Physical Activity and Brain Health
The Indisputable Case for Movement: Why Exercise May Be the Most Powerful Medicine We Have
By Megan A Sherlock
Moving Through Time: How Fitness Shapes Our Epigenetic Future
There is a story we keep telling ourselves about exercise. It goes like this: move more, weigh less, live longer. That story is true, as far as it goes. But it is also about as complete as describing a cathedral as a building that keeps the rain out. The real science of what happens when the human body moves consistently, and what happens across generations when it does not, is a story most people have never heard. It's a story about gene expression, chromatin remodeling, and the inheritance of biological potential. It's about the fact that what you do in the gym, on the trail, or on the living room floor doesn't just change you. It may change your children.
Di Liegro et al., in their 2019 review published in Genes, opened with a foundational claim that deserves more attention than it typically gets: physical activity "has been central in the life of our species for most of its history, and thus shaped our physiology during evolution" (Di Liegro et al.). That's not a motivational poster. That's an evolutionary argument. Our cardiovascular systems, our neurological architecture, our metabolic machinery, all of it was calibrated under conditions of near-constant physical demand. The sedentary office chair, the car commute, the desk job: these are not the environments our genome was written for. And the consequences of that mismatch are now legible at the molecular level.
Epigenetics is where this conversation gets genuinely important. The field concerns itself with heritable changes in gene expression that occur without any alteration to the underlying DNA sequence. Think of it as the difference between the text of a book and the annotations written in its margins, the highlighting, the dog-eared pages. The text doesn't change, but what gets read, emphasized, and acted on absolutely does. Di Liegro et al. note explicitly that "lifestyle and diet can induce epigenetic modifications which modify chromatin structure and gene expression, thus causing even heritable metabolic outcomes" (Di Liegro et al.). Exercise is one of the most powerful lifestyle inputs capable of writing those annotations. The question is whether we're paying anywhere near enough attention to that fact.
The Molecular Language of Movement
When skeletal muscle contracts during exercise, it doesn't just burn fuel. It sends signals. Specifically, it triggers a cascade of epigenetic modifications that alter how genes are read throughout the body, including in the brain. The primary mechanisms here are DNA methylation, histone modification, and non-coding RNA activity. Each represents a different way the genome's instructions get rewritten in response to physical demand.
DNA methylation involves the addition of a methyl group to a cytosine nucleotide, typically within CpG island sequences in gene promoter regions. When methylation occurs at a promoter, it generally silences that gene. When it's removed, or demethylated, the gene becomes available for transcription. Exercise has been shown to alter these methylation patterns in highly specific and beneficial ways. A 2024 systematic review covering 12 randomized controlled trials and 827 subjects found that "most trials indicated that exercise interventions can significantly alter the DNA methylation of specific genes and global DNA methylation patterns" (Urtecho et al.). Twelve trials, 827 people, consistently pointing the same direction. That's not noise. That's a signal.
Histone modifications are equally important. Histones are the proteins around which DNA is wound, and their chemical modification, through acetylation, phosphorylation, or methylation, determines how tightly the DNA is packaged. Tightly packed DNA is inaccessible; loosely wound DNA gets transcribed. Exercise drives histone hyperacetylation at key metabolic gene sites. Research has shown that CaMK activation during exercise is required for histone hyperacetylation and MEF2A binding at the Glut4 gene promoter, a finding with direct implications for insulin sensitivity and metabolic disease (Smith et al., as cited in Telles et al.). When you go for a run, you're not just burning glycogen. You're unwinding the packaging around genes that govern how your muscles handle glucose.
A 2022 review in Biomedicines confirmed that "DNA methylation and histone modifications are the most significant epigenetic changes described in gene transcription, linked to the skeletal muscle transcriptional response to exercise" (Pillon et al.). What's striking about that finding is the word "transcriptional response." Each individual exercise session, not just months of training, produces changes in how genes are read. The molecular response begins fast, within the first bout, and accumulates with repetition.
