Nearly half of all adults in the U.S. are considered obese, and the incidence of obesity has steadily risen over time in nearly every first-world country. Adipose tissue (fat) has for many years been thought of as a relatively inert tissue functioning as a reserve depot during periods of low nutrient availability. However, research has revealed this tissue to be both metabolically and hormonally dynamic, playing a significant role in the overall health of an organism. More recently, research has uncovered evidence that adipose cells are highly susceptible to senescence, an irreversible state of non-proliferation, and the accumulation of senescent cells with age leads to the senescence-associated secretory phenotype (SASP)—a deleterious inflammatory condition thought to be a critical driver of age-related diseases. Obesity and age are top risk factors for developing type 2 diabetes, and it would seem that therapies aimed at reducing SASP would be an ideal approach to improve this condition.
P16, a protein critical in determining a cell’s fate and highly expressed in senescent cells, has been the focus of much of the contemporary research aimed at reducing SASP. The targeted elimination of cells highly expressing p16 has shown success in halting and even reversing age-related pathologies, although this approach has had only moderate success in treating the age-associated dysregulation of glucose metabolism, specifically insulin resistance, the impaired ability to respond to insulin. Recently, researchers have characterized a discrete population of senescent cells in adipose tissue expressing high levels of an alternate cell cycle protein known as p21. Furthermore, their findings suggest that specifically eliminating these cells may be more effective in preventing or reversing the development of age-related type 2 diabetes.
In their Cell Metabolism article, L. Wang et al. demonstrate that populations of senescent cells expressing high levels of p21 (p21hi) are distinct from those expressing high levels of p16 (p16hi), and that selectively eliminating populations of p21hi in mice improves glucose metabolism as well as or better than targeting p16-expressing cells alone. Importantly, the elimination of p21hi cells improves insulin sensitivity, whereas exclusive elimination of p16hi cells does not, a significant finding as insulin resistance is thought to be a key driver of type 2 diabetes in aging individuals.
Previous studies have used a variety of both genetic and pharmaceutical interventions to eliminate senescent cells with the hope of translating these findings from mice to people. (Pharmaceutical interventions are currently the preferred means of intervention as genetic therapies are still early in their development for clinical application.) Importantly, this particular study utilizes a combination of dasatinib and quercetin, an established pharmaceutical cocktail previously used to treat cancer, and may therefore be easily repurposed as a senolytic—a class of small molecules that target senescent cells with the aim of alleviating age-related diseases.
In recent years, treatment with dasatinib plus quercetin has been studied as a senolytic targeting cells expressing high levels of both p16 and p21. Although many senescent cells show elevated levels of both p16 and p21, Wang et. al demonstrate that there are distinct populations of senescent cells differentially expressing high levels of p16 and p21, and these populations may affect overall health in an independent manner. Further characterization of differing senescent cell populations and the specific role they play in disease may offer more effective and robust means of treating various age-related and metabolic diseases such as type 2 diabetes.