Targeting Cellular Senescence for Age-Related Diseases: Path to Clinical Translation.

Abstract

Beyond the palliative reach of today's medicines, medical therapies of tomorrow aim to treat the root cause of age-related diseases by targeting fundamental aging mechanisms. Pillars of aging include, among others, genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, dysregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. The unitary theory of fundamental aging processes posits that by targeting one fundamental aging process, it may be feasible to impact several or all others given its interdependence. Indeed, pathologic accumulation of senescent cells is implicated in chronic diseases and age-associated morbidities, suggesting that senescent cells are a good target for whole-body aging intervention. Preclinical studies using senolytics, agents that selectively eliminate senescent cells, and senomorphics, agents that inhibit production or release of senescence-associated secretory phenotype factors, show promise in several aging and disease preclinical models. Early clinical trials using a senolytic combination (dasatinib and quercetin), and other senolytics including flavonoid, fisetin, and BCL-xL inhibitors, illustrate the potential of senolytics to alleviate age-related dysfunction and diseases including wound healing. Translation into clinical applications requires parallel clinical trials across institutions to validate senotherapeutics as a vanguard for delaying, preventing, or treating age-related disorders and aesthetic aging.