This result is unexpected, I have to say. Type 1 diabetes is not an age-related disease in any way; the majority of cases appear early. It is also understood to be an autoimmune condition, in which the immune system mistakenly attacks a particular tissue type or cell population. Yet researchers here show that senescent cells are a primary driver of the pathology of the condition, the death of beta cells in the pancreas and consequent severe metabolic dysfunction due to a lack of insulin. The accumulation of senescent cells is a mechanism associated with aging, not early life. This work raises many questions, such as will researchers find cellular senescence to be a critical part of other autoimmune conditions? Is the relevance of cellular senescence in mouse models definitely going to be the case in humans as well?
If cellular senescence is important in human type 1 diabetes, and if it is possible to achieve the same sort of results in humans as were obtained in mice in this study, then we will find out quite quickly. Senolytic therapies to clear as much as half of the senescent cells present in many tissues already exist: dasatinib and quercetin, possibly fisetin and piperlongumine. All of these are cheap and readily available for anyone who wishes to self-experiment. I'm sure that a number of type 1 diabetes patients will choose to do so. Further, the market for drugs for type 1 diabetes is so large that trials of senolytics for this condition will commence soon, given this research as a starting point and wake up call.
Type 1 diabetes (T1D) results from the loss of pancreatic beta cells, leading to insulin deficiency and disruption of glucose metabolism. The loss of beta cells is thought to be driven by an underlying autoimmune disorder in which peripheral tolerance is lost and mature autoreactive CD4+ and CD8+ cytotoxic T cells carry out progressive destruction of beta cells with support from innate immune cells. As a consequence, the major focus of current experimental therapies for T1D is to restore normal immune system function. In contrast, comparatively little is known about how beta cells themselves could actively participate and initiate the disease process.
Previous work has established that activation of the terminal unfolded protein response (UPR) in beta cells precedes symptoms of overt T1D. Indeed, inhibitors of the terminal UPR preserve beta cell mass and can reverse diabetes in the non-obese diabetic (NOD) mouse model, the classic model for spontaneous autoimmune diabetes, which recapitulates most of the features of T1D in humans. While it is generally accepted that apoptosis is the main response to terminal UPR, whether a beta cell mounts a protective or destructive stress response depends on the nature and duration of the stress as well as the competence of the beta cell to respond. Recent work has shown that intrinsic beta cell fragility is an underlying feature of both type 1 and 2 diabetes, prompting a closer investigation into the outcomes of the stress responses of beta cells in these diseases.
Cellular stress responses can induce a senescent fate and acquisition of a secretome composed of cytokines, chemokines, growth factors, proteases, and extracellular matrix factors, known as the senescence-associated secretory phenotype (SASP). A growing body of work supports the notion that SASP is beneficial when resolved efficiently, such as during embryonic development, wound healing, and tissue regeneration. However, the accumulation of senescent cells can disrupt tissue architecture and lead to dysfunction. Hence, a variety of age-related diseases in which senescent cell burden is high can be ameliorated either by genetic ablation of senescent cells or by the administration of small molecules that kill senescent cells.
Here, we report that in the NOD mouse model and in human T1D, a subpopulation of beta cells undergoes a stress response leading to senescence and SASP. Elimination of senescent beta cells from NOD mice afforded robust protection against diabetes, indicating that this subpopulation of cells contributes to disease progression. Remarkably, senolytic treatment had no apparent effect on the major lymphoid or myeloid populations infiltrating the islets, in the spleen or pancreatic lymph nodes, suggesting that in these experiments ablation of senescent beta cells does not affect immune cells. Taken together, these findings demonstrate that SASP is a pathogenic mechanism in T1D and that targeted elimination of senescent beta cells prevents this disease.