbara Nicklas, W. Jack Rejeski, John P. Williams, Ashley Xia, Brent G. Albertson, Elisabeth R. Barton, Frank W. Booth, Tiziana Caputo, Michael Cicha, Luis Gustavo Oliveira De Sousa, Roger Farrar, Andrea L. Hevener, Michael F. Hirshman, Bailey E. Jackson, Benjamin G. Ke, Kyle S. Kramer, Sarah J. Lessard, Nathan S. Makarewicz, Andrea G. Marshall, Pasquale Nigro, Scott Powers, Krithika Ramachandran, R. Scott Rector, Collyn Z-T. Richards, John Thyfault, Zhen Yan, Chongzhi Zang, Mary Anne S. Amper, Ali Tugrul Balci, Clarisa Chavez, Maria Chikina, Roxanne Chiu, Marina A. Gritsenko, Kristy Guevara, Joshua R. Hansen, Krista M. Hennig, Chia-Jui Hung, Chelsea Hutchinson-Bunch, Christopher A. Jin, Xueyun Liu, Kristal M. Maner-Smith, D. R. Mani, Nada Marjanovic, Matthew E. Monroe, Ronald J. Moore, Samuel G. Moore, Charles C. Mundorff, Daniel Nachun, Michael D. Nestor, German Nudelman, Cadence Pearce, Vladislav A. Petyuk, Hanna Pincas, Irene Ramos, Alexander Raskind, Stas Rirak, Jeremy M. Robbins, Aliza B. Rubenstein, Frederique Ruf-Zamojski, Tyler J. Sagendorf, Nitish Seenarine, Tanu Soni, Karan Uppal, Sindhu Vangeti, Mital Vasoya, Alexandria Vornholt, Xuechen Yu, Elena Zaslavsky, Navid Zebarjadi, Marcas Bamman, Bryan C. Bergman, Daniel H. Bessesen, Thomas W. Buford, Toby L. Chambers, Paul M. Coen, Dan Cooper, Fadia Haddad, Kishore Gadde, Bret H. Goodpaster, Melissa Harris, Kim M. Huffman, Catherine M. Jankowski, Neil M. Johannsen, Wendy M. Kohrt, Bridget Lester, Edward L. Melanson, Kerrie L. Moreau, Nicolas Musi, Robert L. Newton, Shlomit Radom-Aizik, Megan E. Ramaker, Tuomo Rankinen, Blake B. Rasmussen, Eric Ravussin, Irene E. Schauer, Robert S. Schwartz, Lauren M. Sparks, Anna Thalacker-Mercer, Scott Trappe, Todd A. Trappe, Elena Volpi. Temporal dynamics of the multi-omic response to endurance exercise training . Nature , 2024; 629 (8010): 174 DOI: 10.1038/s41586-023-06877-w

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REVIEW article

Effects of physical exercise on cognitive functioning and wellbeing: biological and psychological benefits.

• 1 Department of Movement Sciences and Wellbeing, Parthenope University of Naples, Naples, Italy
• 2 IRCCS Fondazione Santa Lucia, Rome, Italy
• 3 Istituto di Diagnosi e Cura Hermitage Capodimonte, Naples, Italy
• 4 Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy
• 5 Department of Science and Technology, Parthenope University of Naples, Naples, Italy
• 6 Department of Engineering, Parthenope University of Naples, Naples, Italy
• 7 Institute of Applied Sciences and Intelligent Systems, CNR, Pozzuoli, Italy

Much evidence shows that physical exercise (PE) is a strong gene modulator that induces structural and functional changes in the brain, determining enormous benefit on both cognitive functioning and wellbeing. PE is also a protective factor for neurodegeneration. However, it is unclear if such protection is granted through modifications to the biological mechanisms underlying neurodegeneration or through better compensation against attacks. This concise review addresses the biological and psychological positive effects of PE describing the results obtained on brain plasticity and epigenetic mechanisms in animal and human studies, in order to clarify how to maximize the positive effects of PE while avoiding negative consequences, as in the case of exercise addiction.

Introduction

Many evidences demonstrated that physical exercise (PE) affects brain plasticity, influencing cognition and wellbeing ( Weinberg and Gould, 2015 ; for review see Fernandes et al., 2017 ). In fact, experimental and clinical studies have reported that PE induces structural and functional changes in the brain, determining enormous biological, and psychological benefits.

In general, when reported PE effects, it is customary to separate the biological aspects from the psychological ones. In fact, most of the studies documented either the effects of PE on the brain (and then on the cognitive functioning) or on the wellbeing (in terms of physical and mental health). In this review, we merge both these aspects as they influence each other. In fact, behaviorally appropriate choices depend upon efficient cognitive functioning. Furthermore, emotional states influence cognitive functions through specific cerebral circuitry involving prefrontal areas and limbic structures ( Barbas, 2000 ).

Before analyzing the benefits of PE, it is necessary to define PE precisely. Indeed, PE is a term often incorrectly used interchangeably with physical activity (PA) that is “any bodily movement produced by skeletal muscles that requires energy expenditure” ( World Health Organization, 2010 ). Then, PA includes any motor behavior such as daily and leisure activities and it is considered a determinant lifestyle for general health status ( Burkhalter and Hillman, 2011 ). Instead, PE is “a sub classification of PA that is planned, structured, repetitive, and has as a final or an intermediate objective the improvement or maintenance of one or more components of physical fitness” ( World Health Organization, 2010 ). Examples of PE are aerobic and anaerobic activity, characterized by a precise frequency, duration and intensity.

In this review, we illustrate the biological and psychological benefits of PE on cognition and wellbeing both in health and diseases, reporting data from both animal and human studies. The biological basis at both molecular and supramolecular level have been largely studied. The other aim of present work is to report the actual evidence on the epigenetic mechanisms that determine or modulate the biological effects of PE on the brain. In fact, while the biologic mechanisms are sufficiently studied both at the molecular and supramolecular levels (see Lista and Sorrentino, 2010 ), little is known about the epigenetic ones. Finally, the modality with which PE should be practiced to gain such advantages while avoiding negative consequences will be discussed. In Table 1 are reported the inclusion and exclusion criteria for studies discussed in this review.

Table 1 . Inclusion and exclusion criteria for studies included in this review.

Physical Exercise, Brain, and Cognition

Among the biological effects of PE, those linked to “neuroplasticity” are quite important.

Neuroplasticity is an important feature of the nervous system, which can modify itself in response to experience ( Bavelier and Neville, 2002 ). For this reason, PE may be considered as an enhancer environmental factor promoting neuroplasticity.

In animal studies, the structural changes analyzed concern the cellular (neurogenesis, gliogenesis, synaptogenesis, angiogenesis) and molecular (alteration in neurotransmission systems and increasing in some neurotrophic factors) level ( Gelfo et al., 2018 ), while the functional activity has been measured using the levels of performance in behavioral tasks, such as spatial tasks that allow to analyze the different facets of spatial cognitive functions ( Mandolesi et al., 2017 ). In humans, indicators of structural changes correspond for example to brain volumes, measures of white matter integrity or modulation in neurotrophins levels (by correlation with trophic factors plasma levels). Such metrics can be correlated to cognitive performances, defining the functional neural efficiency ( Serra et al., 2011 ). To this regard, it should be emphasized that any morphological change results in a modification of the functional properties of a neural circuit and vice versa any change in neuronal efficiency and functionality is based on morphological modifications ( Mandolesi et al., 2017 ).

Experimental and clinical studies have shown that PE induces important structural and functional changes in brain functioning. In Table 2 are reported the more evident effects induced by PE.

Table 2 . Structural and functional effects of PE.

Animal Studies

In animals, motor activity or motor exercise are terms often used instead of PE. The effects of motor exercise are mainly studied in rodents by means of specific training on wheels or by locomotor activity analyses.

