Senolytic drugs: from discovery to translation

Area of Science:

• Gerontology and Pharmacology
• Cellular Biology and Aging
• Drug Discovery and Development

Background:

• Senescent cells (SC) accumulate with aging and contribute to chronic diseases.
• SC are resistant to apoptosis and promote inflammation via the senescence-associated secretory phenotype (SASP).
• Existing senolytics target anti-apoptotic pathways in SC, inducing their death.

Purpose of the Study:

• To review the discovery and therapeutic potential of senolytics.
• To highlight the 'hit-and-run' intermittent dosing strategy for senolytics.
• To summarize preclinical and early clinical evidence for senolytic efficacy.

Main Methods:

• Hypothesis-driven discovery of early senolytics (Dasatinib, Quercetin, Fisetin, Navitoclax).
• Preclinical studies in animal models across various age-related diseases.
• Analysis of early-phase human clinical trials for senolytic interventions.

Main Results:

• Senolytics selectively induce apoptosis in senescent cells with a tissue-destructive SASP.
• Preclinical models demonstrate senolytics can delay, prevent, or alleviate frailty and numerous age-related disorders.
• Early human trials indicate senolytics reduce senescent cells, inflammation, and frailty.

Conclusions:

• Senolytics represent a novel therapeutic class targeting fundamental aging mechanisms.
• Potential applications span over 40 conditions, offering a new approach to age-related dysfunction.
• While promising, senolytics require further clinical validation before widespread use.