[Metabolic insights into cellular senescence and in therapeutic approaches].

Abstract

Aging serves as a risk factor for various age-associated disorders, such as cancer and type 2 diabetes. The study of aging is linked with metabolic research, due to the metabolic changes associated with aging. For example, chronic inflammation and the accumulation of DNA damages associated with aging lead to a decrease in NAD⁺ levels and mitochondrial dysfunction, resulting in cells becoming irreversibly cell cycle arrested, known as senescent cells. Senescent cells exhibit metabolic changes distinct from normal cells, along with distinct phenotypic characteristics, such as the senescence-associated secretory phenotypes (SASP), characterized by the excessive secretion of bioactive molecules such as inflammatory cytokines and chemokines. The accumulation of senescent cells has been observed in the pathology of age-related diseases, and their characteristics are thought to contribute to disease progression. Recent research has focused on the characteristics of senescent cells, such as their resistance to apoptosis, and aims to eliminate these cells from the body through pharmacological inhibition. Indeed, experimental evidence has demonstrated improvements in age-related phenotypes following the removal of senescent cells. Here, we review how age-related changes in cell metabolism induce cellular senescence, what are the metabolic characteristics of senescent cells, and how they affect the organism. Additionally, we also review our recent findings on the elimination of senescent cells by pharmacological inhibition of glutaminolysis rate-limiting enzyme GLS1, and outline the prospects for drug discovery targeting senescent cells.