Studies on healthy animals have demonstrated that intense motor activity increases neurons and glia cells proliferation rates in the hippocampus and the neocortex ( van Praag et al., 1999a , b ; Brown et al., 2003 ; Ehninger and Kempermann, 2003 ; Steiner et al., 2004 ; Hirase and Shinohara, 2014 ) and induces angiogenesis in the neocortex, hippocampus, and cerebellum ( Black et al., 1990 ; Isaacs et al., 1992 ; Kleim et al., 2002 ; Swain et al., 2003 ; Ekstrand et al., 2008 ; Gelfo et al., 2018 ). At the molecular level, motor activity causes changes in neurotrasmitters such as serotonin, noradrenalin, and acetylcholine ( Lista and Sorrentino, 2010 ; for a review, see Lin and Kuo, 2013 ) and induces the release of the brain-derived neurotrophic factor (BDNF Vaynman et al., 2004 ; Lafenetre et al., 2011 ) and the insulin-like growth factor-1 (IGF-1; for a review, van Praag, 2009 ).

Animals performing motor exercise showed improvements in spatial abilities ( van Praag et al., 2005 ; Snigdha et al., 2014 ) and in other cognitive domains such as executive functions ( Langdon and Corbett, 2012 ), evidencing thus that motor exercise improve cognitive functions.

Similar structural and functional changes were evident even in older animals ( Kronenberg et al., 2006 ) and in animal models of neurodegenerative diseases ( Nithianantharajah and Hannan, 2006 ), suggesting that motor exercise is a potent neuroprotective factor against physiological and pathological aging ( Gelfo et al., 2018 ). In this context, one can use transgenic models to determine exactly when a structural alteration occurs, and then to study when the animals should undergo motor training in order to maximize its effects. To this regard, converging evidence is showing that motor activity should be performed before the development of neurodegeneration in order to exert its protective role ( Richter et al., 2008 ; Lin et al., 2015 ) such as before the formation of beta amyloid plaques in Alzheimer's disease ( Adlard et al., 2005 ). However, there are some experimental evidences showing that motor exercise performed after neurodegenerative lesions permits to improve spatial abilities, hence being also a potent therapeutic agent ( Sim, 2014 ; Ji et al., 2015 ).

Interestingly, PE induces modifications that can be passed on to the offspring. In fact, positive maternal experiences can influence the offspring at both behavioral and biochemical levels (see Cutuli et al., 2017 , 2018 ). Preclinical studies also indicated that the effects of maternal exercise during pregnancy can be passed on to offspring ( Robinson et al., 2012 ). However, it is not clear if the possibilities of inheritance are limited to motor exercise alone. To this regard, it has been seen that pregnant rats exposed to motor exercise on wheel-running and treadmill running have offspring with improved spatial memory, and increased hippocampal BDNF level ( Akhavan et al., 2008 ; Aksu et al., 2012 ). However, further studies are necessary since it remains unclear whether these beneficial effects result from physiological changes to the in utero environment and/or from epigenetic modifications to the developing embryo ( Short et al., 2017 ). On the other hand, few studies, conflicting and hard to replicate, do not yet allow to explore the transgenerational effects of paternal motor exercise ( Short et al., 2017 ).

Human Studies

Neuroplasticity phenomena following PE have been evidenced even in humans. A great number of studies demonstrated that in adults, PE determines structural changes such as increased gray matter volume in frontal and hippocampal regions ( Colcombe et al., 2006 ; Erickson et al., 2011 ) and reduced damage in the gray matter ( Chaddock-Heyman et al., 2014 ).

Moreover, PE facilitates the release of neurotrophic factors such as peripheral BDNF ( Hötting et al., 2016 ), increases blood flow, improves cerebrovascular health and determines benefits on glucose and lipid metabolism carrying “food” to the brain ( Mandolesi et al., 2017 ).

These effects are reflected on cognitive functioning (for a review see Hötting and Röder, 2013 ). In fact, the results of cross-sectional and epidemiological studies showed that PE enhances cognitive functions in young and older adults ( Lista and Sorrentino, 2010 ; Fernandes et al., 2017 ), improving memory abilities, efficiency of attentional processes and executive-control processes ( Kramer et al., 1999 ; Colcombe and Kramer, 2003 ; Grego et al., 2005 ; Pereira et al., 2007 ; Winter et al., 2007 ; Chieffi et al., 2017 ). Furthermore, structural changes following PE have been related to academic achievement in comparison to sedentary individuals ( Lees and Hopkins, 2013 ; Donnelly et al., 2016 ). In this line, it has been also showed that children who practice regular aerobic activity performed better on verbal, perceptual and arithmetic test in comparison to sedentary ones of same age ( Sibley and Etnier, 2003 ; Voss et al., 2011 ).

Numerous studies have demonstrated that PE prevents cognitive decline linked to aging ( Yaffe et al., 2009 ; Hötting and Röder, 2013 ; Niemann et al., 2014 ), reduces the risk of developing dementia ( Colberg et al., 2008 ; Mandolesi et al., 2017 ), the level of deterioration in executive functions ( Hollamby et al., 2017 ) and improves the quality of life ( Pedrinolla et al., 2017 ). Furthermore, positron emission tomography based studies evidenced that PE determines changes in metabolic networks that are related to cognition ( Huang et al., 2016 ).

Recently, studies on magnetoencephalography based (MEG) functional connectivity evidenced that PE influences network topology ( Foster, 2015 ). It is important to underlie that MEG is a much more direct measure of neural activity in comparison to fRMI, with the advantage of combining good spatial and high temporal resolution. In healthy individuals, PE was related to better intermodular integration ( Douw et al., 2014 ) and to improvements in cognitive functions ( Huang et al., 2016 ). Benefits of PE are evidenced even in individuals at risk for AD ( Deeny et al., 2008 ), thus once again suggesting a protective role of PE.

A possible explanation for these ameliorative structural and functional effects could be that PE stimulates blood circulation in the neural circuits involved in cognitive functioning ( Erickson et al., 2012 ). Another interpretation could be found in the concept of “cerebral reserves” ( Stern, 2002 , 2012 ) a mechanisms that might explain why, in the face of neurodegenerative changes that are similar in nature and extent, individuals vary considerably in the severity of cognitive aging and clinical dementia ( Petrosini et al., 2009 ). Two types of reserves are recognized: brain reserve and cognitive reserve. The former is based on the protective potential of anatomical features such as brain size, neuronal density and synaptic connectivity, the latter is based on the efficient connectivity among neural circuits ( Stern, 2002 ; Mandolesi et al., 2017 ).

According to the reserves hypothesis and taking into account the numerous evidences described above, we could advance that PE is an environmental factor that permits to gain reserves.

However, one must underline that if on the one hand PE improves the cognitive functioning, providing reserves to be spent in the case of a brain lesion, on the other hand the modifications of the clinical expression of neurodegeneration delays the diagnosis. It has been seen that patients with higher cognitive reserve take longer to manifest the symptoms of memory loss ( Zanetti et al., 2017 ). It has been hypothesized a neural compensation mechanism that permits to perform complex activities ( Stern, 2009 ). Obviously, these conclusions open important reflections more for the diagnosis of neurodegenerative disease than for the practice of PE.

The effects of PE on cognitive functioning have been shown across the lifespan from childhood to the old age ( Hötting and Röder, 2013 ). In particular, it has been evidenced that cognitive functions that are influenced the most by brain maturation, such as attention or cognitive flexibility, and the cognitive functions that depend the most upon experiences, such as memory, are the most sensitive ones to PE ( Hötting and Röder, 2013 ). Overall, these studies, together with those analyzing the effects of combined environmental factors, suggest that for a positive effect on cognitive function, it is necessary to maintain an “enriched lifestyle” up to middle life. In fact, the exposure to PE together to other many experiences provides a “reserve”-like advantage which supports an enduring preservation of cognitive function in old age ( Chang et al., 2010 ; Loprinzi et al., 2018 ).

Physical Exercise and Wellbeing

There are consistent evidences that PE has many benefits for people of any age, improving psychological wellbeing ( Zubala et al., 2017 ) and quality of life ( Penedo and Dahn, 2005 ; Windle et al., 2010 ; Table 3 ).

Table 3 . Biological and psychological effects of PE (Adapted from Weinberg and Gould, 2015 ).

In children, PE is correlated with high levels of self-efficacy, tasks goal orientation, and perceived competence ( Biddle et al., 2011 ). In youth and adulthood, most studies evidenced that PE is associated with better health outcomes, such as better mood and self-concept ( Berger and Motl, 2001 ; Landers and Arent, 2001 ; Penedo and Dahn, 2005 ). In the aging population, PE helps maintaining independence ( Stessman et al., 2009 ), favoring social relations and mental health.

