Modulating Aging and Aging-related Symptoms Using Endogenous Small Molecules

Aging and aging related diseases are closely related to wellness and lifespan of aged population. Modulating aging can be achieved by specific gene mutations, intrinsic signaling regulation (e.g. by dietary restriction) and pharmacological perturbations. Recent studies on the role of metabolism and endogenous metabolites in aging process provided hope for new anti-aging approaches to counter aging and aging related diseases. Here we identified a novel anti-aging metabolite, α-ketobutyrate (α-KB), that extends the lifespan of adult Caenorhabditis elegans and aged mice. Utilizing drug affinity responsive target stability assay, in-vitro enzymatic kinetics analysis, and epistasis, we demonstrated that α-KB depends on pyruvate dehydrogenase perturbation as a competitive alternative substrate to extend lifespan. Consistently, rewired pyruvate metabolism was detected in both α-KB treatment and genetic inhibition of pyruvate dehydrogenase in mammalian models. Furthermore, AMP-activated protein kinase (AMPK) pathway activation is required to induce longevity by α-KB. In an Alzheimer’s disease C. elegans model, epistasis demonstrated that α-KB requires pyruvate dehydrogenase and AMPK to delay the age dependent paralysis progression. Besides lifespan extension, α-KB also improves fitness in aged mice, including maintaining healthy hair growth. In the search of its mechanism and additional hair regenerative compounds, we discovered the essential role of autophagy in hair growth cycle and potential application of autophagy activators in hair loss therapy. As a shared effector of anti-aging signaling pathways, including TOR and AMPK pathways, autophagy is successfully induced by known aging modulators, α- ketoglutarate, α-KB, rapamycin, and metformin in mouse skin and confers their hair regeneration effect. Co-treatment of specific autophagy inhibitors blocks the stimulation of hair regeneration, which further confirmed the requirement of autophagy activation by these agents. Consistently, dynamically regulated autophagy level is detected during hair cycle: upregulation from telogen throughout anagen phase and downregulation from catagen until telogen. Our finding that α-KB combats aging and aging related disorders in worms and mice has implications for human anti-aging remedies development