Nature communicationsJul 14, 2026

Citrulline increases age-related fat buildup linked to healthy aging

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Jul 15, 2026

Abstract

Citrulline deficiency reduced aging-related lipid accumulation and shortened lifespan in Caenorhabditis elegans.

Modest lipid deposition during aging is linked to improved healthspan.
Citrulline acts as a critical metabolite that influences lipid deposition related to aging.
Dietary supplementation with citrulline can reverse the effects of its deficiency on lipid accumulation and lifespan.
The transcription factor MXL-3 is activated during aging, leading to increased production of citrulline.
Citrulline activates lipogenic enzymes DGAT-2 and MBOA-2, promoting lipid synthesis for lifespan extension.

Simplified

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.

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PubMed

Citrulline increases age-related fat buildup linked to healthy aging

Abstract

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Funding

Competing interests

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