Movement as Brain Medicine
Benefits of Exercise for the Ageing Brain
Written by: Alexandra Kifak, BSc.
Reviewed and edited by: Tammy Strickland, BSc, MSc.
Focus Paper: https://doi.org/10.1113/JP282894
Epidemiology of Neurodegenerative Diseases and Promising Benefits of Exercise
Far more often than I would like to admit, I hear stories about how loved-ones are devastatingly affected by dementia. Friends and colleagues of mine describe how their once active and attentive grandparents have become frail, frightened and no longer remember family members. Ageing-related brain disorders with an associated cognitive decline have unfortunately become increasingly common in recent years. Shockingly, recent statistics report that 1 in 5 adults aged 65 or above are troubled with Alzheimer’s disease (AD), Parkinson’s disease (PD), or other forms of dementia (1).
What goes on inside of the brain of a person with dementia? Moreover, what specifically causes their progressive forgetfulness? Simply put, most dementias are the result of neurodegeneration and its bedfellow, neuroinflammation. Neurodegeneration quite literally translates as the progressive damage and eventual death of the electrical cells (i.e. neurons) that make us who we are. Neuroinflammation on the other hand, is a complex and diverse group of reactions mediated by the brains non-electrical cells. It is a vicious cycle in that it is simultaneously a response to and a major mediator of neuron damage. In the context of unrestrained neurodegeneration and neuroinflammation, it becomes clear how the brain can become overwhelmed and sick (2).
Scientists have made immense leaps in unraveling the biochemical mechanisms behind neurodegeneration and neuroinflammation in the last 30 years. Despite this, currently available drugs are only directed towards disease management and slowing down symptom progression. Crucially though, they are not a cure. Therefore, a conversation on the imminent need for prevention of excessive neurodegeneration and neuroinflammation in old age arises. The biological benefits of exercise for brain health is a booming area of research. Critically, a more detailed understanding as to why different types of exercise are useful in various disease models is being garnered and the findings translated to humans (3).
This article will outline the main takeaways from a 2022 review by Zsuzsanna Barad, Joana Augusto, and Áine M. Kelly published in the Journal of Physiology (3). The aim of the paper is to decipher the most effective exercise approaches to reduce neurodegeneration across the lifespan and especially in the ageing brain.
Groundskeepers of the Brain: A Collaboration of Many Cellular Players
The central nervous system (CNS) comprises the brain and spinal cord, both of which have a unique and persistent set of chemical and physical conditions. This so-called ‘homeostasis’ relies on the regulated and integrated functioning of many different cell types. Neurons are the main electrical thought processors, while glia (previously considered as inactive brain ‘glue’) look after everything else. Glia are essential for CNS maintenance and consist of microglia (i.e. the brain’s resident immune cells), astrocytes (i.e. metabolic and growth support cells), oligodendrocytes (i.e. electrical insulators), modified endothelial cells (i.e. protective blood vessel components) and ependyma (i.e. cells that produce a nutritious fluid that surrounds and washes through the CNS organs). In the aforementioned review piece, the authors focus most particularly on the beneficial effects of exercise on the brain-resident immune system and on astrocytes.
‘Inflammaging’: Chronic Inflammation in an Ageing Brain
As in many other organs, the CNS experiences and responds to internal and external dangers, such as pathogens, toxins or damaged cells. The immune system (both innate and adaptive arms) directs appropriate responses to specific threats. A myriad of specialized immune cells communicate with each other and with other cells via messenger molecules called “cytokines”. Cytokines are the core messengers of both CNS inflammation (neuroinflammation) and inflammation in the rest of the body. Waves of cytokines, in this case predominantly produced by microglia, provide necessary immune responses to stop an infection or other issue in it’s tracks. Additionally, cytokine signals help neurons to regenerate, develop and regulate new neuronal pathways.
