Use of senolytics to clear a sizable fraction of senescent cells in the tissues of aged mice results in a reversal of many aspects of aging, including muscle aging. Muscle tissue provides a good example of the present state of play regarding the detailed understanding of senescent cells in specific tissues, in that it remains challenging to definitively identify the senescent populations in muscle. This is particularly the case following injury, when a transient, short-lived population of senescent cells are expected to arise to aid in the regenerative process, but common markers such as senescence-associated β-galactosidase are shared with the innate immune cells that also participate in regeneration.
In older individuals, the lingering senescent cells present prior to injury, and the reduced ability of the immune system to rapidly remove senescent cells created in response to injury, once their job is done, results in impaired wound healing. Senolytic drugs can improve this situation, and it seems more than clear that there is enough evidence to run clinical trials targeting frailty, non-healing wounds, and to improve healing in the elderly. The present regulatory system makes it harder to proceed in absence of a complete mechanistic understanding of the processes taking place in response to therapy, however. Thus given the demonstrated effectiveness of senolytic therapies in animal studies, there is considerable interest in better understanding exactly what is going on. Given progress on that front, expect to see a sizable expansion of senolytic research and development programs beyond those already underway.
Senolytics improve muscle adaptation in old mice
Recently, our lab and others have utilized senolytics to examine the contribution of senescent cells to impaired muscle adaptability with age, including regeneration following injury and the anabolic response to mechanical overload, as well as any potential role in sarcopenia. There is little evidence that senescent cells are present in aged muscle causing sarcopenia, but they appear to contribute to the impaired ability of muscle to adapt to exogenous stimuli. Even so, systemic deletion of senescent cells improves physical function and has been implicated in slowing sarcopenia. This apparent disconnect between a lack of senescent cells in muscle and improvements in age-associated conditions could be due to various technical or biological reasons.
Work from our lab shows that seven days following muscle injury, there are approximately 250 times more senescence-associated β-galactosidase positive (SA β-Gal+) cells in injured muscle compared to uninjured in both young and old mice. In young mice, these numbers return close to baseline after 28 days, however, the senescent cell burden remains elevated in old mice. Treating mice with a senolytic cocktail of dasatinib and quercetin (D+Q) lowers the senescence burden in old mice, while subsequently reducing the inflammatory profile of the muscle and improving the regenerative response.
β-Gal+ cells appear to transition to senescence in muscle from old mice, developing a senescence-associated secretory phenotype (SASP) relative to cells isolated from young mice 14 days post injury. Some of these findings were recently confirmed by other researchers, who show a greater abundance of senescent cells early in the regenerative process that is reduced over time and greater in old versus young mice. They also show a reduction in senescent cell abundance in response to D+Q treatment following injury, associated with improved regeneration and improvements in muscle force production.
It is important to note that our work shows young mice treated with D+Q display an attenuated regenerative response, whereas others shows an improvement in the regenerative response of young mice as early as 7 days post injury. Considering senescence has been shown to be required for the full regenerative response in skeletal muscle, the large overlap in phenotype between β-Gal+ non-senescent macrophages and bona fide senescent cells likely contributes to the confusion and warrants further investigation.
In a model of muscle hypertrophy, old mice display a blunted hypertrophic response relative to young mice, which is accompanied by a greater senescent cell burden. Treatment with D+Q improves the hypertrophic response in old mice, in addition to lowering the abundance of senescent cells. In this model, we did not observe any change in many of the SASP genes, although genes that are crucial for extracellular matrix reorganization, along with genes that negatively regulate myostatin, were elevated. In summary, senolytics effectively lower the protracted senescent cell burden that accompanies a regenerative or hypertrophic stimulus in muscle from aged mice, resulting in increased muscle fiber size.
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