Accumulation of senescent cells is one of the root causes of aging. Based on the comparatively few measures established in old tissues, the proportion of cells that are senescent does not rise to more than a few percent of all cells even in very old individuals. That few percent is enough to wreak havok, however. Senescent cells actively secrete a mix of signals that promote chronic inflammation, destructively remodel tissue structure, and change the behavior of surrounding cells for the worse. They are harmful enough to be a significant direct contribution to many age-related diseases. Data exists for their baleful influence to produce osteoarthritis, fibrosis of the lung and other organs, and many other conditions.
Given all of this, there is considerable enthusiasm for the development of means to selectively destroy these cells: small molecule senolytic drugs, immunotherapies, and suicide gene therapies are all under development, the first now in human trials. Interestingly, despite some years of this active development, the ability to accurately and usefully measure the count and life span of senescent cells in tissue has lagged behind. There are methods that work well enough in animal studies, but few approaches that are useful in human medicine, and none of them are yet widely used. So there is really very little data on the degree to which senescent cell counts rise and fall over time, in response to environmental circumstances. All that is known for certain is that old people have more senescent cells. Are those senescent cells lasting for years? Are they created at a small rate and linger for decades? Is there are a rapid turnover in most tissues, and the increasing number is a function of dysfunction in the processes of removal?
In this context, the research reported in the open access paper here is most interesting. The authors show quite large short-term variations in cellular senescence in muscle tissue in response to strength training in young people. Even given the youth of the subjects, taken on its own it suggests a cautious reevaluation of the idea that all senescent cells accumulate slowly and last for a long time, and thus that senolytic therapies would have to be undertaken only infrequently. (Not to mention posing the question of how much of the way in which strength training improves health in older individuals is due to eliminating senescent cells).
Yet this must be balanced with the established evidence for significant lasting benefits to result from a single senolytic treatment in mice, which seems only possible if senescent cells arrive at a slow rate and linger for a long time following creation. It is possible that there are different populations and types of senescent cells, some dynamic, some not. It is also possible that the standard senescent markers show up in cells that are not senescent in some circumstances. It is likely that senescence dynamics are quite different in different tissue types. Whatever the answers, it seems clear that assessment of senescent cell counts and dynamics is overdue a greater level of attention.
Most of the cells in the human body are continuously aging, dying and regenerating to gradually evolve a fairly stable size of multicellular system with a wide range of cell ages. Skeletal muscle is the largest tissue of the human body, in which cell lifespan varies considerably among different cell types. For example, myofibers are long-lived, whereas endothelial cells in capillary surrounding myofibers age rapidly with a short half-life around 2 weeks. Selective elimination of senescence cells in skeletal muscle and other tissues has been shown to increase lifespan in mice, suggesting a promising approach for anti-aging intervention. The protein p16Ink4a, a cyclin-dependent kinase inhibitor CDKN2A, is a widely used senescence marker expressed specifically in aged cells. However, p16Ink4a+ senescence cells in human skeletal muscle are rarely studied. It is currently unclear whether senescent cells are accumulated in human skeletal muscle at young age and whether exercise has significant influence on its number.
Senescent cells can be selectively recognized and rapidly cleared by phagocytic macrophages. One way to direct macrophages into skeletal muscle is resistance exercise. After weight loading, phagocytic macrophages (M1 phenotype) infiltrated into damaged sites, followed by protracted presences of regenerative macrophages (M2 phenotype). The cell turnover process instantly demands nitrogen sources from amino acids or proteins for nucleotide synthesis and DNA replication. A delayed protein supplementation after resistance training can significantly undermine muscle hypertrophy, suggesting a far-reaching impact of protein availability in time around exercise challenge on long-term muscle adaptation. It remains uncertain whether protein availability influences macrophage presences and senescent cell clearance in exercising skeletal muscle.
In this study, senescent cell distribution and quantity in vastus lateralis muscle were examined in young human adults after a single bout of resistance exercise. To determine the effects of dietary protein availability around exercise on senescent cell quantity and macrophage infiltration of skeletal muscle, two isocaloric protein supplements (14% and 44% in calorie) were ingested before and immediately after an acute bout of resistance exercise, in a counter-balanced crossover fashion. An additional parallel trial was conducted to compare the outcome of muscle mass increment under the same dietary conditions after 12 weeks of resistance training.
The main findings of the study are as follows: 1) No senescent myofibers are detected in the skeletal muscle of young men aged between 20-25 y; 2) Most of the senescent cells found around muscle fibers are endothelial progenitor cells; 3) A single bout of resistance exercise reduces the senescent endothelial progenitor cells by 48% in challenged muscle and maintains at low levels for 48 hours; 4) Resistance exercise with low protein availability is associated with greater increases in macrophage infiltration and further depletion of senescent endothelial progenitor cells in muscle tissue during recovery, but prevents muscle hypertrophy for a long term. Taken together, these data suggest that senescence cell clearance and muscle mass increment are associated with the magnitude of muscle inflammation after resistance exercise, which can be influenced by protein supplementation around exercise.