How much would you pay for a pill that grew your hippocampus -the part of your brain that forms new memories- by 2% in twelve months? Because that pill doesn’t exist. What does exist is walking briskly for forty minutes, three times a week, for a year, and that’s exactly what happened to the hippocampus of a group of sedentary older adults in a study published in PNAS in 2011 [1]. Meanwhile, the control group -the one that only did stretching- lost hippocampal volume, as age dictates. The difference between the two groups was stark: it was the difference between a brain that ages and one that turns back the clock.
And honestly, this fact infuriates me as a science writer: any pill with a marketing campaign behind it would sell -and make- millions. It would be all over social media, going for 70 euros a bottle. But because it generates no profit, can’t be patented, and offers no margins to anyone, nobody talks about it with the same enthusiasm they reserve for moringa or marine collagen. The best-documented nootropic in the history of neuroscience isn’t sold. You sweat it out :D.
The study, in depth
Kirk Erickson and his team’s study at the University of Pittsburgh is one of the most beautiful experiments in behavioral neuroscience this century. They took 120 sedentary adults between 55 and 80 years old, split them into two groups -one did aerobic exercise, the other stretching and toning- and put them through an MRI before and after a year. The aerobic exercise group increased their hippocampal volume by 2%, which in practical terms means reversing one to two years of age-related atrophy [1]. The control group, the stretching one, kept shrinking, as you’d expect from any brain over 55 that isn’t doing anything different from usual.
But the interesting part isn’t just the size. That volume increase was directly correlated with serum levels of a protein called BDNF (brain-derived neurotrophic factor), a kind of fertilizer for neurons that promotes survival and the formation of new connections [1]. The more BDNF went up in the blood, the more the hippocampus grew. And the more the hippocampus grew, the better people performed on spatial memory tasks.
On top of that, a later meta-analysis pooling several randomized controlled trials confirmed the effect of aerobic exercise on preserving hippocampal volume, with a small but statistically solid effect size (Hedges’ g = 0.13, confidence interval 0.02-0.24) [2]. In other words: the pattern kept repeating, which only strengthens the case for exercise as a cause, not just a correlation.
What nobody told you: your hippocampus gets a message sent directly from your muscles. For years the underlying mechanism was a mystery: we knew exercise raised brain BDNF, but we didn’t know how the body pulled off that trick. The answer, published by Christiane Wrann’s team in 2013, is the kind that leaves you stunned: in mice, skeletal muscle releases a protein called FNDC5 during exercise, which gets cleaved into a fragment known as irisin and travels through the bloodstream until it crosses the blood-brain barrier, directly activating BDNF expression in the hippocampus [3]. Literally, the animal’s leg sends a chemical message to its memory. Heads up though: this specific mechanism is mostly demonstrated in mice. In humans, several attempts to replicate the rise in muscle FNDC5 after exercise have produced contradictory results, and some research groups have gone as far as questioning whether the human FNDC5 gene is translated efficiently enough for irisin to circulate in meaningful amounts. So take the headline “your leg writes to your brain” as a metaphor that’s well-grounded in animals and still under debate in people.
The mechanism has a technical name, the PGC-1α/FNDC5 pathway, but what matters is the idea: muscle isn’t just the engine that moves you, it can also act as an endocrine gland that talks to the brain [3]. It’s apparently not the only route either: in mice, lactate -yes, the same stuff that builds up when your muscles burn halfway through a workout- also crosses the blood-brain barrier and improves spatial memory in a BDNF-dependent way [4]. So the suffering of exercise seems to pay off, though it’s worth remembering that this last finding also comes from animal models and is still pending full confirmation in people.
What nobody tells you about the dentate gyrus
Here’s a beautiful scientific debate that’s barely known outside the labs. For decades it was assumed that adults kept producing new neurons in one specific part of the hippocampus, the dentate gyrus, based mostly on mouse studies. But in 2018, three weeks apart, two human studies were published with similar methodologies and opposite conclusions. The first, by Shawn Sorrells and his team at the University of California, San Francisco, published in Nature, analyzed hippocampal tissue from 59 people and concluded that neurogenesis drops to undetectable levels in adulthood [5]. Three weeks later, Maura Boldrini and her team at Columbia, publishing in Cell Stem Cell, analyzed 28 brains from people without neurological disease and found thousands of immature neurons in the dentate gyrus, even in elderly individuals [6]. Same type of tissue, similar markers, and results that couldn’t have been more different.
