Effect of Aging on Preadipocyte Differentiation

SPECIFIC AIMS Aging is the leading risk factor for most of the chronic diseases that account for the bulk of morbidity, mortality, and health costs. Recent findings suggest it may be feasible to delay age-related diseases as a group by targeting the fundamental aging mechanisms that appear to be "root cause" contributors, the Geroscience Hypothesis 79 • One such fundamental aging mechanism is cellular senescence 20 ••0 ·• 5 _ Senescence can cause local and systemic inflammation, dysfunction, and spread of senescence to previously normal cells through release of inflammatory cytokines, chemokines, proteases, stem cell/progenitor toxins, reactive metabolites, microRNA's (miRNAs), non-coding nucleotides, and exosomes, the senescence-associated secretory phenotype 13 · 75 (SASP). Our goal is to translate interventions targeting senescent cells into treatments for serious human age-related disorders as a group. Based on the observation that senescent cells are resistant to apoptosis 86, we used bioinformatics and RNA interference to identify the pro-survival senescent cell anti-apoptotic pathway (SCAP) network that is the "Achilles' heel" of senescent cells 1 • Using mechanism-based approaches, we discovered agents that disable the SCAP network, senolytic drugs 67, which cause senescent cell apoptosis due to their own SASP. Our hypothesis is that senolytic targeting of senescent cells can be translated into interventions that enhance healthspan. Since April, 2016, we demonstrated senolytics indeed selectively eliminate senescent cells in vitro and in vivo in mice and humans 3 • 26 · 38• 39 , alleviating a range of senescence-related disorders.