Cellular Senescence in Obesity and Associated Complications: a New Therapeutic Target

Abstract

Purpose of review: Obesity has increased worldwide recently and represents a major global health challenge. This review focuses on the obesity-associated cellular senescence in various organs and the role of these senescent cells (SnCs) in driving complications associated with obesity. Also, the ability to target SnCs pharmacologically with drugs termed senotherapeutics as a therapy for these complications is discussed.

Recent findings: Several studies have shown a positive correlation between obesity and SnC burden in organs such as adipose tissue, liver, and pancreatic-β-cells. These SnCs produce several secretory factors which affect other cells and tissues in a paracrine manner resulting in organ dysfunction. The accumulation of SnCs in adipocytes affects their lipid storage and impairs adipogenesis. The inflammatory senescence-associated secretory phenotype (SASP) of SnCs downregulates the antioxidant capacity and mitochondrial function in tissues. Senescent hepatocytes cannot oxidize fatty acids, which leads to lipid deposition and senescence in β-cells decrease function. These and other adverse effects of SnCs contribute to insulin resistance and type-2 diabetes. The reduction in the SnC burden genetically or pharmacologically improves the complications associated with obesity. The accumulation of SnCs with age and disease accelerates aging. Obesity is a key driver of SnC accumulation, and the complications associated with obesity can be controlled by reducing the SnC burden. Thus, senotherapeutic drugs have the potential to be an effective therapeutic option.

Fig. 1

Obesity-associated cellular senescence. Cellular senescence is an irreversible cell cycle arrest with senescent cells (SnCs) displaying characteristics such as elevated expression of p16^INK4a, p21^CIP1, p53 proteins, increased lysosomal senescence associated β-galactosidase activity (SA-β-gal), altered morphology, decreased lamin B1, elevated ROS levels, and senescence-associated secretory phenotype (SASP) production. Obesity is associated with accumulation of SnCs in various organs such as liver, adipose tissue (AT), and pancreatic β-cells and plays a major role in driving obesity-associated complications. SnC accumulation in AT impairs their ability to store lipids, elevates pro-inflammatory macrophages, and impairs adipogenesis process. Improper lipid storage in AT leads to fat deposition in other organs. Senescent liver cells loss the ability to oxidize fatty acids, resulting in excessive lipid accumulation. Elevated senescent burden in pancreatic β-cells decreases its proliferation capacity and causes metabolic dysfunction. Altogether, these affect the insulin-signaling pathway and glucose homeostasis. Thus, obesity-associated cellular senescence is a major contributor to the development of insulin resistance and impaired glucose tolerance. Targeting the SnCs either genetically or pharmacologically reduces the complications associated with obesity. Thus, senotherapeutic drugs may be an effective therapeutic option. Abbreviations: FA, fatty acid; ROS, reactive oxygen species; SASP, senescence-associated secretory phenotype; SAHF, senescence-associated heterochromatin foci; TAF, telomere-associated foci. Figure created with Biorender.com