The difference is probably down to technical details: Sorrells’s group worked largely with tissue from chronic epilepsy patients, a condition that on its own can alter the population of immature neurons, and used a more aggressive tissue-fixation protocol, one that can destroy the markers that give away a young neuron. Boldrini’s group was more careful, selecting donors without psychiatric illness, addiction, or vascular damage, and used a different fixation protocol [7]. Neither study directly measures the effect of exercise, but the context matters: if adult neurogenesis is real and significant, then the hippocampal volume increase we already saw in Erickson’s study would have a plausible cellular explanation. If it isn’t, hippocampal growth would have to be explained almost entirely through other routes, such as the strengthening of existing connections or increased blood supply.
Open question: why executive function specifically? There’s a hypothesis floating around -and it strikes me as likely correct, though it’s not proven- that executive function depends on a neural network that’s particularly expensive to maintain metabolically, with high energy demand and high synaptic plasticity. If exercise acts mainly by improving vascular supply and trophic support to neural tissue, it would make sense for the benefit to concentrate precisely in the regions that “spend” the most metabolically, rather than spreading evenly across the whole brain. It’s a reasonable conjecture, but there’s still no experiment that isolates that variable cleanly, so take it for what it is: a plausible explanation, not an established fact.
What we do have is an indirect bridge between exercise and neurogenesis that doesn’t depend on who’s right in the Sorrells-versus-Boldrini debate. A team led by Ana Pereira at Columbia used MRI to measure cerebral blood volume in the dentate gyrus -the only hippocampal subregion where neurogenesis occurs in mice- before and after a three-month exercise program [8]. In mice, that increase in blood volume correlated directly with the count of new neurons later confirmed post mortem. In the human participants of the same study, exercise produced the same pattern of selective blood volume increase in the dentate gyrus, and that increase was associated with cognitive improvements measured by memory tests [8]. It’s not definitive proof that exercise generates new neurons in the human brain, because you can’t biopsy a living person’s hippocampus to check. But it’s the most convincing piece of evidence we have that, whatever the exact cellular mechanism turns out to be, the pattern holds up in people too.
And what about executive function?
If the hippocampus is the star of memory, executive function -that bundle of abilities including working memory, inhibitory control, and cognitive flexibility, basically the capacity to plan, decide, and not send that text you know you shouldn’t send- is where exercise seems to hit hardest. Colcombe and Kramer’s classic meta-analysis, published in Psychological Science in 2003 and still religiously cited twenty years later, already found that aerobic fitness training produced robust but selective cognitive benefits, with the largest effect precisely on executive control processes [9].
This isn’t biological coincidence. The prefrontal cortex, the main seat of executive function, is one of the brain regions that benefits most from exercise-induced angiogenesis (the formation of new blood vessels), on top of getting its own dose of neurotrophins. In a way, it’s the region that pays the steepest price for a sedentary life and responds fastest once you stop being sedentary, and not incidentally, it’s also one of the most important ones, the one that represents who we are.
Aerobic isn’t the only thing that counts
Here’s a blind spot that almost all the popular discourse around exercise and the brain carries, and this post wasn’t immune to it either: when people say “exercise that’s good for your brain,” they almost always mean cardio. But the most recent evidence suggests strength training doesn’t lag behind, and in some areas it actually wins.
A network meta-analysis published in 2025 in Experimental Gerontology, combining 35 randomized controlled trials with more than 5,700 older participants, found that strength training produced the largest effect on global cognition among five exercise modalities compared (resistance, aerobic, mind-body practices like tai chi, multicomponent training, and high-intensity interval training), with an effect size notably larger than aerobic exercise alone [10]. Aerobic exercise, to be fair, remained the most effective specifically for memory, while mind-body practices stood out for working memory and task-switching. The practical takeaway is a lot less catchy than a single headline: different types of exercise seem to hit different cognitive targets, and limiting yourself to just walking or running might leave some of the benefit on the table.
What nobody told you: not even the meta-analyses themselves agree on which modality wins. Almost simultaneously with the study above, another team published a different network meta-analysis in Frontiers in Aging Neuroscience, also in 2025, with a similar pool of trials, and found that strength training, aerobic exercise, and high-intensity interval training showed at most trends toward cognitive improvement, without reaching statistical significance [11]. Same year, similar questions, conclusions that don’t quite line up with each other. This doesn’t mean the field is broken: it means network meta-analyses are sensitive to which specific studies get included, how exercise modalities get classified, and which cognitive metrics get prioritized. It’s a useful reminder that when someone quotes you a single number as if it were a law of physics, it’s worth asking which specific meta-analysis that number came from, and whether another one right next to it says something different.