It was now well-accepted that is the interaction between biological and psychological mechanisms linked to PE enhances the wellbeing ( Penedo and Dahn, 2005 ). Biological mechanisms of beneficial effects of PE are mainly related to increasing in cerebral blood flow and in maximal oxygen consumption, to delivery of oxygen to cerebral tissue, to reduction in muscle tension and to increased serum concentrations of endocannabinoid receptors ( Thomas et al., 1989 ; Dietrich and McDaniel, 2004 ; Querido and Sheel, 2007 ; Gomes da Silva et al., 2010 ; Ferreira-Vieira et al., 2014 ). Moreover, neuroplasticity phenomena such as changes in neurotransmitters are recognized to affect wellbeing. For example, PE increases the levels of serotonin ( Young, 2007 ; Korb et al., 2010 ) and the levels of beta-endorphins, such as anandamide ( Fuss et al., 2015 ).

Among the psychological hypothesis proposed to explain how PE enhances wellbeing, it has been underlined feeling of control ( Weinberg and Gould, 2015 ), competency and self-efficacy ( Craft, 2005 ; Rodgers et al., 2014 ), improved self-concept and self-esteem ( Marsh and Sonstroem, 1995 ; Fox, 2000 ; Zamani Sani et al., 2016 ), positive social interactions and opportunities for fun and enjoyment ( Raedeke, 2007 ; Bartlett et al., 2011 ).

Psychological research evidenced that PE can even modulate the personality and the development of Self ( Weinberg and Gould, 2015 ). Moreover, PE has been correlated with hardiness, a personality style that enables a person to withstand or cope with stressful situations ( Weinberg and Gould, 2015 ).

In the following sections, we will focus on correlations among PE and the most common mental illnesses.

Depression and Anxiety

Depression is the most common type of mental illness and will be the second leading cause of disease by 2020 ( Farioli-Vecchioli et al., 2018 ). Similar entity concerns anxiety disorders that are among the most prevalent mental disorders in the world population ( Weinberg and Gould, 2015 ).

Epidemiological studies have consistently reported benefits of PE on reductions in depression ( Mammen and Faulkner, 2013 ) and anxiety ( DeBoer et al., 2012 ). For example, it has been seen that individuals that practice PE regularly are less depressed or anxious than those who do not ( De Moor et al., 2006 ), suggesting the use of exercise as a treatment for these illnesses ( Carek et al., 2011 ).

Most of the research on the relationship between PE and positive changes in mood state has evidenced positive effects, especially as a consequence of aerobic exercise, regardless of the specific type of activity ( Knapen et al., 2009 ), even if the correct intensity of aerobic PE to control and reduce symptoms is debated ( de Souza Moura et al., 2015 ). For example, it has been revealed that after about 16 weeks of an aerobic exercise program, individuals with major depressive disorder (MDD), significantly reduced their depressive symptoms ( Craft and Perna, 2004 ). However, there are evidenced that documented that even anaerobic activity has positive effects on treatment of clinical depression ( Martinsen, 1990 ). For anxiety disorders, it has been evidenced that the positive effects of PE are visible even with short bursts of exercise, independently from the nature of the exercise ( Scully et al., 1998 ).

A physiologic mechanism correlated to the improvement in depressed mood post-exercise PE was identified in modulation of peripheral levels of BDNF ( Coelho et al., 2013 ). In this line, it was suggested recently that the intensity of exercise to improve mood should be prescribed on individual basis and not on the patient's preferred intensity ( Meyer et al., 2016a , b ). Conversely, physical inactivity correlated to worse depressive symptoms and, then, to lower peripheral levels of BDNF ( Brunoni et al., 2008 ). Post-PE mood improvement might also be due to lower oxidative stress ( Thomson et al., 2015 ). In this contest, it was evidenced that there is an abnormal oxidative stress in individuals with MDD or bipolar disorder ( Cataldo et al., 2010 ; Andreazza et al., 2013 ) and that PE, particularly in higher intensity, decreases oxidative stress with consequent mood improvement ( Urso and Clarkson, 2003 ).

Addictive and Unhealthy Behaviors

PE has been widely evidenced to be an effective tool for treating several addictive and unhealthy behaviors. PE tends to reduce and prevent behaviors such as smoking, alcohol, and gambling, and to regulate the impulse for hunger and satiety ( Vatansever-Ozen et al., 2011 ; Tiryaki-Sonmez et al., 2015 ). In this context, several studies evidenced substance abusers benefit from regular PE, that also helps increasing healthy behaviors ( Giesen et al., 2015 ). It has been evidenced that regular PE reduces tobacco cravings and cigarette use ( Haasova et al., 2013 ). Although PE has positive effects on psychological wellbeing, in this context it is right underline that in some cases PE could reveal unhealthy behaviors with negative consequence on health ( Schwellnus et al., 2016 ). It is the case of exercise addiction, a dependence on a regular regimen of exercise that is characterized by withdrawal symptoms, after 24–36 h without exercise ( Sachs, 1981 ), such as anxiety, irritability, guilt, muscle twitching, a bloated feeling, and nervousness ( Weinberg and Gould, 2015 ). There is a strong correlation between exercise addiction and eating disorders ( Scully et al., 1998 ) suggesting thus a comorbidity of these disorders and a common biological substrate. In particular, recent studies have shown that these unhealthy behaviors are associated to lower prefrontal cortex volume, activity and oxygenation, with consequent impairment in cognitive functions, such as the inhibitory control with the consequent compulsive behaviors ( Asensio et al., 2016 ; Wang et al., 2016 ; Pahng et al., 2017 ). Also, it has been seen that a few days of PE increase oxygenation of prefrontal cortex, improving mental health ( Cabral et al., 2017 ).

Epigenetic Mechanisms

Biological and psychological effects of PE could be partly explained through epigenetic mechanisms. The term “epigenetics,” coined by Waddington (1939) , is based on a conceptual model designed to account for how genes might interact with their environment to produce the phenotype ( Waddington, 1939 ; Fernandes et al., 2017 ).

In particular, epigenetics is referred to all those mechanisms, including functional modifications of the genome such as DNA methylation, post-translational histone modifications (i.e., acetylation and methylation) and microRNA expression ( Deibel et al., 2015 ; Grazioli et al., 2017 ), which tend to regulate gene expression, modeling the chromatin structure but maintaining the nucleotide sequence of DNA unchanged.

The current literature clearly demonstrates that these mechanisms are strongly influenced by different biological and environmental factors, such as PE ( Grazioli et al., 2017 ), which determine the nature and the mode of epigenetic mechanisms activation.

Epigenetics plays an essential role in neural reorganization, including those that govern the brain plasticity ( Deibel et al., 2015 ). For example, a growing body of evidence indicates that regulates neuroplasticity and memory processes ( Ieraci et al., 2015 ).

Several animal studies reveal how motor activity is able to improve cognitive performances acting on epigenetic mechanisms and influencing the expression of those genes involved in neuroplasticity ( Fernandes et al., 2017 ). The main molecular processes that underlie the epigenetic mechanisms are the following: through DNA methylation, histone modifications and microRNA expression ( Fernandes et al., 2017 ).

DNA methylation is a chemical covalent modification on the cytosine of the double stranded DNA molecule. It has been recognized that DNA methylation plays a key role in long-term memory ( Deibel et al., 2015 ; Kim and Kaang, 2017 ). In particular, mechanisms related to DNA methylation relieve the repressive effects of memory-suppressor genes to favor the expression of plasticity-promoting and memory consolidation genes. Several evidences showed that PE is able to coordinate the action of the genes involved in synaptic plasticity that regulate memory consolidation ( Molteni et al., 2002 ; Ding et al., 2006 ).

Histone modifications are post-translational chemical changes in histone proteins. They include histone methylation/demethylation, acetylation/deacetylation, and phosphorylation, all due to the activity of specific enzymes, which modify the chromatin structure, thereby regulating gene expression. It has been demonstrated that histone acetylation is a requisite for long-term memory (LTM) ( Barrett and Wood, 2008 ; Fernandes et al., 2017 ). In animals, motor activity increases these genetic mechanisms in the hippocampus and the frontal cortex, improving memory performances in behavioral tasks ( Cechinel et al., 2016 ). Recently, following 4 weeks of motor exercise, it has been evidenced an increasing of the activity of enzymes involved in histone acetylation/deacetylation, the epigenetic mechanisms that determine an enhancing in the expression of BDNF ( Maejima et al., 2018 ).

