Recently, researchers have demonstrated that senescence of pancreatic β cells is important in both the autoimmunity of type 1 diabetes and the metabolic dysfunction of type 2 diabetes. This was very surprising in the first case, less so in the second, since type 2 diabetes emerges more readily in older individuals. The specific mechanisms by which increased cellular senescence arises in the pancreas is probably different in each case, but the use of senolytic treatments to clear senescent cells has produced significant benefits in animal models of both conditions. This adds to the many other conditions in which targeted removal of senescent cells is a viable therapy.
Here, researchers outline more evidence for an important role for cellular senescence in type 2 diabetes. It is compelling. It has to be said that s time moves on, senolytic therapies look ever more like a panacea of sorts, capable of improving near any condition where incidence is correlated with aging, and even a few where that is not the case. Given that the first senolytic drugs and supplements with well-explored pharmacological safety data, good results in mouse studies, and an emerging set of human trial results are both very cheap and readily available given a little investigation of the options, I fully expect that patients will start to take matter into their own hands long before companies can obtain regulatory approval for the first therapies in their senolytic pipelines.
Type 2 diabetes (T2D) is an age-related disease characterized by a decrease of β cell mass and function, representing a failure to compensate for the high insulin demand of insulin-resistant states. Yet, the role of aging as it pertains to pancreatic β cells is poorly understood, and therapies that target the aging aspect of the disease are virtually non-existent. For many years, β cells can compensate for increased metabolic demands with increased insulin secretion, keeping hyperglycemia at bay. This compensation may be limited by the age-related decline in β cell proliferation seen in rodents. This deficiency in proliferative response to increased demand may arise partly from the accumulation of senescent β cells.
Cellular senescence is a state in which cells cease to divide but remain metabolically active with an altered phenotype. There are no universal markers of senescence, and the markers that exist are not consistent in every senescent tissue. p16Ink4a, a cyclin-dependent kinase inhibitor encoded by the Cdkn2a locus, has been identified as both marker and effector of β cell senescence. An increase in p21, another effector of cellular senescence, is thought to mark the entry into early senescence leading to increased p16Ink4a expression, which then maintains senescence, resulting in the expression of the senescence-associated secretory phenotype (SASP).
SASP profiles differ with tissue type and can include soluble and insoluble factors (chemokines, cytokines, and extracellular matrix affecting proteins) that affect surrounding cells and contribute to multiple pathologies. With age, accumulation of dysfunctional senescent β cells likely contributes to impaired glucose tolerance and diabetes. Yet, the specific contribution of β cell aging and senescence to diabetes has received little attention, and the specific SASP profile of β cells remains to be determined.
We generated a β cell senescence signature and found that insulin resistance accelerates β cell senescence leading to loss of function and cellular identity and worsening metabolic profile. Senolysis (removal of senescent cells), using either a transgenic INK-ATTAC model or oral ABT263, improved glucose metabolism and β cell function while decreasing expression of markers of aging, senescence, and SASP. Beneficial effects of senolysis were observed in an aging model as well as with insulin resistance induced both pharmacologically (S961) and physiologically (high-fat diet). Human senescent β cells also responded to senolysis, establishing the foundation for translation. These novel findings lay the framework to pursue senolysis of β cells as a preventive and alleviating strategy for T2D.