To what degree is the burden of senescent cells in the tissues of old or obese people dynamic, capable of being reduced by circumstances? Cells become senescent constantly throughout life, and are then cleared by the immune system or destroy themselves via programmed cell death mechanisms. That clearance falters with advancing age, however. We might also think that the pace at which cells become senescent is likely higher in tissues stressed by the molecular damage of aging or by the aberrant metabolism of obesity, but there is less direct evidence for this to be the case than there is for impaired immune clearance of senescent cells. It is certainly the case that obese individuals have a higher burden of senescent cells than their similarly aged peers, and this makes it worth paying some attention to what is learned of the way in which this burden changes in response to lifestyle.
Can one produce much the same effects of a senolytic therapy to clear senescent cells, but slowly over time via exercise? It seems to the case that either slowing the creation of senescent cells or incrementally improving clearance via the immune system can reduce the number of senescent cells in tissue over time. A study of senescent cells in skin treated with a topical mTOR inhibitor, which does not kill senescent cells, but does slow their creation, shows that even in older people the immune system is still destroying senescent cells. Given enough time of a lower pace of creation the immune system can catch up to reduce the burden of senescent cells to a lower level. Whether exercise is acting through a slowed pace of creation of senescent cells or an improvement to immune function is an interesting question – there are good arguments in either case.
That said, the size of the effect of exercise on the burden of cellular senescence leaves something to be desired; today’s open access paper shows that exercise clearly isn’t as good as a senolytic drug after only four weeks of physical training. The aforementioned topical mTOR inhibition study ran for half a year, so it is always possible that better effects would be be seen after a much longer period of training. Nonetheless, there really isn’t that much data on how the burden of cellular senescence can be shifted by lifestyle choice alone. Given the amazing results in reversal of age-related conditions produced by senolytic therapies in mice, and the inability to achieve the same outcome by exercising mice, it does seem unlikely that six months of becoming more fit could achieve the same results as a robust senolytic treatment, however.
Physical training reduces cell senescence and associated insulin resistance in skeletal muscle
Cell senescence (CS) is a conserved aging mechanism characterized by the irreversible arrest of the cell cycle along with alterations in cell function and the secretion of pro-inflammatory factors collectively known as the senescence-associated secretory phenotype (SASP). This process contributes to chronic inflammation, tissue dysfunction and a reduced capacity for cell regeneration. As individuals age, senescent cells accumulate in various tissues, including skeletal muscle (SkM), impairing muscle function and leading to sarcopenia, the age-related loss of muscle mass and strength. Impairment of SkM function can lead to significant metabolic disturbances. Since SkM is a primary site for glucose uptake, dysfunction in this tissue results in reduced insulin responsiveness, contributing to metabolic disorders such as type 2 diabetes (T2D). This highlights the importance of maintaining muscle health to prevent adverse metabolic outcomes.
Obesity is a well-established risk factor for numerous chronic diseases which can accelerate the onset of aging in several metabolic tissues, including SkM, by promoting CS. Indeed, obesity triggers local tissue inflammation, oxidative stress and metabolic abnormalities, which are key drivers of CS also in SkM. Chronic low-grade inflammation originating from the adipose tissue in obesity, as well as insulin resistance and altered muscle metabolism, are factors that can contribute to the acceleration of muscle aging and dysfunction.
CS can impact multiple cell types within SkM, including muscle stem cells (satellite cells), fibrogenic/adipogenic progenitors and resident immune cells, each of which plays a crucial role in muscle regeneration and maintenance. Satellite cells, which are normally quiescent, become activated in response to muscle injury or stress leading to proliferation and differentiation into new muscle fibers, thereby playing a critical role in skeletal muscle generation and repair. Thus, senescence in satellite cells can have profound consequences on SkM health, leading to diminished muscle maintenance, impaired regeneration, reduced responsiveness to exercise, and increased metabolic dysfunction.
Regular physical exercise is a highly effective strategy for preserving SkM function and metabolic health, while also reducing several chronic diseases associated with age. Exercise interventions have also been shown to reduce circulating biomarkers of CS in man and the burden of senescent cells linked to aging and age-related conditions in colon mucosa. However, very little is known about the impact of exercise on CS in SkM itself. Understanding if exercise may influence senescence markers in SkM is crucial, as it could provide insights into mechanisms that promote healthy aging of SkM and improve metabolic health.
In this study, we investigated the effects of physical exercise on CS markers in human SkM by analyzing muscle biopsies from people with normal body weight and with obesity, before and after regular exercise. Notably, physical intervention led to significant improvements in metabolic parameters, a reduction in CS markers and activation of satellite cell responses. Moreover, in vitro experiments demonstrated that senescence negatively impacts satellite cells by reducing key regulatory genes and impairing insulin signaling. Together these findings underscore the critical role of CS in regulating insulin sensitivity and highlight the potential of physical exercise as a therapeutic strategy to mitigate these effects in human.
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