Cellular Senescence as a Therapeutic Target for Age-Related Diseases: A Review

Abstract

Life expectancy has increased substantially over the last few decades, leading to a worldwide increase in the prevalence and burden of agingassociated diseases. Recent evidence has proven that cellular senescence contributes substantially to the development of these disorders. Cellular senescence is a state of cell cycle arrest with suppressed apoptosis and concomitant secretion of multiple bioactive factors (the senescence-associated secretory phenotype-SASP) that plays a physiological role in embryonic development and healing processes. However, DNA damage and oxidative stress that occur during aging cause the accumulation of senescent cells, which through their SASP bring about deleterious effects on multiple organ and systemic functions. Ablation of senescent cells through genetic or pharmacological means leads to improved life span and health span in animal models, and preliminary evidence suggests it may also have a positive impact on human health. Thus, strategies to reduce or eliminate the burden of senescent cells or their products have the potential to impact multiple clinical outcomes with a single intervention. In this review, we touch upon the basics of cell senescence and summarize the current state of development of therapies against cell senescence for human use.

SARS-CoV-2 Mediated Endothelial Dysfunction: The Potential Role of Chronic Oxidative Stress

“…The selective targeting of senescence may be another means by which the potential acute and long-term effects of SARS-CoV-2 infection can be mitigated, as stimulated senescent cells produce SASP proteins that can facilitate systemic inflammation. Based on recent evidences, some of the most promising anti-senescent therapeutics include treatments that decrease SASP biomarker levels ( McHugh and Gil, 2018 ; Amaya-Montoya et al, 2020 ). Most studies that have displayed significant inhibition of SASP biomarkers have focused on the suppression of signaling mechanisms (e.g., NF-kB, mTOR, p38MAPK, BRD4) in fibroblasts rather than ECs ( Chien et al, 2011 ; Freund et al, 2011 ; Moiseeva et al, 2013 ; Laberge et al, 2015 ; Tasdemir et al, 2016 ; Wang et al, 2017 ).…”

“…Future studies should explore the use of p90RSK inhibitors, such as FMK-MEA, as potential therapeutics for EC senescence caused by SARS-CoV-2 infection. Furthermore, senescent cells can be effectively targeted through a class of drugs known as senolytics, which are aimed at inducing apoptotic pathways in senescent cells ( McHugh and Gil, 2018 ; Amaya-Montoya et al, 2020 ). For example, Navitoclax, a potent senolytic drug, works by impeding the actions of anti-apoptotic Bcl proteins in senescent cells and has robust apoptotic outcomes in HUVECS ( Zhu et al, 2016 ; McHugh and Gil, 2018 ).…”

Novel insights into ferroptosis: Implications for age-related diseases

“…Over the past several decades, human life expectancy has steadily increased due to benefits from nutrition, technological advances, and improvements in medical care and vaccination 1 . It is estimated that by 2050, the number of people over the age of 60 will reach 2.1 billion 2 . With this steady increase in the number of older adults, age has become a major risk factor for age-related diseases (ARDs).…”

Cell Senescence: A Nonnegligible Cell State under Survival Stress in Pathology of Intervertebral Disc Degeneration

“…Another promising strategy is targeting the SASP for blocking the adverse effects of specific components like proinflammatory factors and matrix catabolic enzymes, without changing the inner antioncogenic pathways and cell cycle in senescent cells [ 108 , 116 ]. This could be achieved by targeting signaling cascade upstream of the SASP of senescent disc cells, such as NF- κ B or p38 MAPK as well as related regulators [ 12 , 87 , 117 ].…”