Sometimes, although well intentioned, the CNS immune system can go into overdrive and induce an excessive inflammatory response that is, in fact, harmful to our nervous system. Unrestrained neuroinflammation in many instances leads to neurodegeneration and is regarded as a major driver of neurological diseases including (but not limited to) dementias, seizures and movement disorders. Interestingly, ageing (i.e. the progressive biological changes that develop naturally with time) is associated with chronic low-grade inflammation. Now referred to by experts in the field as ‘inflammaging’, this chronic phenomenon appears to be part of normal ageing process somewhat. When it is severe or excessive however, it can manifest into the pathologies mentioned above.
Figure 1: Inflammaging in an Ageing Brain. Diagram depicting the effect of sedentary lifestyle on the brain cell health during ageing. Overreactive astrocytes and microglial release excessive pro-inflammatory cytokines which cause neuron cells to break down. This neurodegeneration may cause impaired cognitive function and development of brain diseases in older age. Created with BioRender by Alexandra Kifak.
No Homeostasis without Physical Activity: Trick of a Modern Sedentary Lifestyle
From an evolutionary standpoint, physical activity was crucial to our survival. Our shared ancestors needed to hunt the mammoth, run from tigers and migrate astounding distances by foot. Therefore, movement is essential to who we are. The modern habit of being seated all day, which is referred to as a “sedentary lifestyle” disrupts our body’s homeostatic balance, accelerating inflammation in the brain. In addition, these behaviors lead to the development of “sleeping” immune cells that lose their ability to divide and function coherently. Research has shown that repeated and structured physical activity, especially endurance running, combats disease-causing disequilibrium. Trading in static habits for more movement-centric behaviors restores homeostatic regulation in many organs, including the brain and its resident immune system (4).
To Live is to Keep Moving: How the Brain Benefits from Exercise
Good news: your exercise routine does not have to match that of a professional athlete for you to reap the health benefits in older age. While lifelong regular physical activity seems to be necessary for a healthy and functional CNS, research suggests that even short-term exercise protocols implemented in later life results in improved memory, movement and increased emotional resilience, with reduced reports of depression and anxiety (3). Treadmill running is widely studied in rodents with age-related neurodegeneration. It turns out that even 30 minutes of low-intensity daily running for two weeks can induce beneficial brain changes in mice and rats. Some exercise is better than none, and often, the more the better. A large body of literature suggests that regular long-term endurance running compounds the positive effects over time, resulting in reversal of neuroinflammation, improved clearance of toxic protein aggregates, and even memory improvement in mice (5). While a pre-disease healthy state is unlikely to be restored fully, exercise can help our brains adapt to their new internal environment (6, 7).
Interestingly, human studies in the elderly link regular exercise to increased cognitive resilience and reduced microglia-driven inflammaging (8). It appears that the brains of seniors who exercise regularly are protected from disease compared to their most sedentary, age-matched counterparts. Mechanistically speaking, research has shown that molecules produced by the muscles during physical activity, such as irisin, reduce exaggerated microglial activation and prevented neurodegeneration (9). Exercise appears to foster the development of “neuroprotective” microglial states, which in turn guard neurons from damage and death (10). Moreover, while normally astrocytes inhabit neuroprotective archetype in their management of brain metabolism, they can at times become overactive, just like microglia. Overstimulated astrocytes can exert toxic effects on neurons, worsening neurodegeneration with age. Exercise promotes “metabolic reprogramming” of both microglia and astrocytes, which instructs them to start preserving neuronal health instead of mistakenly destroying it.
Figure 2: Beneficial Effects of Exercise on Ageing Brain. Diagram represents how exercise in older age can promote healthy brain cell homeostasis. Astrocytes and microglia release anti-inflammatory cytokines which regenerate neurons, grow new neuronal connections, improve cognition, clear out toxins from the brain and result in overall improved function of Nervous System. Created with BioRender by Alexandra Kifak.
