Tauroursodeoxycholic acid targets HSP90 to promote protein homeostasis and extends healthy lifespan.

As the elderly population expands, the pursuit of therapeutics to reduce morbidity and extend lifespan has become increasingly crucial. As an FDA-approved drug for chronic cholestatic liver diseases, tauroursodeoxycholic acid (TUDCA), a natural bile acid, offers additional health benefits beyond liver protection. Here, we show that TUDCA extends the lifespan and healthspan of C. elegans. Importantly, oral supplementation of TUDCA improves fitness in old mice, including clinically relevant phenotypes, exercise capacity and cognitive function. Consistently, TUDCA treatment drives broad transcriptional changes correlated with anti-aging characteristics. Mechanistically, we discover that TUDCA targets the chaperone HSP90 to promote its protein refolding activity. This collaboration further alleviates aging-induced endoplasmic reticulum (ER) stress and facilitates protein homeostasis, thus offering resistance to aging. In summary, our findings uncover new molecular links between an endogenous metabolite and protein homeostasis, and propose a novel anti-aging strategy that could improve both lifespan and healthspan.

The Endogenous Metabolite Glycerophosphocholine Promotes Longevity and Fitness in Caenorhabditis elegans.

Metabolism and aging are closely connected. The choline derivative glycerophosphocholine (GPC), an important precursor of the neurotransmitter acetylcholine, plays important roles in brain and nervous system function. Although it has been reported to alleviate cognitive decline in aged mice, whether GPC could promote longevity and other fitness factors remains unclear. Here, we find endogenous GPC level declines in the plasma of ageing humans. In Caenorhabditis elegans (C. elegans), GPC extends lifespan and improves exercise capacity during aging. Likewise, GPC inhibits lipofuscin accumulation. We further show that GPC treatment has no adverse effect on nematodes' reproductive abilities and body length. In addition to its benefits under normal conditions, GPC enhances the stress resistance of C. elegans. Mechanically, we find GPC significantly inhibits the reactive oxygen species (ROS) accumulation in worms. Our findings indicate the health benefits of GPC and its potential application in strategies to improve lifespan and healthspan.