Hormetic fasting extends Caenorhabditis elegans lifespan via H3K27 acetylation of lipid catabolism and antioxidant genes.

Yifei Zhou, Fasih M Ahsan, Sainan Li, Mengjiao Song, Jen F Rotti, Armen Yerevanian, Yidong Shen, Alexander A Soukas

Department of Pharmaceutical Analysis, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China; Center for Genomic Medicine and Diabetes Unit, Endocrine Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Electronic address: [email protected]. · pubmed

Paper

Abstract

Exposure to low levels of environmental challenges, known as hormetic stress, fosters subsequent stress resistance and promotes healthy aging in later life. However, specific mechanisms governing transcriptional reprogramming upon hormetic nutrient stress remain elusive. Here, we identify histone H3 lysine 27 acetylation (H3K27ac) as a crucial driver of transcriptomic adaptation to hormetic fasting. Beyond its immediate function of enhancing lipid catabolism for alternative energy sources, stress-induced H3K27ac activates lifelong antioxidant defenses, thereby reducing reactive oxygen species (ROS) produced by stress-induced fatty acid oxidation and their accumulation during aging. Induced H3K27ac at metabolic genes, mediated by the pioneer factor PHA-4/FOXA, the cooperating transcription factor NHR-49/HNF4, and the nucleoporin 50 (NPP-16/NUP50), is crucial for lifespan extension under hormetic nutrient stress in Caenorhabditis elegans. Our findings establish H3K27ac as a key transcriptional switch bridging nutrient status with transcriptomic reprogramming, underpinning the longevity of hormetic fasting through orchestrating lipid catabolism and antioxidant defenses.

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Research summary

The paper claims that hormetic fasting extends lifespan in Caenorhabditis elegans through H3K27 acetylation of lipid catabolism and antioxidant genes. This research is relevant as it explores mechanisms that may contribute to lifespan extension and healthy aging, addressing fundamental aspects of aging biology rather than merely treating age-related diseases.

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