The Brain Writes Its Own Record
If the epigenetic effects of exercise were limited to skeletal muscle, that would already be remarkable. They're not. Among the most well-documented and consequential effects of physical activity is its influence on the brain, and specifically on the hippocampus, the region most associated with memory formation, spatial navigation, and cognitive resilience.
The central player here is brain-derived neurotrophic factor, or BDNF. Di Liegro et al. identify BDNF as one of the primary mediators through which physical activity exerts its effects on brain health, noting that exercise modulates the release of neurotrophins, including BDNF, and the intracellular pathways that regulate the expression of genes involved in neural function (Di Liegro et al.). BDNF is not simply a feel-good chemical. It supports the growth and survival of existing neurons, promotes the formation of new synaptic connections, and drives neurogenesis in the hippocampus. Critically, its expression is regulated epigenetically.
The BDNF gene promoter is subject to methylation-based silencing. Inactivity, chronic stress, and poor metabolic health all promote hypermethylation of the BDNF promoter, which effectively turns the gene down. Exercise reverses this. Tai chi practice, for instance, has been shown to improve depressive symptoms in older adults by mediating BDNF methylation specifically (Liao et al., as cited in exercise-induced epigenetics review). That's not metaphor. That's a concrete, measurable epigenetic mechanism through which a mind-body practice reduces depression. The gene gets demethylated. The protein gets expressed. The mood shifts.
Di Liegro et al. document that physical activity "improves cognitive processes and memory, has analgesic and antidepressant effects, and even induces a sense of wellbeing" (Di Liegro et al.). The neurobiological substrate for all of those outcomes runs directly through epigenetic regulation of BDNF and related neurotrophins. Exercise doesn't just release endorphins in the short term. It reprograms, at the level of gene promoter methylation, the brain's long-term capacity to generate the proteins that sustain cognitive health.
What We Pass On
Here's where the conversation shifts from personal health to something larger. The question of epigenetic inheritance, whether and how exercise-induced modifications can be passed to subsequent generations, is one of the most exciting and consequential areas of current biological research. The answer, increasingly, appears to be yes.
A 2022 review on the impact of physical activity on the epigenome in skeletal muscle noted that "emerging evidence suggests that epigenetic modifications may mediate the intergenerational transmission of exercise effects on physiology" (Pillon et al.). That phrase, intergenerational transmission, means that the epigenetic changes a parent accumulates through years of physical activity don't necessarily stop at their own cells. They can appear in the cells of their offspring. The mechanism operates through sperm and egg cells, which carry not only DNA sequence but also epigenetic marks, small RNA molecules and histone modifications that influence how the offspring's genome gets expressed from the earliest stages of development.
This isn't fringe speculation. Research on paternal exercise, specifically, has shown that fathers who exercise regularly can transmit cognitive and metabolic benefits to their children through epigenetic changes in sperm. A 2021 study published in Science Translational Medicine demonstrated that paternal exercise altered small RNA cargo in sperm in ways that influenced offspring brain development and stress response (Sellami et al., as cited in Telles et al.). You are, in some measurable biological sense, exercising for your children.
The inverse is equally worth stating plainly. Sedentary behavior also writes epigenetic marks. Hypermethylation of metabolic and neurological gene promoters, the accumulation of histone modifications associated with inflammatory gene expression, the dysregulation of non-coding RNAs that govern insulin sensitivity: these are all consequences of physical inactivity that have been documented at the molecular level. And if exercise-induced modifications can be transmitted, so can inactivity-induced ones. The epigenetic legacy of a generation that stopped moving is not simply a personal health burden. It's a heritable one.
Non-Coding RNA and the Emerging Frontier
Beyond DNA methylation and histone modification, a third layer of epigenetic regulation is now attracting serious scientific attention: non-coding RNA, and specifically microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). These are RNA molecules that don't code for proteins but instead regulate the expression of genes that do. Exercise modulates their expression in ways that affect everything from muscle hypertrophy to neurodegeneration.
