Senotherapeutics: emerging strategy for healthy aging and age-related disease

Abstract

Cellular senescence (CS) is one of hallmarks of aging and accumulation of senescent cells (SCs) with age contributes to tissue or organismal aging, as well as the pathophysiologies of diverse age-related diseases (ARDs). Genetic ablation of SCs in tissues lengthened health span and reduced the risk of age-related pathologies in a mouse model, suggesting a direct link between SCs, longevity, and ARDs. Therefore, senotherapeutics, medicines targeting SCs, might be an emerging strategy for the extension of health span, and prevention or treatment of ARDs. Senotherapeutics are classified as senolytics which kills SCs selectively; senomorphics which modulate functions and morphology of SCs to those of young cells, or delays the progression of young cells to SCs in tissues; and immune-system mediators of the clearance of SCs. Some senolytics and senomorphics have been proven to markedly prevent or treat ARDs in animal models. This review will present the current status of the development of senotherapeutics, in relation to aging itself and ARDs. Finally, future directions and opportunities for senotherapeutics use will discussed. This knowledge will provide information that can be used to develop novel senotherapeutics for health span and ARDs.

Exploring the Relevance of Senotherapeutics for the Current SARS-CoV-2 Emergency and Similar Future Global Health Threats

“…Ongoing clinical trials with SASP inhibitors targeting IL-6 as well as with ruxolitinib (NCT04331665) may provide useful information in this field. This research could eventually pave the way to exploration of whether other senotherapeutics, such as senolytics (compounds that selectively kill senescent cells) [90,91], or compounds able to promote clearance of senescent cells by the immune system [16,92], may eventually provide an additional advantage in the COVID-19 therapy.…”

“…Regarding this last aspect, T-cells engineered to express the NKG2D chimeric antigen receptor (CAR), which recognizes NKG2D ligands on the surface of SCs, may be used to target senescent cells [16,35]. In turn, the recent discovery of dipeptidyl peptidase 4 (DPP4) as a selective membrane marker of cellular senescence may provide a target for the development of immune-mediated clearance of senescent cells [16,93]. However, senescence immune surveillance in the lung may work through specific and different mechanisms than those reported for other tissues [37].…”

“…In the original paper describing the senolytic activity of this drug, an effect on mitochondria and mitochondrial oxygen consumption rate was reported [21], which are well known metabolic targets to induce apoptosis in senescent cells [94,95]. Azithromycin can also induce apoptosis by down-regulating Bcl-xL [96], which is a target of various senolytic compounds including ABT-263, ABT-737 and B1331852 [16]. So far, there has not been much attention paid to the mechanism of action of senolytics, as the goal of most research in this area is aimed at removing senescent cells independently from the mechanism of action.…”

“…Hydroxychloroquine induces senescence in endothelial cells [18,20,21] Ruxolitinib Bioinformatic study (supported by BenevolentAI) Clinical trial (NCT04331665) JAK inhibitor, SASP suppressor [15][16][17] Rapamycin Network-based drug repurposing methodology for HCoV…”

Development of an in vitro senescent hepatic cell model for metabolic studies in aging

“…In this regard, senescent AML12 cells would be useful to identify SASPs and understand their roles in causing inflammation in hepatic cells. These cells also could be useful for understanding the pathological molecular and metabolic changes that occur in age-related chronic hepatic diseases such as NASH, hepatic cirrhosis, and HCC, as well as for screening nutraceuticals and pharmaceuticals that might be useful to treat the pathological features associated with aging and senescence, and their associated metabolic conditions [4,16,17,48,49,51,52].…”