MicroRNAs (miRNAs) are small, single stranded RNA molecules able to inhibit the expression of target genes. They are widely expressed in the brain, participating in epigenetic mechanisms and acting as regulators of numerous biological processes in the brain, ranging from cell proliferation, differentiation, apoptosis, synaptic plasticity, and memory consolidation ( Saab and Mansuy, 2014 ). Recent evidences demonstrate that PE can mitigate the harmful effects of traumatic brain injury and aging on cognitive function by regulating the hippocampal expression of miR21 ( Hu et al., 2015 ) and miR-34a ( Kou et al., 2017 ). Furthermore, PE contributes to attenuate the effects of stress-related increase in miR-124, involved in neurogenesis and memory formation ( Pan-Vazquez et al., 2015 ).

What Kind of Physical Exercise?

Sport psychology has suggested that the success or failure of PE programs depends on several factors such as the intensity, frequency, duration of the exercise, and whether the PE is done in group or alone ( Weinberg and Gould, 2015 ). These aspects are important in terms of maintenance of PE practice and in order to gain benefits for brain and behavior, and they are affected by individual characteristics. Although such aspects have to be taken into account when training is proposed, scientific reports have evidenced different effects on cognitive functioning and wellbeing if PE is performed in aerobic or anaerobic modality.

Aerobic exercise allows the resynthesis of adenosine—triphosphate (ATP) by aerobic mechanisms, adjusting intensity (from low to high intensity), duration (usually long), and oxygen availability. The intensity depends on the cardiorespiratory effort with respect to the maximum heart rate (HRmax) or the maximum oxygen consumption (Vo2max), which determines an increase in oxygen consumption with respect to the rest condition. Examples of aerobic PE are jogging, running, cycling, and swimming.

On the contrary, anaerobic exercise has high intensity, short duration and unavailability of oxygen, determining the depletion of the muscles' ATP and/or phosphocreatine (PCr) reserves, shifting the production of ATP, to anaerobic energy mechanisms, lactacid or alactacid. Examples of anaerobic exercises are weight lifting or sprint in 100 m.

Robust literature demonstrated that chronic aerobic exercise is associated with potent structural and functional neuroplastic changes, with an improvement in cognitive functions ( Colcombe et al., 2006 ; Hillman et al., 2008 ; Erickson et al., 2009 ; Mandolesi et al., 2017 ) and increased feeling of general wellbeing ( Berger and Tobar, 2011 ; Biddle et al., 2011 ) (Table 4 ).

Table 4 . Effects of physical aerobic exercise on cognitive functioning and wellbeing.

Recently, growing evidence showed that acute aerobic exercise, defined as a single bout of exercise, relates to improved cognitive functions, especially prefrontal cortex-dependent cognition ( Tomporowski, 2003 ; Lambourne and Tomporowski, 2010 ; Chang et al., 2011 ; Ludyga et al., 2016 ; Basso and Suzuki, 2017 ). However, the effects of a single session of exercise on cognitive functioning are generally small ( Chang et al., 2012 ). In this line, it was evidenced that even a single bout of moderate-intensity aerobic exercise enhances, mood and emotional states and improves the wellbeing in MDD individuals ( Bartholomew et al., 2005 ; Basso and Suzuki, 2017 ) (Table 4 ).

Beside frequency and duration over time, even the intensity is a parameter to be considered when evaluating the PE effects. It has been showed that moderate intensity exercise is related to increased performance in working memory and cognitive flexibility, whereas high-intensity exercise improves the speed of information processing ( Chang and Etnier, 2009 ). In this context, it has been reported that peripheral BDNF was significantly increased after high intensity exercise, but not after low-intensity exercise ( Hötting et al., 2016 ). In fact, it is evidenced that high-intensity exercise provides greater benefit to cognitive functions than low-intensity exercise in the elderly ( Brown et al., 2012 ).

With regard to the psychological beneficial effects related to PE, research has evidenced that major benefits in reduction of anxiety and depression are determined by longer training program (several months), as compared to shorter ones (some days) for training session lasting over 30 min. Moreover, anxiety and depression reduction after aerobic exercise may be achieved with exercise intensity between 30 and 70% of maximal heart rate ( Weinberg and Gould, 2015 ). To achieve positive mood changes, an important role is played even by anaerobic activity, such as yoga, or in all PEs in which there is rhythmic abdominal breathing, enjoyment, rhythmic, and repetitive movements and relative absence of interpersonal competition ( Berger and Motl, 2001 ).

PE determines positive biological and psychological effects that affect the brain and the cognitive functioning and promote a condition of wellbeing. PE plays an important role in counteract normal and pathological aging. Recent evidences have shown that PE triggers potent neuroplastic phenomena, partly mediated by epigenetic mechanisms. In fact, PE cause profound alterations in gene expression and its protein products in the form of epigenomic manifestations ( Fernandes et al., 2017 ).

A growing body of literature indicates that both chronic and aerobic PE can achieve similar benefits.

These results should lead to reflect on beneficial effects of PE and to promote its use as a modifiable factor for prevention, to improve cognitive abilities and to enhance mood.

Despite all these positive effects, it must be underlined that PE should be tailored to the individual. In fact, even PE, when excessive, can have a dark side, when PE becomes compulsive and facilitates addictive behaviors.

Author Contributions

LM, AP, SM, FF, GF, PS, and GS: designed the review; LM and GS: wrote the paper. All authors read, revised, and approved the final manuscript.

The present paper was supported by University of Naples Parthenope Ricerca Competitiva 2017 (D.R. 289/2017) to LM and GF.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Keywords: physical exercise, cognition, wellbeing, brain, epigenetic mechanisms

Citation: Mandolesi L, Polverino A, Montuori S, Foti F, Ferraioli G, Sorrentino P and Sorrentino G (2018) Effects of Physical Exercise on Cognitive Functioning and Wellbeing: Biological and Psychological Benefits. Front. Psychol . 9:509. doi: 10.3389/fpsyg.2018.00509

Received: 04 January 2018; Accepted: 26 March 2018; Published: 27 April 2018.

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Copyright © 2018 Mandolesi, Polverino, Montuori, Foti, Ferraioli, Sorrentino and Sorrentino. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Laura Mandolesi, [email protected]

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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No More Pain: Study Evaluates No-Pain Exercise To Help Peripheral Artery Disease Patients

University of Oklahoma Health Sciences researcher receives $2.4 million National Institutes of Health grant to study revolutionary new exercise regimen for peripheral artery disease patients.

OKLAHOMA CITY, OKLA. – Pain-free movement is something that many of us take for granted. But for patients with peripheral artery disease, or PAD, merely walking a block or two can mean disabling leg pain — pain that often causes these patients to reduce their overall level of activity well below recommended amounts for a healthy lifestyle.

A researcher with the University of Oklahoma College of Medicine recently received funding from the National Institutes of Health National Institute on Aging — more than $2.4 million over five years — to study the efficacy of a new painless exercise protocol to treat the symptoms of PAD and ultimately increase patients overall physical activity. The research effort is led by Andrew Gardner, Ph.D., a professor in the cardiovascular section of the OU College of Medicine.

“Having PAD doesn't necessarily mean that patients are going to have a heart attack or stroke, but they are at higher risk,” Gardner said. “It's disabling. So, guess what? They do less walking because it hurts. And so, because they walk less, now they're totally inactive and that's a high-risk factor for cardiovascular disease to develop even further.”

Peripheral artery disease is when narrowed arteries reduce blood flow to the extremities which can cause pain, called claudication, in the legs. The pain is caused by ischemia or lack of oxygen due to the reduced blood flow to the muscles. This pain occurs during exercise of any kind, particularly walking, and is relieved by rest. However, one of the common treatment protocols for reducing claudication in PAD patients is, in fact, exercise.

Gardner explains that often these patients are prescribed exercise, typically walking, wherein they are instructed to walk until they are experiencing a moderate level of pain, stop and rest until the pain recedes and then repeat the process. They continue this until they have accomplished 20 to 30 minutes of walking, he says. Patients often see results after just a few months of following this regimen regularly.

