Scientists have shown that the removal of non-dividing senescent cells, which are normally associated with aging, also appears to prevent Type 1 diabetes in diabetic mouse strains.
Clearing senescent beta cells prevents T1 diabetes
Type 1 diabetes (T1D) is a chronic condition in which the pancreas produces little or no insulin. Insulin is a hormone that allows sugar (glucose) to enter cells in order to create energy, so it is critical to cellular function and life.
T1D is an autoimmune disease, which means that the immune system, instead of protecting the body from invading pathogens, identifies a part of the body as a threat and attacks it. In T1D, the immune system targets the insulin-producing beta cells in the pancreas and destroys them.
In a new study, researchers demonstrate that senescent cells play a key role in the development of type 1 diabetes and that clearing them using senolytic therapy is sufficient to prevent diabetes in T1D diabetic mouse strains [1].
The research team used Bcl-2 inhibitors to block the survival pathways that senescent beta cells use to evade apoptosis, a built-in self-destruct system that destroys damaged cells. We have seen previous senolytic research that uses the drug navitoclax, which also blocks the Bcl-2 protein family [2]. Bcl-2 is also the target of the senolytic drug candidate UBX1967, which is being developed by UNITY Biotechnology to treat ophthalmologic diseases.
The end result here was that blocking Bcl-2 allowed the selective destruction of senescent beta cells, which, in turn, appeared to prevent T1D.
SummaryType 1 diabetes (T1D) is an organ-specific autoimmune disease characterized by hyperglycemia due to progressive loss of pancreatic beta cells. Immune-mediated beta cell destruction drives the disease, but whether beta cells actively participate in the pathogenesis remains unclear. Here, we show that during the natural history of T1D in humans and the non-obese diabetic (NOD) mouse model, a subset of beta cells acquires a senescence-associated secretory phenotype (SASP). Senescent beta cells upregulated pro-survival mediator Bcl-2, and treatment of NOD mice with Bcl-2 inhibitors selectively eliminated these cells without altering the abundance of the immune cell types involved in the disease. Significantly, elimination of senescent beta cells halted immune-mediated beta cell destruction and was sufficient to prevent diabetes. Our findings demonstrate that beta cell senescence is a significant component of the pathogenesis of T1D and indicate that clearance of senescent beta cells could be a new therapeutic approach for T1D.
Conclusion
The results of this new study are unusual given that type 1 diabetes is an autoimmune disease, not an age-related one, yet this data suggests that senescent cells play a role in its development. This previously unknown association has some interesting implications for autoimmune diseases. If the same association is found in human T1 diabetes, this opens the door for treating it with senolytic therapy in the same way.
The market for an effective T1 diabetes treatment is also considerably large, so it would not be a surprise to see senolytics being used in clinical trials for it in the near future.
Literature
[1] Thompson, P. J., Shah, A., Ntranos, V., Van Gool, F., Atkinson, M., & Bhushan, A. (2019). Targeted Elimination of Senescent Beta Cells Prevents Type 1 Diabetes. Cell metabolism.
[2] Zhu, Y., Tchkonia, T., Fuhrmann‐Stroissnigg, H., Dai, H. M., Ling, Y. Y., Stout, M. B., … & Wren, J. D. (2016). Identification of a novel senolytic agent, navitoclax, targeting the Bcl‐2 family of anti‐apoptotic factors. Aging cell, 15(3), 428-435.
