The Romans gave us the aqueduct, sanitation, the roads, irrigation, medicine, education, wine, public order and baths (1). But apart from that? Well, they bequeathed us the idea that physical exercise was an essential part of health and mental wellbeing. This idea was built into the Scottish post-war educational system, which is why I rowed, ran and played rugby (the three R’s) between STEM classes.
The Romans inherited this idea from the Greeks, and from Hippocrates who did NOT say “Let food be thy medicine, let medicine be thy food” (2). What he actually said was ‘Walking is the best medicine,’ before hedging his bets with ‘Food and exercise work together to produce health,’ and then adding ‘If you are in a bad mood, go for a walk. If you are still in a bad mood, go for another walk.’
If Hippocrates were alive today Big Pharma would first discredit him and then send a wetwork team after him, because his ideas attack the very foundations of today’s drug- and profit-centred medical model. His ideas are also substantially correct, as we see in Blue Zones such as mid-Victorian England (3); and have been further proven in multiple clinical studies measuring the impact of diet and exercise on cardiovascular, oncological and psychological end-points.
In particular, the last two decades have seen a rapid accumulation of evidence that physical exercise does indeed support brain health (4).
While many studies have looked at hippocampal neurogenesis (5, 6), it has become obvious that the effects of physical exertion are more global. Weight loss, the prevention or reversal of insulin resistance and improved circulatory physiology (7) play contributory roles, but there are very specific additional benefits which include enhanced neuroplasticity in many areas of the brain and increased production of various neurotrophic factors; and it is a combination of all of these that leads to improved cognition (5, 8, 9), resilience (10, 11) and mood (12, 13), and the slowing or prevention of brain ageing (14).
We were made to move; and our increasingly sedentary lifestyles are making a substantial contribution to our failing public health. They are also contributing, along with our ultra-processed diet, to the rising tides of degenerative disease and depressive illness (ie 15) and the receding tides of intelligence (16-19). These last four papers indicate that the Flynn Effect, long thought to be universal and inevitable, is faltering …
Exercise and particularly weight-bearing exercise increases neurogenesis in a part of the hippocampus called the sub-ventricular zone, an area where neural stem cells produce new neurons. Limiting physical activity drastically reduces neural stem cells in this area in mammals (20), and recent work is providing insights into how this occurs. Couch potatoes read on, but you might want to go for a brisk, Hippocratic walk before proceeding …
Physical activity exercises the brain via three main transducers: muscle, bone and one other. As per the new science of endocrinology, which holds (I’m paraphrasing) that ALL tissues are exocrine or endocrine organs, both muscle and bone produce messenger compounds that touch on many other systems, and on each other.
Physical exercise imposes torque and load on bone, which responds inter alia by secreting osteocalcin (21, 22). This hormone encourages new bone formation, providing all the bone-trophic nutrients such as vitamins K, D, C and B6 are present, along with trace elements copper, zinc, manganese and iron. These all occur in a reasonable diet, but most or all are depleted in ultra-processed foods which is one reason why osteopenia and osteoporosis are so prevalent today.
But osteocalcin does much more.
Osteocalcin acts in muscle to improve insulin sensitivity and ATP production (23-25), and also in the brain where it regulates the synthesis of many neurotransmitters (26, 27). As we age, most of us tend to become less active. Osteocalcin levels fall, contributing to age-related declines in muscle and brain function; which can be prevented and reversed (at least pre-clinically) by osteocalcin injections or transfusions (25, 28). This is almost certainly clinically relevant because people with high activity levels maintain higher calcitonin levels (21, 22), and experience less sarcopenia and age-related cognitive decline (ie 29).
It may well also be a future public health concern. The current generation of children are both inactive and malnourished, and therefore very unlikely to reach optimal peak bone mineral mass. Their calcitonin levels will fall earlier, and from lower start-points, than in their parents’ generation; and they will probably start to dement earlier. They already have more depressive illness ..which takes us from bone to muscle.
The second transducer, muscle, affects brain function in a very different way.
L-tryptophan is an essential amino acid found in many foodstuffs. Dietary tryptophan is incorporated into proteins but is also processed via other metabolic routes, which largely produce kynurenine. High levels of kynurenine affect glutamate neurotransmission, cause neuronal inflammation and death (30, 31), and are strongly linked to depression (32). Kynurenine is formed in the peripheral tissues and particularly in the liver, and its rate of formation is increased by inflammation (33) and by stress (34, 35), two factors known to cause depression (36). Blocking kynurenine synthesis in the liver has a marked anti-depressant effect (34), and wonder of wonders, new research shows that physical exercise – which is anti-depressant (37) – also prevents the accumulation of kynurenine by favouring an alternative metabolic route to kynurenic acid, which does not enter the brain (38, 39).
Incidentally, for those familiar with exercise mimetics such as AICAR and ActivAMP, these fascinating compounds reproduce many of the effects of exercise on muscle and on fitness but do not appear to convey its neurological benefits (40).
Which brings us to the third transducer, namely the liver. Indirectly involved in the exercise / brain connection via kynurenine metabolism, the liver also produces an exercise mediating messenger of its own, Gpld1 (41). This hormone triggers increased synthesis of nerve cell growth factors such as BDNF and increased generation of new brain cells in aged mice, and improves their learning and memory (41). These profoundly anti-brain ageing effects mimic the effects of exercise in every respect; so biohackers looking for brain rejuvenation without breaking a sweat should start here.
Viewed through a long (evolutionary) lens, it is possible to see how physical activity and brain function might work together. Hunting for food or a mate, taking avoiding action when necessary, remembering where a resource or threat was located, all those activities and more might be expected to harness muscle, bone and brain in the ways listed above. But how does the liver fit into this nexus?
I suspect that the microbiota may be the fourth partner in this quadrille. They have a vested interest in the survival of their host, after all, and their metabolisms overlap considerably with ours. Tryptophan and its metabolites have profound effects on gut microbial composition, microbial metabolism, the host’s immune system, the host-microbiome interface, and on host immune system-intestinal microbiota interactions (42). The microbiota affect the kynurenine system (43-46), and it would be surprising if they did not also impact on Gpld1. Tryptophan-rich foods include eggs, meat and nuts, so successful hunting and foraging would lead to tryptophan ingestion, from which the microbiota would benefit. It is therefore conceivable that they evolved a feed-forward loop to improve their host’s cognition, memory and motivation / mood.
Looking ahead, there is accumulating evidence that the neurotrophic effects of exercise may be protective against both Alzheimer’s (47) and Parkinsonism (48). Now go put on your sailin’ shoes.
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