Sex Matters: A Need for More Female Representation in Studies
A key limitation of the current review article is that it analyses the results of rodent studies that are largely focusing on male animal behavior. Fluctuations of female hormones throughout the month and dramatic changes occurring following the menopause significantly influence the effects of physical activity on women’s bodies. Furthermore, women are twice as likely as men to develop AD in older age and are therefore key stakeholders for society wide interventions (11). The scientific community needs to focus on developing more representative study designs in order to address this shocking difference between the sexes. The results of more inclusive studies could potentially inform more stratified, sex-specific exercise protocols for maximum neurological benefits.
Future Directions: Ageing Community Interventions & Preventative Medicine
Taking all of these findings together, it is clear that exercise is worth our attention. Thankfully, community-based physical activity programmes are currently being developed, with the hope to aid loneliness, depression and isolation in retirement. Initiatives such as Ireland’s Active Ageing Programme, the EU-backed Active Ageing Communities, and The Life-Changing Benefits of Exercise After 60 in the US all aim to provide a structured and accessible approach to physical activity for the elderly population.
The burden of age-related neurodegenerative diseases does not sit on the shoulders of the patient alone. It directly effects the lives of their family members and caretakers, and ultimately adds economic and resource pressures on the health system. It is therefore extremely promising that introducing regular endurance training exercise sessions into our weekly schedule can preserve our cognitive function, protect us from neurodegenerative disease and promote lifelong brain health.
References
1. Wang S, Jiang Y, Yang A, Meng F, Zhang J. The Expanding Burden of Neurodegenerative Diseases: An Unmet Medical and Social Need. LID - 10.14336/AD.2024.1071 [doi]. (2152-5250 (Electronic)).
2. Zhang W, Xiao D, Mao Q, Xia H. Role of neuroinflammation in neurodegeneration development. Signal Transduction and Targeted Therapy. 2023;8(1):267.
3. Barad Z, Augusto J, Kelly ÁM. Exercise-induced modulation of neuroinflammation in ageing. The Journal of Physiology. 2023;601(11):2069-83.
4. Silverman MN, Deuster PA. Biological mechanisms underlying the role of physical fitness in health and resilience. (2042-8898 (Print)).
5. Connolly MG, Bruce SR, Kohman RA. Exercise Duration Differentially Effects Age-related Neuroinflammation and Hippocampal Neurogenesis. Neuroscience. 2022;490:275-86.
6. Zhang Y, Cao RY, Jia X, Li Q, Qiao L, Yan G, et al. Treadmill exercise promotes neuroprotection against cerebral ischemia–reperfusion injury via downregulation of pro-inflammatory mediators. Neuropsychiatric Disease and Treatment. 2016;12(null):3161-73.
7. Lu J, Wang J, Yu L, Cui R, Zhang Y, Ding H, et al. Treadmill Exercise Attenuates Cerebral Ischemia–Reperfusion Injury by Promoting Activation of M2 Microglia via Upregulation of Interleukin-4. Frontiers in Cardiovascular Medicine. 2021;8.
8. Casaletto KB, Lindbergh CA, VandeBunte A, Neuhaus J, Schneider JA, Buchman AS, et al. Microglial Correlates of Late Life Physical Activity: Relationship with Synaptic and Cognitive Aging in Older Adults. The Journal of Neuroscience. 2022;42(2):288.
9. Islam MR, Valaris S, Young MF, Haley EB, Luo R, Bond SF, et al. Exercise hormone irisin is a critical regulator of cognitive function. Nature Metabolism. 2021;3(8):1058-70.
10. Kohman RA, DeYoung EK, Bhattacharya TK, Peterson LN, Rhodes JS. Wheel running attenuates microglia proliferation and increases expression of a proneurogenic phenotype in the hippocampus of aged mice. Brain, Behavior, and Immunity. 2012;26(5):803-10.
11. Moutinho S. Women twice as likely to develop Alzheimer’s disease as men — but scientists do not know why. Nature Medicine. 2025;31(3):704-7.