But there are two main drawbacks to this method. Because the ischemia is happening, and the leg muscles are being deprived of oxygen, there can be muscle damage. And because the regimen does require the patient to walk to the point of moderate pain, those who would benefit most are less likely to adhere to the protocol, Gardner said.

To address these challenges, the research team will conduct a randomized controlled trial during which 100 patients – 20 per year for five years – will complete the program. Half of the participants, the control group, will follow the traditional ischemic exercise routine. The other half will be prescribed the non-ischemic, or pain-free, exercise plan.

Gardner explains it this way: This experimental group will be asked to walk slower and for shorter sessions – stopping before their leg muscles get ischemic and painful. A monitor on their calf during the walking sessions will measure the oxygen in the muscle.

For example, the control group may be walking at a leisurely two-miles-per-hour pace for perhaps four to five minutes when they reach moderate pain level and must stop for rest. Gardner’s experimental group will walk at a slower one-and-a-half miles per hour pace for merely a minute or two, stop to rest, then repeat.

“We're hypothesizing that, because we're eliminating, or at least decreasing, the pain, that there's going to be less inflammation and better microvascular circulation,” Gardner said.

After five years, they will compare the two groups with walking performance on a treadmill and measure their circulation along with any inflammation.

The value of this study is clear. It could change the whole approach of exercise training with PAD patients, says Gardner. Since it’s pain-free, they may like it better, which could cause better participation rates in these programs for PAD patients nationwide, he says.

“Because, as you can imagine, a lot of these patients have not exercised at all in their life and now they're 70 years old and they've got this problem, and now every time they walk, they hurt,” he says. Gardner hopes this pain-free exercise protocol could help change that dynamic for these patients. And he knows the value of exercise. His background is in exercise physiology, bringing more than 30 years of experience in the cardiovascular field.

But better participation rates aren’t the only thing Gardner hopes to achieve with this study.

“I'm very interested in physical activity throughout the day [for PAD patients],” he said. He plans to monitor patients’ daily activity levels both before and after study participation. The idea, says Gardner, is that if patients are seeing an improvement in walking without pain, that should translate into more activity throughout the day.

“So [study participants] are really becoming more active, which then has all sorts of benefits for them,” Gardner said.

About the research

Research reported in this press release is supported by the National Institute on Aging, a component of the National Institutes of Health, under the award number 1R01AG071778-01A1.

About the University of Oklahoma

Founded in 1890, the University of Oklahoma is a public research university located in Norman, Oklahoma. As the state’s flagship university, OU serves the educational, cultural, economic and health care needs of the state, region and nation. OU was named the state’s highest-ranking university in  U.S. News & World Report’s  most recent Best Colleges list .  For more information about the university, visit  ou.edu .

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Benefits of Physical Activity

Obesity and Excess Weight Increase Risk of Severe Illness; Racial and Ethnic Disparities Persist

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Immediate Benefits

Weight management, reduce your health risk, strengthen your bones and muscles, improve your ability to do daily activities and prevent falls, increase your chances of living longer, manage chronic health conditions & disabilities.

Regular physical activity is one of the most important things you can do for your health. Being physically active can improve your brain health , help manage weight , reduce the risk of disease , strengthen bones and muscles , and improve your ability to do everyday activities .

Adults who sit less and do any amount of moderate-to-vigorous physical activity gain some health benefits. Only a few lifestyle choices have as large an impact on your health as physical activity.

Everyone can experience the health benefits of physical activity – age, abilities, ethnicity, shape, or size do not matter.

Some benefits of physical activity on brain health [PDF-14.4MB] happen right after a session of moderate-to-vigorous physical activity. Benefits include improved thinking or cognition for children 6 to 13 years of age and reduced short-term feelings of anxiety for adults. Regular physical activity can help keep your thinking, learning, and judgment skills sharp as you age. It can also reduce your risk of depression and anxiety and help you sleep better.

Both eating patterns and physical activity routines play a critical role in weight management. You gain weight when you consume more calories through eating and drinking than the amount of calories you burn , including those burned during physical activity.

To maintain your weight:  Work your way up to 150 minutes a week of moderate physical activity, which could include dancing or yard work. You could achieve the goal of 150 minutes a week with 30 minutes a day, 5 days a week.

People vary greatly in how much physical activity they need for weight management. You may need to be more active than others to reach or maintain a healthy weight.

To lose weight and keep it off: You will need a high amount of physical activity unless you also adjust your eating patterns and reduce the amount of calories you’re eating and drinking. Getting to and staying at a healthy weight requires both regular physical activity and healthy eating.

See more information about:

• Getting started with weight loss .
• Getting started with physical activity .
• Improving your eating patterns .

Learn more about the health benefits of physical activity  for children, adults, and adults age 65 and older.

See these tips  on getting started.

The good news [PDF-14.5MB]  is that  moderate physical activity , such as brisk walking, is generally  safe for most people .

Cardiovascular Disease

Heart disease and stroke are two leading causes of death in the United States. Getting at least 150 minutes a week of moderate physical activity can put you at a lower risk for these diseases. You can reduce your risk even further with more physical activity. Regular physical activity can also lower your blood pressure and improve your cholesterol levels.

Type 2 Diabetes and Metabolic Syndrome

Regular physical activity can reduce your risk of developing type 2 diabetes  and metabolic syndrome. Metabolic syndrome is some combination of too much fat around the waist, high blood pressure, low high-density lipoproteins (HDL) cholesterol, high triglycerides, or high blood sugar. People start to see benefits at levels from physical activity even without meeting the recommendations for 150 minutes a week of moderate physical activity. Additional amounts of physical activity seem to lower risk even more.

Infectious Diseases

Physical activity may help reduce the risk of serious outcomes from infectious diseases, including COVID-19, the flu, and pneumonia. For example:

• People who do little or no physical activity are more likely to get very sick from COVID-19 than those who are physically active. A CDC systematic review [PDF-931KB] found that physical activity is associated with a decrease in COVID-19 hospitalizations and deaths, while inactivity increases that risk.
• People who are more active may be less likely to die from flu or pneumonia. A CDC study found that adults who meet the aerobic and muscle-strengthening physical activity guidelines are about half as likely to die from flu and pneumonia as adults who meet neither guideline.

Some Cancers

Being physically active lowers your risk for developing several common cancers .  Adults who participate in greater amounts of physical activity have reduced risks of developing cancers of the:

• Colon (proximal and distal)
• Endometrium
• Esophagus (adenocarcinoma)
• Stomach (cardia and non-cardia adenocarcinoma)

If you are a cancer survivor, getting regular physical activity  not only helps give you a better quality of life, but also improves your physical fitness.

Learn more about Physical Activity and Cancer

As you age, it’s important to protect your bones, joints, and muscles – they support your body and help you move. Keeping bones, joints, and muscles healthy can help ensure that you’re able to do your daily activities and be physically active.

Muscle-strengthening activities like lifting weights can help you increase or maintain your muscle mass and strength. This is important for older adults who experience reduced muscle mass and muscle strength with aging. Slowly increasing the amount of weight and number of repetitions you do as part of muscle strengthening activities will give you even more benefits, no matter your age.

Everyday activities include climbing stairs, grocery shopping, or playing with your grandchildren. Being unable to do everyday activities is called a functional limitation. Physically active middle-aged or older adults have a lower risk of functional limitations than people who are inactive.

For older adults, doing a variety of physical activity improves physical function and decreases the risk of falls or injury from a fall . Include physical activities such as aerobic, muscle strengthening, and balance training. Multicomponent physical activity can be done at home or in a community setting as part of a structured program.

Hip fracture is a serious health condition that can result from a fall. Breaking a hip have life-changing negative effects, especially if you’re an older adult. Physically active people have a lower risk of hip fracture than inactive people.

See physical activity recommendations for different groups, including:

• Children age 3-5 .
• Children and adolescents age 6-17 .
• Adults age 18-64 .
• Adults 65 and older .
• Adults with chronic health conditions and disabilities .
• Healthy pregnant and postpartum women .

An estimated 110,000 deaths  per year could be prevented if US adults ages 40 and older increased their moderate-to-vigorous physical activity by a small amount. Even 10 minutes more a day would make a difference.

