Coming of age: could obesity-related metabolic complications be treated by targeting senescent cells?

Abstract

Aging is characterized by gradual deterioration of organ or tissue function and its ability to maintain homeostasis of the different physiological processes. This leads to the development of structural and functional alterations accompanied by an increased risk for diverse pathologies. Cellular senescence is a controlled biological process that could contribute to the development of many age-related diseases and related metabolic dysfunctions. Two major chronic diseases associated with premature accumulation of senescent cells that impose an enormous burden on global health systems are obesity and type 2 diabetes mellitus with its related complications. The purpose of this review is to highlight the links between aging, obesity, and type 2 diabetes mellitus, focusing on the role of cellular senescence in disease development and progression. Additionally, this review will discuss the potential of targeting cellular senescence as a promising therapeutic strategy for managing these interrelated diseases, therefore offering a novel approach to prevention and treatment.

Keywords: cellular senescence; metabolic complications; obesity; senolytics; type 2 diabetes mellitus.

FIGURE 1

Role of autocrine, paracrine and endocrine signalling in development and maintenance of senescence in the organism. This figure illustrates how senescent cells (represented here by adipose tissue) contribute to both local and systemic senescence. Throughout the autocrine/paracrine singaling, senescent cells maintain the senescent phenotype and promote senescence in neighboring cells. Additionally, release of SASP factors into the circulation promotes senescence in distant organs, thereby contributing systemic inflammation and tissue dysfunctions. Created in https://BioRender.com.

FIGURE 2

Mechanisms and impacts of cellular senescence. This figure illustrates the induction, characteristics and role of cellular senescence. Various stress factors–mitochondrial and telomere dysfunction, reactive oxygen species (ROS), DNA damage, physical stress (e.g., radiation) and chemotherapeutic agents–trigger a senescent phenotype characterized by cell cycle arrest, increased senescence-associated β-galactosidase activity (SA-β-gal), elevated reactive oxygen species (ROS) production, and transcriptional changes. Senescent cells secrete a complex combination of bioactive molecules, collectively known as a senescence-associated secretory phenotype (SASP), which influences the tissue microenvironment. Cellular senescence plays beneficial roles in physiological processes such as tissue repair, regeneration or tumor suppression. The persistent accumulation of senescent cells however promotes deleterious effects, contributing to the development of metabolic diseases, cardiovascular complication, tissue dysfunction and tumor promotion. Created in https://BioRender.com.

FIGURE 3

Systemic obesity- and T2DM-related complications connected with the accumulation of senescent cells. This figure highlights the systemic consequences of obesity and T2DM, with a focus on their link to the accumulation of senescent cells across multiple organs. Senescent cells through their SASP contribute to β-cell dysfunction in the pancreas, microvascular complications, hepatic steatosis and fibrosis in the liver, kidney, or lungs, impaired tissue regeneration, and complications including retinopathy and peripheral neuropathy. These pathologies underscore the systemic nature of senescence-driven dysfunction in obesity and T2DM. Created in https://BioRender.com.