The skeptics
As with every post, it’s worth weighing the opposition to the research and conclusions, and exploring every angle. The reality is that there’s a genuine scientific controversy over how much of this effect is real and how much is a statistical mirage built on small studies, publication bias, and analytical flexibility.
On one side is the “established” camp: dozens of meta-analyses, including Colcombe and Kramer’s [9] and a later one by Northey and colleagues focused on adults over 50, which find consistent positive effects of exercise on cognition, particularly executive function [12]. On the other side, a 2015 Cochrane review on aerobic exercise and cognition in cognitively normal older people concluded that evidence from randomized controlled trials was insufficient to claim an effect [13]. And in 2022 an even more uncomfortable piece of work showed up: an umbrella review by Ciria and colleagues that analyzed 24 meta-analyses on exercise and cognition in healthy populations, and found low statistical power in the primary trials, selective inclusion of studies, publication bias, and enormous variation in how each team processed and analyzed the data [14]. It’s worth clarifying that this work, as of today, is still a preprint -it hasn’t gone through peer review- so its conclusions should be taken as an active critical voice within an open debate, not as the final word. Even with that caveat, its argument, summed up without sugarcoating, is this: the causal evidence that exercise improves cognition in healthy populations might be considerably more fragile than popular discourse -and part of the academic discourse- suggests.
So who do you believe? Probably both sides have a piece of it. The effect looks real in populations that have something to gain: older adults with early decline, people with depression, kids with ADHD, people starting from very low fitness levels. There, the effect size is more consistent and easier to detect. In young, already-healthy populations, the room for cognitive improvement is much narrower, and that’s where the signal gets weak and noisy, which lines up with what the two 2025 network meta-analyses above show: the more finely you slice the analysis, the more the results depend on exactly which population and which modality you’re looking at.
In other words, everything points to exercise not being magic that makes you smarter if you’re already at your peak and already exercise regularly with some variety. It’s an intervention that repairs and prevents decline, and that nuance -which seems small- completely changes how we should read the headline. But it’s worth noting that even in the most skeptical research, there was still some improvement.
What nobody told you: dose matters more than you’d think, but not in the way you’d think. You don’t need to train like an Olympic athlete to get the cognitive benefit. A 2022 Bayesian meta-analysis examining the dose-response relationship between exercise and cognition in adults over 50 estimated that the minimum dose associated with clinically relevant changes was roughly what you’d get from 150 minutes of moderate activity spread across the week -coincidentally exactly what the WHO recommends, for entirely different reasons. And going beyond roughly 280 minutes a week brought increasingly unclear benefits [15]. The curve isn’t linear, and surprisingly, the researchers didn’t find a minimum threshold below which the effect disappeared entirely. In other words: up to a modest amount, it seems to add something. But doing a lot more than that reasonable range doesn’t give you a proportionally better brain. It’s diminishing returns, not an infinite staircase.
So what do we actually take away from this?
I’m not going to close this post with a motivational line about “move your body, transform your life,” because any Instagram account with a protein discount code in its bio already tells you that. What I can tell you, based on the evidence on the table, is this: sustained exercise over time, whether aerobic or strength-based, is currently the intervention with the best-characterized biological mechanism, the most consistent replication across labs, and an almost total absence of negative side effects, for keeping the hippocampus and executive function running well as the years go by. It’s not the only variable that matters, its effect is modest when you’re starting from an already healthy baseline, and even the experts don’t agree on the finer details of which modality wins in which domain. But no supplement, no brain-training app, and no over-the-counter nootropic pill comes anywhere close to that level of experimental backing.
And the irisin that climbs from your leg to your brain isn’t sold in pharmacies, whatever the ads say; you make it yourself, for free, every time you go out for a brisk forty-minute walk, or every time you lift something heavy twice a week.
References
[1] Erickson, K. I., Voss, M. W., Prakash, R. S., et al. (2011). Exercise training increases size of hippocampus and improves memory. Proceedings of the National Academy of Sciences, 108(7), 3017-3022. Reliable
[2] Wilckens, K. A., et al. (2021). Exercise interventions preserve hippocampal volume: A meta-analysis. Hippocampus, 31(3), 335-347. Reliable
[3] Wrann, C. D., White, J. P., Salogiannnis, J., et al. (2013). Exercise induces hippocampal BDNF through a PGC-1α/FNDC5 pathway. Cell Metabolism, 18(5), 649-659. Caveats apply
Establishes the PGC-1α/FNDC5/irisin mechanism in mice. Human replication attempts of the muscle FNDC5 increase after exercise have been mixed, so this is presented as a proposed mechanism demonstrated in an animal model, not as an established fact in humans.