Taking more steps a day also helps lower the risk of premature death from all causes. For adults younger than 60, the risk of premature death leveled off at about 8,000 to 10,000 steps per day. For adults 60 and older, the risk of premature death leveled off at about 6,000 to 8,000 steps per day.

Regular physical activity can help people manage existing chronic conditions and disabilities. For example, regular physical activity can:

• Reduce pain and improve function, mood, and quality of life for adults with arthritis.
• Help control blood sugar levels and lower risk of heart disease and nerve damage for people with type 2 diabetes.
• Health Benefits Associated with Physical Activity for People with Chronic Conditions and Disabilities [PDF-14.4MB]
• Key Recommendations for Adults with Chronic Conditions and Disabilities [PDF-14.4MB]

Active People, Healthy Nation SM is a CDC initiative to help people be more physically active.

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Home-Based Exercise Programs for the Oldest-Old to Attenuate Physical Frailty: A Scoping Review

• Published: 02 May 2024

Cite this article

• Bruna da Silva Capanema 1 ,
• F. Fank 1 ,
• M. C. Machado Trento 1 ,
• D. Lima Costa 1 ,
• A. R. Amaral da Rocha 1 &
• G. Zarpellon Mazo 1  

With the significant increase in the number of long-lived elderly people living at home, the development of effective physical exercise interventions at home becomes essential to preserve their independence and delay institutionalization and hospitalizations.

to map and describe home exercise programs for elderly people aged 80 or over with physical frailty.

The scoping review allowed the inclusion of several methodologies and varied perspectives, maintaining rigor in accordance with the methodological steps of the Joanna Briggs Institute (JBI). The systematic search covered studies available until May 2023 in five databases and gray literature. Frailty was assessed according to the criteria of Fried et al. (2001), physical performance scale (SPPB), such as gait and mobility, and the authors’ assessment of reduced physical function were considered. The study followed the PRISMA Extension for Scoping Reviews (PRISMA-ScR) guidelines and is publicly available in the Open Science Framework (OSF) repository.

Twenty studies were identified that met the inclusion criteria. The total number of elderly people investigated in the study was 1,796. The most important physical interventions were muscular strength training, mainly of the lower limbs, together with flexibility, balance, aerobic and functional training. These home interventions have demonstrated potential, safety and effectiveness in preventing and alleviating physical frailty. These home interventions demonstrated potential, safety and effectiveness in preventing and alleviating physical frailty, adherence in most studies varied between 72% and 89%.

This study will allow us to design home-based exercise interventions, potentially providing practical solutions and assisting healthcare professionals in home-based interventions to reduce and mitigate physical frailty in the growing population of older adults. It will also help fill the existing knowledge gap and provide recommendations for future research.

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Funding: This work was supported by National Council for Scientific and Technological Development (CNPq, Brazil), Coordination for the Improvement of Higher Education Personnel (CAPES, Brazil) and UNIEDU - program in the State of Santa Catarina run by the State Department of Education (SED).

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Contribution declarations: All authors contributed to the conception and design of the study. The preparation of the material, data collection and analysis were carried out by Bruna Capanema, Felipe Fank, Maria C. Trento, Damiana Costa and Ana Rocha. The first draft of manuscript was written by Bruna Capanema. All authors commented on previous versions of the manuscript. All authors read and approved the final text manuscript.

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da Silva Capanema, B., Fank, F., Machado Trento, M.C. et al. Home-Based Exercise Programs for the Oldest-Old to Attenuate Physical Frailty: A Scoping Review. J Frailty Aging (2024). https://doi.org/10.14283/jfa.2024.41

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DOI : https://doi.org/10.14283/jfa.2024.41

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Changes in physical activity in people with idiopathic pulmonary fibrosis before and after virtual pulmonary rehabilitation: a feasibility study

• Orlagh O’Shea 1 ,
• Grainne Murphy 2 ,
• Lynn Fox 3 &
• Katherine M.A. O’Reilly 3 , 4  

BMC Pulmonary Medicine volume  24 , Article number:  215 ( 2024 ) Cite this article

Metrics details

Pulmonary rehabilitation (PR) is recommended for the treatment of people with idiopathic pulmonary fibrosis (IPF). Physical activity is an important health behaviour, closely linked to survival in people with IPF. Little is known about the impact of virtual (V) PR on physical activity in people with IPF.

To explore the feasibility of conducting a trial to explore effect of virtual PR on objectively measured physical activity in people with IPF.

All patients with a diagnosis of IPF in a stable phase of the disease were invited to participate in VPR: a 10 week exercise programme delivered twice-weekly for one hour. Data were collected at baseline (BL) and post VPR (10 weeks): Kings Brief Interstitial Lung Disease (K-BILD), Exercise capacity (6-minute walk test (6MWT) or 1-minute sit-to-stand (STS)) and Physical Activity. Physical activity was measured with a triaxial accelerometer for seven days. Screening, recruitment, adherence and safety data were collected.

68 people were screened for this study. N  = 16 participants were recruited to the study. There was one dropout. N  = 15 completed VPR. All results reported in mean (standard deviation) (SD). Participants attended 18.1(2.0) of the 20 sessions. No adverse events were detected. The mean age of participants was 71.5(11.5) years, range: 47–95 years; 7 M:9 F. Mean (SD) FEV 1 2.3(0.3)L, FVC 2.8(0.7)L. No statistically significant changes were observed in outcome measures apart from exercise capacity. Light physical activity increased from 152(69.4) minutes per day ( n  = 16) to 161.9(88.7) minutes per day ( n  = 14), mean change (SD) (CI) p-value : 9.9 (39.8) [-12.3 to 30.9] p =  0.4. Moderate-to-vigorous physical activity increased from 19.1(18.6) minutes per day ( n  = 16) to 25.7(28.3) minutes per day ( n  = 14), mean change (SD) (CI) p-value : 6.7 (15.5) [-2.1 to 15.1] p  = 0.1. Step count increased from 3838(2847) steps per day ( n  = 16) to 4537(3748) steps per day ( n  = 14), mean change (SD) (CI) p-value : 738 (1916) [-419.3 to 1734.6] p  = 0.2. K-BILD ( n  = 15) increased from 55.1(7.4) at BL to 55.7(7.9) post VPR mean change (SD) [95% confidence interval] (CI) p-value : 1.7(6.5) [-1.7 to 5.3], p  = 0.3. 6MWT ( n  = 5) increased from 361.5(127.1) to 452.2(136.1) meters, mean change (SD) (CI) p-value : 63.7 (48.2) [-3.8 to 123.6], p  = 0.04 and 1-minute STS increased from 17.6(3.0) ( n  = 11) to 23.7(6.3) ( n  = 10), mean change (SD) (CI) p - value 5.8 (4.6) [2.6 to 9.1], p  = 0.003.

VPR can improve physical activity in people with IPF. A number of important feasibility issues included recruitment, retention, adherence and safety have been reported which are crucial for future research in this area. A fully powered trial is needed to determine the response of people with IPF to PR with regard to physical activity.

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Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive lung disease of unknown aetiology that is associated with significant morbidity and mortality [ 1 ]. IPF is characterised by progressive scarring of the lung parenchyma leading to distorted lung architecture and progressive deterioration of lung function and impaired gas exchange. Patients experience increasing dyspnoea and frequently develop hypoxemia [ 2 , 3 ]. Consequently, people with IPF reduce their levels of physical activity [ 4 ]. Lower levels of physical activity are associated with worse physiological function [ 5 ]. In general low levels of physical activity are detrimental to individuals’ health, leading to muscle wasting and fatigue [ 6 ], ultimately leading to a significantly worse survival for people with IPF [ 5 ].

