Senescent Cells & Longevity

The senescence-centric view of aging posits that cellular senescence is central to the aging process itself, and over time the accumulation of senescent cells contributes to the age-related loss of vital functions and regenerative processes we associate with declining physical and mental capacity, and ultimately a shortened healthspan and lifespan. Cellular senescence occurs when a cell exceeds some threshold of injury, such as unrepaired DNA damage, mitochondrial dysfunction, oxidative damage, telomere shortening, epigenetic modification, etc. At this point, as an alternative to undergoing apoptosis (programmed cell death), these cells enter a growth-restricted phase; although they no longer divide, they do continue to release a brew of chemical signals (chemokines, cytokines, matrix remodeling proteases, etc.) which induce senescence in neighboring cells (paracrine senescence). It is this hypersecretion of inflammatory mediators (collectively known as the senescence-associated secretory phenotype, or SASP) which leads to an accumulation of senescent cells, resulting in so-called “inflammaging,” and cellular, tissue, and organ dysfunction.

The list of tissues/organs affected by senescent cells and SASP appears to be complete. Senescent cells are thought to play a role in degenerative diseases in the eye, bone (osteoporosis), muscle (sarcopenia), joints (osteoarthritis), kidneys, pancreas, liver, cardiomyocytes, immune cells, neurons, etc., and even play a role in hair loss. For example, senescence in pancreatic β cells is considered one of the main mechanisms by which these insulin-producing cells age, and senescence in adipose tissues is a primary driver of age-associated insulin resistance. 

Despite the substantial detrimental effect of cellular senescence, this process does have several positive physiological effects which may help to explain why it occurs somewhat frequently, or even at all. For example, senescent cells play a role in wound healing and provide a degree of cellular plasticity during embryonic development, though in both of these types of “acute senescence,” the cells are eventually targeted for destruction. Perhaps most importantly, senescent cells have an important role as tumor suppressors, preventing the proliferation of damaged cells. A cell that has a critical number of DNA mutations that continues to divide uncontrollably is clearly a detriment to any organism, and from an evolutionary perspective, senescence provides a clear benefit, particularly during reproductive years. Senescent cells do have some of the same alterations as cancer cells, including an upregulation of survival genes and oncogenes, which help them to evade immune-targeted destruction and apoptosis. Paradoxically, later in life, senescent cells appear to promote cancer formation (via SASP) despite having an anti-cancer function earlier in life.

While completely preventing senescence is likely to cause harm (by preventing the positive effects described above), much research in recent years has focused on senotherapeutics. These are therapies that either have direct senolytic activity (i.e., they destroy senescent cells), or that have senomorphic activity, i.e., rather than directly targeting these cells for destruction, they inhibit SASP, the inflammatory compounds which promote metabolic dysfunction and accumulation of senescent cells. Many natural compounds, especially flavonoids, appear to have either senolytic or senomorphic activity, or both, though most research on senotherapeutics has been done only in preclinical or animal trials so far. This is an extremely promising field of research because it appears to target the mechanism of aging itself, which drives so many of the chronic diseases we associate with advanced age.

Perhaps the most well-studied natural compound at this point is quercetin, used with or without dasatinib. Initial studies found that among 46 drugs and natural compounds, quercetin and dasatinib appeared the most promising. Quercetin by itself had senolytic activity toward senescent human endothelial cells, while dasatinib (a chemotherapeutic that targets multiple tyrosine kinases) was more effective at targeting senescent preadipocytes. Subsequent publications suggest these compounds together may have efficacy for osteoporosis, obesity, glaucoma, and more. For example, results of a study recently published in Aging Cell indicate this combination has senolytic and senomorphic activity in white adipose tissue (WAT), suggesting the potential to improve metabolism in older animals. Older mice treated with the combination showed reduced gene expression of inflammatory SASP factors, and improved glucose tolerance (likely via suppression of hepatic gluconeogenesis), as well as a reduction in triglycerides and improved lipid tolerance (lipid increase in response to oral intake). Additionally, a reduction in the number of macrophages and T-cells found in adipose tissue was observed with treatment, suggesting a potential reduction in the inflammatory/immune component of adipose tissue dysfunction. Human pilot trials are just beginning, such as the use of this combination for idiopathic pulmonary fibrosis, an age-related condition associated with a heavy burden of senescent cells. 

Many other natural compounds appear promising as well, such as polyphenols like fisetin and apigenin, and other phytochemicals such as anthocyanins, catechins, and curcumin, which appear to have senotherapeutic activity in addition to their well-recognized antioxidant and anti-inflammatory effects. It seems quite plausible that the presence of a broad array of phytochemicals in a plant-rich diet, such as the Mediterranean diet, may provide the senotherapeutic activity responsible for its longevity-related benefits. For example, the Mediterranean diet positively influences multiple hallmarks of aging, including cellular senescence, which may explain its overall reduction in risk for many age-related diseases as well as improved longevity.

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