Considering Exercise as a Means to Slow the Progression of Aging

It is well known that regular exercise can slow the progression of many age-related declines, and reduce mortality risk in late life. Different forms of exercise, such aerobic exercise versus strength training, appear to produce different, overlapping benefits. This is concretely demonstrated in animal models, while the human epidemiological data, which can only show correlations, is supportive of the thesis that exercise produces changes in metabolism that modestly slow the onset of age-related declines.

Exercise is a lifestyle intervention with known antiaging effects capable of counteracting several of the hallmarks of aging including senescence and age-associated inflammation. We propose that 5' adenosine monophosphate-activated protein kinase (AMPK) can orchestrate many of the antiaging effects of exercise through its regulation of diverse cellular pathways in the setting of energetic stress.

Activating AMPK is sufficient to extend lifespan in many organisms. It is naturally activated in response to muscle contraction and nutrient depletion, both of which are components of exercise. Whereas most of the studies supporting AMPK as an antiaging strategy are based in animal models, the use of metformin (an AMPK activator) in clinical trials (TAME) as an antiaging drug is based on its capacity to delay heart disease, cancer, cognitive decline, and death in people with diabetes. These results suggest that the antiaging effects of AMPK are also relevant in humans, but the molecular mechanisms underlying these effects remain to be determined.

A landmark 21-year longitudinal study that followed runners and compared them with a sedentary group, found that those who exercise had a significantly lower risk of dying (15%) during that time frame than the sedentary group (34%) while also having reduced disabilities. It is unclear whether the beneficial effects of exercise in this study were due to a delay in secondary aging or to countering of the effects of sedentarism. Regardless of this limitation, numerous studies have shown that maintaining a minimum quantity and quality of exercise improves cardiorespiratory fitness and muscle function, flexibility, and balance.

Current guidelines recommend a minimum of 150 min/week of moderate intensity aerobic activity for maximum longevity benefits, with higher duration and intensity increasing cardiovascular and metabolic effects. It has been estimated that performing three to five times the recommended physical activity (450-750 min/week) reaches the maximal healthspan benefit that can be achieved with endurance exercise. Strength training should be added to minimize loss of muscle mass that is characteristic of aging and disease.

In summary, exercise is an effective strategy to prevent aging and enhance longevity and health span both on a clinical and a cellular level due to its capacity to modulate all nine hallmarks of aging. Additionally muscle, one of the main systemic effectors of exercise, is recognized as an endocrine organ that produces and releases myokines, implying a complex cross talk between muscles and other tissues. The AMPK pathway, a well-known mediator of exercise effects in muscle could be activated in different tissues and drive many of the health-promoting and lifespan-extending capabilities of exercise. We propose that it is a central effector node able to impact the hallmarks of aging and integrate the effects of exercise on many tissues.