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Introduction
Impaired cognition and mobility are common in older adults and they often coexist due to shared pathophysiology.1 Worldwide, one new case of dementia is detected every 3 s.2 Exercise improves cognitive function and reduces the risk of mobility disability and falls.3–5
Leaders in physical activity and exercise research are aiming to delineate what (e.g., type, duration, frequency and intensity) exercise should be recommended and when (e.g., midlife versus late life) it is best done for promoting cognitive and mobility outcomes in healthy individuals and in those at risk for cognitive impairment. Two other key questions are how (e.g., neurotrophic factors, cardiovascular fitness) and for whom (e.g., biological sex, gender) does exercise benefit cognition and mobility. Understanding mediators (i.e., how) could help maximise gains by enhancing intervention elements that impact key mechanisms at lower cost and/or risk. Identifying moderators (e.g., who, when)—factors that either attenuate or amplify the effects of exercise—will enable precise recommendations for individuals with similar characteristics (i.e., subgroups).
In this two-part editorial series, we focus on for whom factors that may moderate the effect of exercise on cognitive function and mobility outcomes. In Part 1, we focus on biological sex and gender. Biological sex is defined as the genetics, gonadal hormones and phenotype resulting from XX versus XY chromosomes. Gender refers to the social, environmental, cultural and behavioural factors that influence individual actions and experiences. In Part 2, we will discuss the impact of pre-existing physical and cognitive health as well as genetic polymorphisms.
Biological sex
Underlying biological differences between females and males are associated with differences in age-related physiological changes, disease risk and health outcomes. Males may be more likely to develop mild cognitive impairment (MCI) but females seem to progress faster from MCI to Alzheimer’s disease dependent on APOE4 genotype.6 7 Mobility disability is more prevalent among older females than males.8
Females and males have different physiological responses to exercise. Females exhibit greater relative muscle fatigue resistance than males due to a combination of sex differences in muscle mass, substrate utilisation and muscle morphology.9 Males possess a larger aerobic capacity than females;10 females have greater pulmonary vascular compliance during maximal exercise testing.11 Thus, specific forms of exercise at the same intensity and dose may have different impacts on males versus females due to different physiological responses.
Evidence supports the notion of biological sex moderating the efficacy of exercise to promote brain health and mobility. Colcombe and Kramer12 first suggested a sex difference favouring females in the magnitude of gains in executive functions, a set of higher order cognitive processes required for the planning, control and coordination of complex goal-directed behaviour, from aerobic exercise interventions. This greater effect of aerobic exercise in females may be independent of gains in cardiovascular capacity,13 though further research is required. The results of a meta-analysis by Barha and colleagues14 support and extend this proposition. However, in another meta-analysis, sex did not moderate the effects of exercise training on cognitive function.15 It is important to highlight that neither human meta-analysis had the capacity to report data disaggregated by sex—a key limitation that needs to be addressed by future research.
Exercise is an effective primary and secondary fall prevention strategy in older adults.4 16 However, whether there are sex differences in the magnitude of benefit from these exercise strategies for falls prevention has yet to be directly examined. Future research is also needed to better understand sex differences in the risk and management of impaired mobility and falls; it is a largely unexplored research area.
Research is also needed to determine whether sex differences in exercise efficacy are consistent across adulthood. Implementing exercise interventions during midlife may be of utmost importance for females for cognitive and mobility outcomes. The menopause transition (MT) negatively impacts multiple systems in the body. Notably, the MT, through loss of estradiol, significantly impacts the female brain and is proposed to be a key contributor to a female’s greater lifetime risk for dementia.17 The MT is also associated with skeletal muscle and bone losses; the endocrine changes during MT predispose women to sarcopaenia and osteoporosis and consequently, to mobility disability and fall-related fractures in later life.18
Gender
Gender may moderate the impact of exercise on both risk and health outcomes. Many of us exercise in social environments. Gender differences exist in the benefits of social interactions, with women benefitting more than men.19 Men are more active than women across the lifespan;20 the degree exercise training impacts cognitive and physical health may be in part due to systemic, societal issues in how physical activity is promoted from early childhood onward. Thus, it is of considerable importance for research to continue to address how both biological sex and gender moderate the efficacy of exercise training on cognitive function and mobility.
Conclusion and future directions
Thus far, a large portion of the evidence for the role of sex and gender in the effects of exercise on healthy ageing comes from observational studies. Researchers need to conduct randomised controlled trials designed to specifically examine the moderator of interest, rather than rely on posthoc analyses, which are not definitive because statistical power is lacking. These randomised controlled trials will be challenging as they will require equal representation of the moderator. For example, if we want to specifically examine the moderating effect of biological sex, it will require equal recruitment of females and males. While it is clear that a precision medicine approach will greatly advance the field of exercise in healthy ageing, currently we lack the prerequisite knowledge to provide evidence-based, personalised exercise recommendations tailored to individual characteristics.
Acknowledgments
We thank all the workshop delegates for their participation and discussion.
References
Footnotes
Twitter @dr_cindy_b, @STSkou, @UBC_CogMobLab
Contributors All authors contributed to the conception and design on this paper. TLA, CKB and RSF drafted the work and STS provided substantial feedback on content and edits. All authors approve the final version.
Funding Canadian Institutes of Health Research (MOP-142206 and PJT-148902) to TLA. STS is currently funded by a grant from Region Zealand (Exercise First) and a grant from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (grant agreement no. 801790). TLA is a Canada Research Chair in Physical Activity, Mobility and Cognitive Neuroscience. CKB is an Alzheimer Association of USA and Brain Canada Postdoctoral Fellow. Content for this commentary was in part generated from a workshop (May 2019) hosted by the Physical Activity for Precision Health (PA4PH) Research Cluster (https://activehealth.ubc.ca/), University of British Columbia, Vancouver, BC, Canada. STS is associate editor of Journal of Orthopaedic & Sports Physical Therapy, he has received grants from The Lundbeck Foundation, personal fees from Munksgaard, all outside the submitted work. He is cofounder of Good Life with Osteoarthritis in Denmark (GLA:D), a not-for profit initiative hosted by the University of Southern Denmark aimed at implementing clinical guidelines for osteoarthritis in clinical practice.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.