Pulmonary rehabilitation (PR) is a non-pharmacological exercise and education based programme recommended for people with IPF both nationally in Ireland and internationally [ 7 , 8 ]. PR can increase exercise capacity and HRQoL in people with IPF [ 9 ] and Cox et al. reported that virtual PR (VPR) can achieve outcomes similar to those of traditional centre-based PR, with no safety issues [ 10 ]. However, the review by Cox et al. is limited with regard to evidence for IPF, the studies included in this review only involved patients with COPD [ 10 ]. There is therefore a limited evidence based for VPR for people with IPF. Furthermore, the impact of PR on physical activity in people with IPF is not well documented. Only two studies have explored changes in physical activity following PR specifically in people with IPF [ 11 , 12 ]. However, both these studies used self-report measures of physical activity [ 11 , 12 ]. Self-report measures of physical activity have been reported to have multiple sources of error, including recall bias and an caution is advised when using self-report measures to evaluate an intervention [ 13 , 14 ]. Ng et al. conducted a systematic review on changes in physical activity following exercise interventions in COPD [ 15 ]. This review recommended that all future studies employ triaxial accelerometry to accurately assess the impact of exercise interventions on physical activity levels [ 15 ]. To the authors’ knowledge to date no study has explored the impact of VPR on physical activity as measured with a trixial accelerometer in people with IPF. Therefore, the aim of this study is to explore the feasibility of conducting a trial to explore effect of VPR on objectively measured physical activity in people with IPF.

This reporting of this feasibility study follows the CONSORT 2010 statement: extension to randomised pilot and feasibility trials [ 16 ] with further guidance from Lancaster and Thabane 2019 [ 17 ]. Ethical approval was obtained from the Mater Misericordiae University Hospital, Research Ethics Committee. Institutional review board reference: 1/378/2111.

Participant recruitment

We aimed to recruit 30 individuals to this feasibility trial [ 18 ]. All individuals with IPF who were referred to PR were screened for eligibility by the author GM. Those meeting the inclusion criteria for PR: functionally limited by breathlessness and in stable phase of IPF were invited to participate by GM during a telephone consultation. A stable phase of IPF was defined as patients who do not have rapidly escalating symptoms or rapidly increasing oxygen needs. Patients needed to provide their own device (e.g. tablet or laptop) and internet access to participate in the programme. Unfortunately, due to a lack funding we were not able to provide participants with devices or internet access to enable participation. Written informed consent was obtained by post. Patients referred for palliative care were excluded from the programme as patients currently under the care of palliative care have access to a dedicated PR programme run within the hospice and support from hospice based physiotherapy. Those wishing to participate in the VPR but not research aspect were not excluded from the programme.

Intervention - pulmonary rehabilitation

All participants underwent a 10 week VPR programme. There was no in-person PR being delivered at this time due to the COVID-19 pandemic. The VPR was delivered by a senior physiotherapist (GM) with 27 years experience as a senior respiratory physiotherapist delivering PR programmes. This programme was specifically designed for people with interstitial lung diseases (ILD) including IPF. The programme consisted of twice-weekly, one hour group exercise classes for 10 weeks. There was a maximum of six participants in a group. The programme was delivered via the Salaso platform (Salaso Health Solutions, Ireland). Salaso is a video conferencing platform similar to Zoom.

The VPR exercise classes participants completed in a series of exercises including a warm up, upper and lower limb strengthening exercises (e.g. squats, shoulder press) and aerobic exercises (e.g. marching on the spot, heel taps). The participants participated in interval based training whereby the exercised for one minute and then had a 30 s rest period. Over the course of the 10 weeks this one minute was gradually increased to 1.5 min of exercise, the rest period remained the same. Participants were advised to exercise at an intensity of BORG 4 during this period. Individual progressions were made whereby participants progressed to using weights when they felt able. These weights which were obtained by participants themselves, they either acquired dumbbells or used household items (e.g. a 500 ml bottle of water or a tin of beans). No further equipment was used during the exercise classes. Furthermore participants could progress individually by increasing the number of repetitions they were completing during the time for exercise. Oxygen saturations, heart rate and BORG are documented at the beginning of the class. They were reassessed at the end of every bout of exercise participants’ oxygen saturation, heart rate and exertion level. Furthermore, prior to participation all participants had to provide an emergency contact of an individual who would be readily available in the event of an adverse event as safety measure.

Two formal education sessions (45 min in duration) were delivered: the benefits of exercise (including a home exercise programme) and Conservation of Energy. Breathing control methods were taught throughout each class and relaxation was performed at the end of each class. Individual consultations with the facilitator were facilitated on an informal basis before or after the class at the request of participants.

Data collection

Demographic data including age, gender and pulmonary function tests (FEV 1 , (forced expiratory volume in the first second) FVC, (forced vital capacity) TLCO (transfer capacity of lung for carbon monoxide) were collected at baseline. Health related quality of life (HRQoL), exercise capacity tests and physical activity measurements were collected at baseline and post intervention. Adherence to PR was also recorded.

HRQoL was measured using The Kings Brief Interstitial Lung Disease (K-BILD). K-BILD is a health status questionnaire developed and validated specifically for patients with ILD [ 19 ]. The K-BILD contains 15 items that measures health status in three domains: (1) psychological, (2) breathlessness and activities and (3) chest symptoms. The K-BILD is scored on a scale of 0-100, with 100 representing the best possible health. The minimal clinical important difference for the K-BILD is 3.9 points [ 19 ]. The MCID estimates for KBILD-Psychological, KBILD-Breathlessness and activities, and K-BILD Chest symptoms were 5.4, 4.4 and 9.8 points, respectively [ 20 ].

Exercise capacity: due to COVID-19 related restrictions at various times throughout the study period, different exercise capacity tests were used. Details of the COVID-19 restrictions throughout the study period are summarised in the e-supplement. Including the 6 min walk test (6MWT) [ 21 ] which was conducted in person or the 1-minute sit-to-stand (STS) conducted remotely [ 22 , 23 ]. For the one-minute STS participants were instructed to use a stable kitchen or dining room chair.

Physical activity was measured using a triaxial accelerometer (Actigraph gt3x) (Actigraph LLC; Pensacola, FL) which was worn around the waist for seven consecutive days during waking hours. Participants wore the Actigraph before commencing PR and within one week of finishing PR. Further details regarding the how the Actigraph was worn are available in Table  1 .

Data analysis

The Actigraph data were analysed in Actilife version 6. See Table  1 Actigraph data reporting checklist [ 24 ]. All data were entered in STATA (StataCorp, United States of America) 17.0 and analysed for descriptive statistics. Data were tested for normality and paired student t test were performed to explore changes.

Participants

Sixty-eight participants were referred to the programme over a 33 month study period (August 2020-April 2022). The mean (standard deviation) (SD) age of participants was 71.5 (11.5) years, range: 47–95 years. There were seven male and nine female participants in this study. Four participants were home oxygen users ( n  = 1 on 4 L/min, n  = 2 on 6 L/min and n  = 1 on 10 L/min). Ten participants were on oral antifibrotic medications. Full demographic details are available in Table  2 . Since completion of the study five participants have died, these participants died between 1 and 22 months after finishing the programme, a mean survival time of 12 months was observed for these participants.

Feasibility Data

Sixteen were recruited, see Fig.  1 for full screening details. Fifteen participants completed the VPR, n  = 1 dropped out as they experienced an acute worsening of their disease. We were unable to collect post PR physical activity outcomes for one participant due to COVID-19 related complications. The mean (SD) adherence to the programme was 18.1 (2.0) classes. All participants, had >/ 80% adherence except for one participant who only adhered to 65% of classes due to illness. No adverse events were reported.

CONSORT flow diagram

HRQol and Exercse Capacity

Results for HRQoL and exercise capacity are available in Table  3 .

• Physical activity

All participants met the wear time data rules of a minimum of ten hours on five days. The mean (SD) wear time across all the data was 831 (76) minutes over a mean of 7 (0.4) days.

Light physical activity increased from mean (SD) 152 (69.4) minutes per day at baseline to 161.9 (88.7) minutes post VPR (mean (SD) difference 9.9 (38.8) minutes per day. Light physical activity is defined as any activity between > 1.5–3 metabolic equivalents (METS). Moderate to vigorous physical activity (MVPA) increased from mean (SD) 19.1 (18.6) minutes per day to 25.7 (28.3) minutes post VPR (mean (SD) difference 6.7 (15.5) minutes per day. Moderate physical activity is defined as any activity > 3 METS. Step count increased from mean (SD) 3838 (2847) steps per day at baseline to 4576 (3748) steps post VPR per day (mean (SD) difference 738 (1916) steps). None of these improvements in physical activity were statistically significant. Table  3 for details on mean difference, 95% confidence intervals and p-values. Figures  2 , 3 and 4 demonstrate the variations across individual changes in physical activity with SD error bars included in the line graphs.