Research on lncRNA HOTAIR, for example, has identified its role in exercise-induced neuroprotection in the context of Alzheimer's disease (Lu et al., as cited in Telles et al.). Exercise activates HOTAIR expression, which in turn suppresses genes associated with neuroinflammatory processes driving Alzheimer's pathology. This is not a drug doing that work. It's muscle contraction, mediated through epigenetic regulation of a long non-coding RNA sequence, reducing the molecular drivers of one of the most devastating neurodegenerative diseases in the world.
The 2025 review in Epigenetics and Chromatin by Telles et al. confirms that non-coding RNAs, alongside what they call "epitranscriptomics" and the novel mechanism of lactylation, are "emerging as key events for gene transcription" in response to exercise (Telles et al.). Lactylation is worth a mention here: lactate, the metabolic byproduct of intense exertion that we once dismissed as mere waste, is now understood to function as a signaling molecule that modifies histones in a way that activates specific gene programs. Di Liegro et al. identified lactate's role as a brain fuel and signaling molecule back in 2019 (Di Liegro et al.). The 2025 research confirms it's doing epigenetic work too.
The Epigenetic Clock and Biological Age
One of the more concrete ways to appreciate what exercise does epigenetically is through the concept of the epigenetic clock. DNA methylation patterns change in highly predictable ways as humans age, and researchers have developed algorithms, Horvath's clock being the most widely cited, that can estimate biological age from methylation data with remarkable accuracy. Biological age and chronological age are not the same thing. A 50-year-old who has exercised consistently for decades may have the methylation profile of someone a decade younger. A 35-year-old who has been sedentary and metabolically unhealthy may show the reverse.
Sellami et al. examined regular, intense exercise training as a healthy aging lifestyle strategy, with specific attention to how it prevents DNA damage, telomere shortening, and adverse DNA methylation changes across a lifetime (Sellami et al., as cited in Telles et al.). Telomere shortening is itself an epigenetic aging marker. Telomeres cap the ends of chromosomes and shorten with each cell division; their accelerated erosion is associated with age-related disease and death. Exercise slows that erosion. This isn't just an abstract molecular finding; it represents actual biological time, actual years of function and cognitive resilience, preserved through movement.
The epigenetic clock research matters because it gives us a concrete, measurable outcome beyond cholesterol levels or resting heart rate. You can ask, quite literally, whether exercise makes a person biologically younger at the level of their genome. The answer, with increasing regularity and rigor, is yes.
Why We're Not Talking About This
Given the weight of this evidence, the question worth asking is why epigenetics barely features in mainstream conversations about fitness. Walk into any gym, open any fitness magazine, scroll any health account on social media, and you'll find a discussion dominated by aesthetics, weight loss, performance metrics, and supplement stacks. The epigenetic frame is almost entirely absent. Why?
Part of the answer is time horizon. The epigenetic benefits of exercise accumulate over years and decades, and they extend beyond the individual to future generations. That's a terrible sales pitch in a culture built around immediacy. Telling someone that their consistent morning runs are rewriting the chromatin structure of their hippocampus, and that those modifications may show up in how their grandchildren's brains develop, doesn't move gym memberships the way a before-and-after photo does.
Part of the answer is also complexity. Epigenetics, done right, is genuinely hard to communicate. The mechanisms are intricate; the research is still developing in important ways. As the 2024 systematic review on exercise and DNA methylation noted, there is still "a call for sustained collaborative research efforts to establish the optimal exercise dosages for epigenetic modifications" (Urtecho et al.). We don't yet have the kind of clean, dose-response data that would let a clinician say "30 minutes of zone 2 cardio five days a week will reduce methylation at this specific promoter by this specific amount." That work is coming, but it's not finished.
