Abstract
Aging is defined as a progressive decrease in physiological function accompanied by a steady increase in mortality. The antagonistic pleiotropy theory proposes that aging is largely due to the natural selection of genes and pathways that increase fitness and decrease mortality early in life but contribute to deleterious effects and pathologies later in life. Cellular senescence is one such mechanism, which results in a permanent cell cycle arrest that has been described as a mechanism to limit cancer cell growth. However, recent studies have also suggested a dark side of senescence in which a build-up of senescent cells with age leads to increased inflammation due to a senescence-associated secretory phenotype (SASP). This phenotype that includes many cytokines promotes tumorigenesis and can exhaust the pool of immune cells in the body. Studies clearing senescent cells from mice using the p16-based transgene INK-ATTAC have shown that senescent cells can impact both organismal aging and lifespan. Here we discuss these advances that have resulted in the development of a whole new class of compounds known as senolytics, some of which are currently undergoing clinical trials in humans for treating a variety of age-related pathologies such as osteoarthritis.
Highlights
Aging is defined as a progressive decrease in physiological function accompanied by a steady increase in mortality
Recent studies have suggested a dark side of senescence in which a build-up of senescent cells with age leads to increased inflammation due to a senescence-associated secretory phenotype (SASP)
Analyzing cancer tissues with this epigenetic clock, composed of methylation levels from 353 CpGs, indicated that tissues from cancer patients treated with various therapies appeared to be an average of 36 years older compared to the actual chronological age of the patients, while induced pluripotent stem cells from the same individuals showed resetting of the clock to an epigenetic age of zero
Summary
Studies clearing senescent cells from mice using the p16-based transgene INK-ATTAC have shown that senescent cells can impact both organismal aging and lifespan We discuss these advances that have resulted in the development of a whole new class of compounds known as senolytics, some of which are currently undergoing clinical trials in humans for treating a variety of age-related pathologies such as osteoarthritis. Up to 50% of mouse embryonic fibroblasts (MEF’s) exhibit a senescence phenotype after a mere five passages resulting from oxygen sensitivity due to ROS-induced DNA damage (Parrinello et al, 2003) These interdependent features of cell cycle withdrawal, macromolecular damage, dysregulated metabolism and an altered senescenceassociated secretory phenotype (SASP) have been described as hallmarks of the senescence phenotype, no markers appear to be universal for all types of senescent cells. To ensure the accurate identification of senescent cells it has been recommended by the International Cell Senescence Association that multiple markers be used in a three-step senescence identification protocol (Gorgoulis et al, 2019)
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