Changes in minutes of mean daily light physical activity (1.6–2.9 METS) with standard error bars * VPR = virtual pulmonary rehabilitation

Changes in minutes mean daily moderate to vigorous physical activity (3 ->6 METS) with standard error bars * VPR = virtual pulmonary rehabilitation

Changes in mean daily step count with standard error bars * VPR = virtual pulmonary rehabilitation

The aim of this study to explore the feasibility of conducting a trial to explore effectiveness of VPR on objectively measured physical activity in people with IPF was achieved. We observed changes in physical activity among participants; unsurprisingly these were highly variable given the heterogeneity of the population. There are a number of important considerations in terms of recruitment and outcome measures to assess HRQoL in a future trial.

Importantly, participants in the current study demonstrated improvements in physical activity including daily step count and light physical activity despite the serious and progressive nature of their disease. There is little available literature on the amount and intensity of physical activity, for people with IPF; Hur et al. 2019 reported a minimal important difference (MID) of 12–69 min per week for MVPA, this was calculated over a six-month period with no intervention [ 25 ]. We observed an improvement of 47 min of MVPA per week which is line with this MID. There is no available guidance for light physical activity, there are only two studies to our knowledge that have reported on light PA levels in people with IPF [ 2 , 26 ]. This is interesting given that there has been a shift in current literature towards promoting light physical activity in those with chronic respiratory disease [ 27 ]. We observed a mean increase of 10 min of light PA. It is unclear what the potential clinical impact of this is in an IPF population. Driver et al. have reported that an increase of 22 min of light physical activity per day can improve symptoms in those with COPD [ 27 ]. Furthermore, we observed a mean increase of 738 steps per day. Again, while we don’t have evidence to judge the potential impact of this improvement for people with IPF it is encouraging to see increased activity levels in this cohort with a progressive life limiting condition. More research exploring the impact of changes in physical activity on clinical outcomes in IPF is needed.

The recruitment rate for the IPF population in this study was 34%. This appears to be line with other research for PR in people with IPF (32–35%) [ 28 , 29 ], however, the numbers screened and the reasons for non-participation are not fully detailed in these published works [ 30 , 31 , 32 ]. The primary reason for patients declining VPR in our study was lack of IT support. Despite this, those who did participate reported few problems with the technology aspect of the rehabilitation and any problems were quickly resolved [ 33 ]. The World Health Organisation expects digital technology to create a more equitable future for healthcare [ 34 ]; researchers, clinicians and policy makers should therefore strive to enable those who currently cannot access programmes due to lack of IT support. Finally, the results of this feasibility study enabled us to calculate a sample size for a fully powered trial to detect changes in physical activity before and after PR. Depending on the physical activity variable employed (light physical activity /step count/MVPA) a sample size is 22 (MVPA), 149 (light) or 1379 (step count) is required. The large standard deviations and wide confidence intervals in our results are noteworthy demonstrating the heterogeneous nature of our sample, which is reflected in the disease severity of participants. Strategies to enhance recruitment for a fully powered trial to explore changes in physical activity following PR in people with IPF would be needed for example offering a choice between remote and in-person rehabilitation and additional delivery sites. We observed no adverse events and high retention (94%) and adherence rate (90%).

We observed a small improvement in HRQoL. However, this improvement was only attributed to changes the psychological domain of the K-BILD, but did not meet the MCID for this domain [ 20 ]. The improvement in the psychological domain in the current study was reflected in the qualitative arm of this study where all participants expressed high levels of enjoyment and satisfaction with the programme despite some people experiencing a physical decline [ 33 ]. It is not clear if the K-BILD is the best tool to assess changes in HRQoL before and after PR, none of the studies included in the Cochrane review by Dowman et al. [ 9 ] used the K-BILD to measure changes in HRQoL. Future research should explore the sensitivity and responsiveness of the available measures of HRQoL measures in people with IPF before and after PR.

This novel research reports on objectively measured changes in physical activity in people with IPF following VPR. We have completed a checklist (Table  1 ) recently published by Iwakura et al., to promote higher standards of reporting with regard to accelerometer measured physical activity in people with IPF [ 24 ]. While this research provided us with a number of important insights into this population it is not without its limitations. We did not reach our target of 30 participants, it is not clear what impact this had on our findings, nonetheless important feasibility data relating to recruitment, retention, adherence and safety were gathered. This study was conducted during the COVID-19 pandemic, research has indicated reduced physical activity levels across populations during this time [ 35 ] and some participants in the current study also reported that reduced activity in the qualitative arm of the study [ 33 ]. It is therefore not clear if changes in physical activity would be different if data were collected under normal conditions. Furthermore, due to the COVID-19 restrictions two different measures of exercise capacity were employed in the current study, given the small sample size we are unable to discuss changes in exercise capacity in the context of the wider literature. There was also a lack of standardisation across the one-minute STS as participants were not instructed to use a standard chair height. Lastly, this study lacked both a control group in terms of individuals who did not receive VPR and a comparison against traditional centre based PR, future research should explore this.

Data availability

Data are available on reasonable request from the corresponding author.

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OOS, GM, LF and KOR contributed to the development of the study. OOS, GM, KOR, and LF contributed to the planning of the analyses. OOS, LF and KOR contributed to the conduct of the analyses and interpretation of the data. OOS wrote the main manuscript and prepared the tables and figures. All authors reviewed the paper.

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O’Shea, O., Murphy, G., Fox, L. et al. Changes in physical activity in people with idiopathic pulmonary fibrosis before and after virtual pulmonary rehabilitation: a feasibility study. BMC Pulm Med 24 , 215 (2024). https://doi.org/10.1186/s12890-024-03030-9

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New Study Finds Physical Fitness Can Improve Mental Health in Children and Young Adults

Researchers in Taiwan tracked children's performance in sporting activities like running, sit-ups and jumping to study how it impacted their mental health diagnoses over time

Charlotte Phillipp is a Weekend Writer-Reporter at PEOPLE. She has been working at PEOPLE since 2024, and was previously an entertainment reporter at The Messenger.

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A new study out of Taiwan has found that children and adolescents who are more physically active have lower rates of mental health disorders .

The study, published in the journal JAMA Pediatrics on Monday, April 29, used anonymous data from the Taiwan National Student Fitness Tests, which measures students' physical fitness activities in school, and compared it with the National Insurance Research Databases, which compiles information about patients' diagnosis and other medical information.

Using data spanning back to 2009 and ending in 2019, researchers studied the data of students aged 10 to 11 years old, following up for at least 3 years to see the progression of their physical fitness in school compared to their mental health diagnosis, especially concerning anxiety disorders, depressive disorders and ADHD/ADD.

The study split the types of physical fitness into several groups, These included cardio fitness, which was measured by each student's performance in an 800-meter (about one mile) run, muscular endurance, measured by how many sit-ups a student could do, muscular power, measured by how far each student's standing jump was, and flexibility, measured by a sit-and-reach test.

A decreased risk of mental health was linked to better performance in each one of the types of fitness, the study found. Cardio fitness — marked by a 30-second faster half-mile — was associated with lower risks of anxiety, depression and ADHD in female students, and lower risks of anxiety and ADHD in male students.

Better muscular endurance, quantified by the study as 5 more sit-ups per minute, was linked to a lower risk of depression and ADHD in girls as well as lower anxiety and ADHD risks in boys. Better muscular performance, meaning almost 8-inch longer standing jumps was associated with lower risks of anxiety and ADHD in girls and reduced anxiety, depression and ADHD in boys.

Researchers also found better performance in each of the fitness activities could be "dose-dependent," meaning that fitness could serve as a preventative measure for mental health disorders.

"This study highlights the potential protective role of cardiorespiratory fitness, muscular endurance and muscular power in preventing the onset of mental disorders," researchers wrote in the study.

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Exercise and mental health and long been linked by scientists, with many experts advocating for kids to become physically active in the wake of the COVID-19 pandemic.

"Physical activity has a small but significant effect on the mental health of children and adolescents ages 6 to 18," the American Psychological Association wrote in April 2020, citing other research that also linked children's long-term mental health to exercise.

"The finding underscores the need for further research into targeted physical fitness programs," the study's authors wrote, noting that these programs could "hold significant potential as primary preventative interventions against mental disorders in children and adolescents."

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