*4.3. Obesity, Diabetes Mellitus, and DKD*

Obesity is a major predictor contributing to type 2 diabetes (T2D), CKD, CVD, and increased mortality [135,136]. Besides being risk factors for CKD, obesity and T2D also contribute to cellular senescence per se [137,138]. Furthermore, the adverse e ffects of an increased fat mass are at least partly related to the secretion of proteins from adipocytes into the circulation, that is, adipocytokines. Indeed, adipocytokines associate with adverse metabolic status and the SASP [71,139]. Interestingly, treatment of obese mice with the senolytic agents dasatinib and quercetin improves glucose tolerance, enhances insulin sensitivity, lowers circulating inflammatory mediators, and increases levels of the beneficial adipocytokine adiponectin [140]. Furthermore, distinct adipocytokines can also contribute to attenuated vascular calcification in CKD, such as chemerin [141].

With respect to DKD, both humans and mice with DKD have an increased expression of senescence markers, including SA-β-gal, p<sup>16</sup>INK4A, and p21Waf1/Cip1, in di fferent renal cell types, and diabetic, p21-deficient mice are protected from DKD compared to diabetic wildtype mice [127]. However, future studies need to validate whether hyperglycemia rather than DKD itself might cause this pro-senescent phenotype.