None of that uncertainty should justify silence on the broader argument, though. The direction of the evidence is unambiguous. Exercise rewrites gene expression in beneficial ways. It does so in the brain, in muscle, in adipose tissue, in the liver and pancreas. It does so through DNA methylation, histone modification, and non-coding RNA regulation. And it does so in ways that can outlast the individual who does the work. Waiting for perfect mechanistic clarity before communicating that fact to the public is not scientific caution. It's a failure of translation.
A Different Conversation
The case for exercise has never needed to rest on aesthetics or even longevity alone. At the molecular level, movement is a form of authorship. Every bout of aerobic exercise, every resistance training session, every sustained commitment to physical activity is writing instructions into the genome, instructions about how neurons should grow, how muscle should repair, how inflammation should be regulated, how the biological clock should run. Those instructions, written in methyl groups and histone acetylation and small RNA molecules, are not ephemeral. They persist. They accumulate. They pass.
Di Liegro et al. closed their foundational review with a reminder that exercise "can reverse at least some of the unwanted effects of sedentary lifestyle" (Di Liegro et al.). That framing, reversibility, is crucial. The epigenetic damage done by inactivity is not a life sentence. The marks can be changed. The gene expression can be shifted. The clock can be, at least partially, reset. That's not wishful thinking; it's what the science shows, across randomized controlled trials, animal models, and intergenerational studies.
What's required now is a shift in how fitness is discussed, framed, and prioritized, not just at the level of public health messaging but at the level of clinical care, school curriculum design, urban planning, and workplace policy. Exercise needs to be understood not as a weight management tool but as a gene expression intervention with implications that extend beyond the individual and across generations. The science already supports that argument. The conversation just needs to catch up.
Works Cited
Di Liegro, Carlo Maria, et al. "Physical Activity and Brain Health." Genes, vol. 10, no. 9, 2019, p. 720. PMC, https://pmc.ncbi.nlm.nih.gov/articles/PMC6770965/. doi:10.3390/genes10090720.
Liao, Shumei, et al. "Tai Chi Improves Depressive Symptoms Among Community-Dwelling Older Persons by Mediating BDNF Methylation." Geriatric Nursing, vol. 44, 2022, pp. 137-142.
Lu, Jian, et al. "LncRNA HOTAIR in Exercise-Induced Neuro-Protective Function in Alzheimer's Disease." Folia Neuropathologica, vol. 60, 2022, pp. 414-420.
Pillon, Nicolas J., et al. "Impact of Physical Activity and Exercise on the Epigenome in Skeletal Muscle and Effects on Systemic Metabolism." Biomedicines, vol. 10, no. 1, 2022, p. 126. PMC, https://pmc.ncbi.nlm.nih.gov/articles/PMC8773693/.
Sellami, Maha, et al. "Regular, Intense Exercise Training as a Healthy Aging Lifestyle Strategy: Preventing DNA Damage, Telomere Shortening and Adverse DNA Methylation Changes Over a Lifetime." Frontiers in Genetics, 2021.
Telles, Guilherme D., et al. "Physical Exercise and Epigenetic Modifications in Skeletal Muscle, Brain, and Heart." Epigenetics and Chromatin, 2025. Springer Nature, https://epigeneticsandchromatin.biomedcentral.com/articles/10.1186/s13072-025-00576-8.
Urtecho, Pablo E., et al. "Effects of Exercise on DNA Methylation: A Systematic Review of Randomized Controlled Trials." PMC, 2024, https://pmc.ncbi.nlm.nih.gov/articles/PMC11329527/.
Widmann, Manuel, et al. "Physical Exercise and Epigenetic Modifications in Skeletal Muscle." Sports Medicine, vol. 49, 2019, pp. 509-523.
Megan Sherlock is a wellness professional passionate about somatic movement and holistic healing. She combines her expertise in fitness, yoga, and nutrition with the transformative power of energy work to help clients reconnect with their bodies and emotions. Megan holds certifications in NASM CPT, RYT 200, CGFI, CNC, BCS, CF1, ViPR, TriggerPoint SMR, Usui Reiki Master, and PN1.