Exercise as a Mild Senotherapeutic – Innovita Research

Exercise is known to improve health and extend the healthy portion of life span, but not extend life span itself in mice. This is a much lesser effect than that of calorie restriction, which does extend maximum life span in addition to improving health. From a very high level view, both exercise and calorie restriction are similar, in that they trigger many of the same stress response mechanisms, making those mechanisms work harder to maintain cell function than they would otherwise have done. Evidently exercise and calorie restriction achieve this goal in quite different ways at the detail level, given the quite different outcomes.

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One noted aspect of aging is the accumulation of senescent cells throughout the body. Cells become senescent constantly throughout life, in response to a variety of circumstances, but are removed quickly and efficiently in youth, either self-destructing or being destroyed by the immune system. This removal slows down with age, alongside an increased pace of creation of new senescent cells, allowing senescent cells to linger in ever increasing numbers. These cells adopt the senescence-associated secretory phenotype (SASP), producing inflammatory, disruptive signals that contribute to the development of tissue dysfunction and age-related disease. The size of this effect is meaningful, the harms done considerable, as illustrated by the rejuvenation produced in animal studies when senescent cells are selectively destroyed by senolytic therapies.

Age-slowing interventions such as exercise and calorie restriction, based on stress response upregulation over time, largely appear to reduce the burden of senescent cells in older individuals. That may not mean a reduction in the numbers of senescent cells, but rather involve suppression of the SASP. Where it does reduce numbers of senescent cells, it may not achieve that end by destroying these errant cells directly, but rather by slowing the pace of creation, or producing general improvements in immune surveillance of senescence. A good example is mTOR inhibition via drugs such as rapamycin, an approach shown to reduce the burden of senescence in skin over a period of months, but which is well proven not to directly destroy senescent cells. The effect size of exercise is nowhere near that of pharmaceutical approaches when it comes to the burden of senescence, however, as today's review illustrates.

Is exercise a senolytic medicine? A systematic review

Senescent cells are the hallmark and therapeutic target of cellular senescence involved in a wide range of biological processes, including tumor suppression, embryonic development, wound healing and tissue repair, and aging. Although senescent cells are detrimental to the body during aging and can lead to chronic diseases, such as obesity, diabetes, and sarcopenia, they also suppress cancer and fibrosis.

Senolytics is a new class of medicines that target senescent cells, which has emerged rapidly in the past few years. Preclinical studies on rodents have been applied to explore the potential targets of senescent cells and the preliminary effects of senolytic medicine in vivo. In addition to transgenic mice, senolytic drugs, including dasatinib and quercetin, ABT263, and SSK1, showed the therapeutic effects on senescent cells and alleviated the radiation and age-related symptoms and pathology. Strikingly, two small clinical trials on senolytic treatments with dasatinib and quercetin were completed last year and reported therapeutic effects for patients with diabetic kidney disease (N = 9) and idiopathic pulmonary fibrosis (N = 14).

Physical exercise is widely recognized as a safe, effective, and cost-effective “medicine” for a broad range of age-related diseases. Moreover, a lack of exercise is a major contributing factor to accelerated aging and age-associated chronic conditions, including cancer, obesity, and cardiovascular diseases. A clearer delineation of anti-aging and anti-disease effects and underlying mechanisms of exercise is needed. While the accumulation of senescent cells has been identified as the mechanism of aging and multiple diseases for decades, senolytics targeting senescent cells has just been developed in recent years. In addition, exercise has shown its capacity to lower the marker of senescent cells over the past decade. In the current systematic review of all available literature, we explored the potential senolytic effects of exercise in both human and animal models under healthy or disease states. We aimed to improve the understanding of the cellular senescence-based mechanisms underlying exercise as anti-aging medicine.

The findings of this systematic review and meta-analysis provided some evidence that exercise may be a senolytic medicine for p16INK4a-positive senescent cells in humans and for p21Cip1-positive senescent cells in obese but not healthy animals. Future studies should examine the optimal form and dosage of exercise, targeted cells/tissues, different disease states, and the underlying cellular mechanisms in humans and animals. A greater understanding of the senolytic effects of exercise can lead to significant clinical and public health impact.

Source: Fight Aging!