Citrulline drives age-related lipid deposition for healthspan.

Too much or too less lipid deposition increases mortality, while in contrast, modest lipid deposition during aging is crucial for healthspan. How animals determine the aging state and then promote appropriate lipid deposition for lifespan benefits are largely unknown. In this study, we identified citrulline as a key metabolite driving aging-related lipid deposition for healthspan in Caenorhabditis elegans. Citrulline deficiency reduced aging-related lipid accumulation and shortened lifespan, an effect reversible by dietary supplementation. Mechanistically, during aging, the transcription factor MXL-3 is activated to upregulate the expression of pyr-1, encoding ornithine transcarbamylase (OTC), for the production of citrulline, which then activates the lipogenic enzymes DGAT-2 and MBOA-2 to consequently promote lipid synthesis and deposition for lifespan extension. Collectively, we uncover a MXL-3-citrulline-lipogensis axis to ensure healthspan, providing distinct insights into metabolic aging.