[4] El Hayek, L., Khalifeh, M., Zibara, V., Abi Assaad, R., Emmanuel, N., Karnib, N., et al. (2019). Lactate mediates the effects of exercise on learning and memory through SIRT1-dependent activation of hippocampal BDNF. Journal of Neuroscience, 39(13), 2369-2382. Caveats apply
A mouse study, not a human one. The finding (lactate crossing the blood-brain barrier and inducing hippocampal BDNF in a SIRT1-dependent manner) is solid within its experimental design, but its direct applicability to humans is not yet confirmed.
[5] Sorrells, S. F., Paredes, M. F., Cebrian-Silla, A., et al. (2018). Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults. Nature, 555, 377-381. Reliable
Peer-reviewed study in a top-tier journal. Presented alongside Boldrini et al. (2018) precisely because both are methodologically sound and reach opposite conclusions: the controversy itself is the relevant data point, not a flaw in either study individually.
[6] Boldrini, M., Fulmore, C. A., Tartt, A. N., et al. (2018). Human hippocampal neurogenesis persists throughout aging. Cell Stem Cell, 22(4), 589-599. Reliable
[7] Lee, H., & Thuret, S. (2018). Adult human hippocampal neurogenesis: Controversy and evidence. Trends in Molecular Medicine, 24(6), 521-522. Reliable
[8] Pereira, A. C., Huddleston, D. E., Brickman, A. M., et al. (2007). An in vivo correlate of exercise-induced neurogenesis in the adult dentate gyrus. Proceedings of the National Academy of Sciences, 104(13), 5638-5643. Reliable
The correlation between dentate gyrus blood volume and post-mortem confirmed neurogenesis is demonstrated in mice; in the human arm of the same study, the same blood volume pattern is observed, but without direct histological confirmation, for obvious reasons. Treated as convergent indirect evidence, not as definitive proof of exercise-induced human neurogenesis.
[9] Colcombe, S., & Kramer, A. F. (2003). Fitness effects on the cognitive function of older adults: A meta-analytic study. Psychological Science, 14(2), 125-130. Reliable
[10] Zhang, J., Ye, W., Li, W., Zhang, F., & Wu, Z. (2025). Comparative efficacy of exercise interventions for cognitive health in older adults: A network meta-analysis. Experimental Gerontology, 206, 112768. Reliable
[11] Han, H., Zhang, J., Zhang, F., Li, F., & Wu, Z. (2025). Optimal exercise interventions for enhancing cognitive function in older adults: A network meta-analysis. Frontiers in Aging Neuroscience, 17, 1510773. Caveats apply
No obvious methodological flaws; flagged “caveats apply” because its results for strength and aerobic training (non-significant trends) contradict reference [10], published almost simultaneously with a similar methodology. Included precisely to show that real discrepancy between recent meta-analyses, not to take sides between the two.
[12] Northey, J. M., Cherbuin, N., Pumpa, K. L., Smee, D. J., & Rattray, B. (2018). Exercise interventions for cognitive function in adults older than 50: A systematic review with meta-analysis. British Journal of Sports Medicine, 52(3), 154-160. Reliable
[13] Young, J., Angevaren, M., Rusted, J., & Tabet, N. (2015). Aerobic exercise to improve cognitive function in older people without known cognitive impairment. Cochrane Database of Systematic Reviews. Reliable
[14] Ciria, L. F., et al. (2022). A call to rethink the cognitive benefits of physical exercise. Preprint, bioRxiv. Under review
A preprint: it has not gone through peer review. Included because it represents an active, well-argued critical voice within a real scientific debate over whether the effect size of exercise on cognition is overestimated in the literature, so it’s treated as open controversy, not a validated conclusion.
[15] Gallardo-Gómez, D., del Pozo-Cruz, J., Noetel, M., Álvarez-Barbosa, F., Alfonso-Rosa, R. M., & del Pozo Cruz, B. (2022). Optimal dose and type of exercise to improve cognitive function in older adults: A systematic review and Bayesian model-based network meta-analysis of RCTs. Ageing Research Reviews, 76, 101591. Reliable