A new review paper delivers evidence that exercise, a powerful anti-aging tool, may be a natural senolytic [1].
Progress in the field of senolytics has been mixed. After the initial hype that had spawned dozens of startups, enthusiasm has waned somewhat in the wake of the failure of the much-anticipated experimental drug UBX0101, which was developed by Unity Biotechnology [2]. While this one setback does not invalidate the whole concept, and Unity itself has its hopes vested in a new senolytic, there are other ways of dealing with these harmful cells.
Exercise and senescence: is there a link?
This new review posits a link between exercise and senescent cell load. Exercise, of course, is one of the best anti-aging interventions we have to date. It has been proven to alleviate many processes associated with aging; it keeps your weight, blood pressure, and glucose levels at bay while delaying sarcopenia and frailty. This review shows that one of the underlying mechanisms of exercise is that it diminishes the number of senescent cells.
One study has found that lifelong exercise prevents thymic involution – the age-related degeneration of the thymus, a gland that produces T cells, which are a vital element of our immune system [3]. Another study demonstrated that thymic involution is associated with cellular senescence [4]. In another example, one of the most well-researched beneficial effects of exercise is on the vascular system, while cellular senescence promotes vascular stiffness [5], a major factor in cardio-vascular diseases. Finally, strong evidence links physical activity to lower risk of several types of cancer, while cellular senescence plays an important, if equivocal, role in cancer development (early-stage senescence protects from cancer, while prolonged senescence promotes it) [6].
It is rather peculiar, then, that this topic is not well-researched. The reviewers were only able to identify 21 related studies, including eight human studies, twelve animal studies, and one that included both humans and animals. The total number of participants in human studies was 535. The studies were heterogeneous in many aspects. In different studies, participants included sedentary or active volunteers, athletes or casual exercisers, healthy or ill people, as well as various age groups. Four out of nine human studies were cohort studies, while three were intervention studies (i.e. measured amounts of physical activity were applied and studied as a medical intervention). Animal studies showed even more variance: for instance, some of them included forced exercise, which researchers cannot do to humans for obvious reasons.
The results are in
Of the 21 articles, 16 demonstrated the senolytic effects of exercise on various markers of senescent cells. The P16INK4a protein, a popular marker of cellular senescence, was used in most of the studies. The main takeaway from the human studies was that, in general, physically active people have fewer senescent cells than sedentary people. Three of the studies have found that habitual physical activity is negatively associated with p16INK4a in the immune cells of healthy participants aged 18–80. According to two other studies, chronic exercise training reduced senescence markers in the mononuclear cells (lymphocytes and monocytes) and the vascular endothelial cells of healthy, regularly exercising participants compared to sedentary controls.
In animal studies, prolonged voluntary wheel running decreased p16INK4a levels in various organs, tissues, and cells of mice and rats, including heart, blood vessels, and fat. In summary, 10 out of 13 animal studies showed senolytic effects, which were dependent on the form and dosage of exercise, type of senescent tissue, health, and age. Remarkably, forced exercise showed contradictory effects on senescence markers, while acute bouts of exercise, including prolonged swimming, actually drove them higher. This is evidence that common knowledge is correct: forced exercise or too much exercise is not as good for you as a healthy helping of voluntary physical activity.
Despite the limited number of studies, the scientists consider the evidence for the senolytic effect of exercise to be convincing, and they call for more research on humans and animals and on various organs and tissues.
A clearer picture of mechanisms underlying senolytic effects of exercise may contribute to the discovery and development of ‘exercise mimetics’ or ‘exercise pills’ against senescent cells.
Conclusion
While aging research is looking for new interventions and therapies that would extend our lifespan and healthspan, among the few we have now, exercise is one of the most powerful and widely available. This review uncovers one of the possible mechanisms behind the anti-aging effect of exercise.
Literature
[1] Chen, X. K., Yi, Z. N., Wong, G. T. C., Hasan, K. M. M., Kwan, J. S. K., Ma, A. C. H., & Chang, R. C. C. (2020). Is exercise a senolytic medicine? A systematic review. Aging Cell, e13294.
[2] Dolgin, E. (2020). Send in the senolytics. Nature Biotechnology.
[3] Duggal, N. A., Pollock, R. D., Lazarus, N. R., Harridge, S., & Lord, J. M. (2018). Major features of immunesenescence, including reduced thymic output, are ameliorated by high levels of physical activity in adulthood. Aging cell, 17(2), e12750.
[4] Barbouti, A., Evangelou, K., Pateras, I. S., Papoudou-Bai, A., Patereli, A., Stefanaki, K., … & Gorgoulis, V. G. (2019). In situ evidence of cellular senescence in Thymic Epithelial Cells (TECs) during human thymic involution. Mechanisms of ageing and development, 177, 88-90.
[5] Katsuumi, G., Shimizu, I., Yoshida, Y., & Minamino, T. (2018). Vascular senescence in cardiovascular and metabolic diseases. Frontiers in cardiovascular medicine, 5, 18.
[6] Zeng, S., Shen, W. H., & Liu, L. (2018). Senescence and Cancer. Cancer translational medicine, 4(3), 70–74. https://doi.org/10.4103/ctm.ctm_22_18
