The Cellular Polarity Regulator PAR-1 Plays An Important Role In C. Elegans Aging

Aging is characterized by functional decline and increased vulnerability of diseases and death overtime. As the global population is undergoing accelerated aging and living standards have improved, the needs for delaying aging and treating age-related diseases become urgent. Caenorhabditis elegans has a short life cycle, completed cell lineage, highly conserved genome and it is easy to be cultured and genetically manipulated in laboratories. These advantages make it a convenient and powerful tool to study the molecular mechanisms of aging. C. elegans researchers have elucidated several pathways that modulating aging, including mTOR, IGF-1 and AMPK. Moreover, environmental approaches such as dietary restriction, hypoxia and low ambient temperature were found to extend lifespan. Besides, rapamycin and metformin were developed to treat age-associated diseases. These results have been confirmed in various species.Interestingly, many essential genes that are critical for development also play important roles in aging. PAR-1, a highly conserved serine/threonine kinase, functions as a key cellular polarity regulator during embryonic development. Besides, depletion of PAR-1 during larval development causes a protruding vulva phenotype. The roles of PAR-1 during adulthood remain to be characterized. Our studies showed that inhibition of PAR-1 only during adulthood is sufficient to slow down aging. We observed extended lifespan, increased resistance of stress and proteotoxicity, reduced age-related muscle decline after inhibition of par-1. Tissue-specific analysis indicated that PAR-1 functions in the epidermis to regulate aging. Genes rsks-1 and aak-2 are key mediators of the mTOR pathway and isp-1 is part of the mitochondrial electronic transport chain. Inhibition of PAR-1 in rsks-1 and isp-1 mutants cannot further prolong lifespan, whereas a deletion mutant in aak-2 fully abolished the lifespan extension by par-1 RNAi. All these genes have been shown to play important roles in aging. The genetic experiments suggested that PAR-1 functions in overlapping mechanisms by mTOR and mitochondrial pathway to determine lifespan. Together, we have identified PAR-1 as a novel regulator of aging.