Targeting senescent cells alleviates obesity‐induced metabolic dysfunction

Abstract

Adipose tissue inflammation and dysfunction are associated with obesity‐related insulin resistance and diabetes, but mechanisms underlying this relationship are unclear. Although senescent cells accumulate in adipose tissue of obese humans and rodents, a direct pathogenic role for these cells in the development of diabetes remains to be demonstrated. Here, we show that reducing senescent cell burden in obese mice, either by activating drug‐inducible “suicide” genes driven by the p16Ink4a promoter or by treatment with senolytic agents, alleviates metabolic and adipose tissue dysfunction. These senolytic interventions improved glucose tolerance, enhanced insulin sensitivity, lowered circulating inflammatory mediators, and promoted adipogenesis in obese mice. Elimination of senescent cells also prevented the migration of transplanted monocytes into intra‐abdominal adipose tissue and reduced the number of macrophages in this tissue. In addition, microalbuminuria, renal podocyte function, and cardiac diastolic function improved with senolytic therapy. Our results implicate cellular senescence as a causal factor in obesity‐related inflammation and metabolic derangements and show that emerging senolytic agents hold promise for treating obesity‐related metabolic dysfunction and its complications.

Accelerated osteocyte senescence and skeletal fragility in mice with type 2 diabetes

“…In addition to acquiring an oftentimes complex SASP, senescent cells can display a variety of biomarkers, including profound changes in heterochromatin (i.e., SADS) (27), DNA damage colocalized with telomeres (i.e., TAF) (28), and increased expression of the cyclin-dependent kinase inhibitors p16 Ink4a and p21 Cip1 (21). Accelerated accumulation of senescent cells has been identified in mice during obesity in adipose tissue, liver, and brain (13)(14)(15) and with T2D in the pancreas (e.g., senescent β cells) (16). In the latter study, HFD-induced obesity and insulin resistance in mice caused accelerated β cell senescence with a specific SASP, whereas senolysis (i.e., clearance of senescent cells) using either genetic or pharmacological approaches improved glucose homeostasis, β cell function, and the gene expression profile of β cells (16).…”

“…We have previously identified senescent cells in the bone microenvironment with aging (11) and found that targeting cellular senescence improved age-related bone loss (12). Furthermore, senescence has been shown to increase in adipose tissue, liver, and brain during obesity (13)(14)(15) and in pancreatic β cells, contributing to T2D (16). This led us to hypothesize that cellular senescence may be a mechanistic link between poor bone quality and T2D.…”

Development of an in vitro senescent hepatic cell model for metabolic studies in aging

“…Moreover, the mRNA expression of senescence marker genes, P53, P21 and P16 were increased in the senescent AML12 cells compared to control AML12 cells (Figure 1d). Similarly, the expression of these genes also was increased in livers from old mice (100-108 week age) compared to those from young mice (12)(13)(14)(15)(16)(17)(18)(19)(20) week age) (Figure 1e). Furthermore, multiple H2O2 treatments increased senescence since there was increased activated -Gal (SA -Gal)-positive cells (Figure 2a,b) and H2A.X-positive cells containing condensed chromatin in larger nuclei (Figure 2c,d).…”

“…Recent studies in the liver show that inducing hepatocyte senescence promotes fat accumulation and hepatic steatosis in vitro and in vivo [17]. Likewise, targeting senescent hepatocytes and adipocytes reduce overall hepatic steatosis and improve obesity-induced metabolic dysfunction [14,17]. These findings suggest that senescence plays an important role in the development of chronic hepatic diseases and their metabolic abnormalities.…”

“…Under pathological stress conditions, excessive accumulation of senescence cells in affected tissues adversely affects the tissue's regenerative ability and creates a proinflammatory environment that can resemble various age-related disorders such as Alzheimer's disease, cancer, arthritis, cataracts, osteoporosis, atherosclerosis, hypertension, cardiovascular disease, Type 2 diabetes, and chronic liver disorders [3,5,7,[9][10][11][12]. Targeting senescent cells has the potential to delay age-associated disorders and/or reverse pathological metabolic phenotypes [3,[13][14][15][16]. Recent studies in the liver show that inducing hepatocyte senescence promotes fat accumulation and hepatic steatosis in vitro and in vivo [17].…”