UCLA

AbstractAs organisms age, they often experience declining health and an increased risk of debilitating diseases, ultimately leading to mortality. With the aging population growing rapidly in the United States and globally, medical expenditures for treating age-related conditions are skyrocketing. Decades of research into aging have accumulated vast knowledge, paving the way for the development of treatments and therapeutic strategies to combat these issues. The extraordinary findings have shown that aging processes can be regulated, as evidenced by model organisms whose lifespan has been doubled through specific gene mutations, offering promising avenues for controlling aging and associated diseases. Here we show that supplementation with the endogenous metabolite α-ketobutyrate (α-KB) prolongs the healthspans and lifespans of C. elegans and mice. Using an unbiased biochemical approach, drug affinity responsive target stability (DARTS), we identified microtubule-actin cross-linking factor (MACF1) protein to be the target of α-KB, as MACF1 exhibited resistance to proteolysis in the presence of α-KB. MACF1, a cytoskeletal linker protein critical for cellular and tissue integrity, has not previously been studied for its influence on longevity pathways. Our research revealed that α-KB's longevity effects require VAB-10, the worm ortholog of mammalian MACF1. Knockdown of VAB-10 via RNA interference increased the phosphorylation of AMP-activated protein kinase (AMPK), a sensor and regulator of cellular energy balance. We found that AMPK was also activated by α-KB treatment in wildtype animals. Furthermore, AMPK downstream effectors CRTC-1 and NHR-49 were found to be essential for lifespan extension by α-KB in this study. AMPK activation has been shown to preserve mitochondrial homeostasis during aging, and we found that α-KB treated worms had maintained youthful mitochondrial network during aging. α-KB’s longevity effect is abrogated by loss-of-function mutation of mitochondrial fusion component. These findings collectively propose a model wherein α-KB promotes longevity by modulating AMPK via VAB-10/MACF1 interaction. Crucially, our study demonstrated that α-KB prolonged the lifespan of aged male mice and enhanced the healthspan of both male and female mice. Our findings provide hope for developing therapeutic strategies that utilize endogenous metabolites to target longevity pathways linked to cellular energy metabolism and mitochondrial dynamics.