Developmental priming of adult proteostasis and longevity by NuA4 complex activity in early life.

Authors

Yihan Wang, Xiong Xiong, Runshuai Zhang, Long Xiao, Xinyu Ruan, Tianyi Ni, Zicheng Liu, Jie Chen, Shenlu Qin, Zhuo Du, Yanxiao Zhang, Lianfeng Wu

Published in

The EMBO journal. Jul 16, 2026. Epub Jul 16, 2026.

Abstract

Proteostasis collapse, a hallmark of aging and neurodegeneration like Alzheimer's disease (AD), causes irreversible damage in late life. Whether late-life proteostasis capacity is developmentally programmed remains unclear, as mechanistic studies requiring lifelong tracking and molecular manipulation are challenging or impossible in long-lived species. Using C. elegans as a lifelong, genetically tractable AD model, we uncover a critical early-life window during which reducing TIP60/NuA4 acetyltransferase complex activity enduringly enhances proteostasis and extends lifespan. Mechanistically, NuA4 reduction depletes H4K16ac, triggering a compensatory, early-life-biased, XBP-1-mediated unfolded protein response (UPR^ER). This UPR^ER activation remodels endoplasmic reticulum (ER) morphology and reprograms lipid metabolism, driving selective oleic acid (OA) accumulation. Crucially, this developmentally-installed OA reservoir confers lasting resilience against proteotoxic stress, an effect mimicked by OA supplementation. Together, these findings establish a chromatin-ER-lipid axis that developmentally primes adult proteostasis and suggest early-life interventions as a strategy to promote healthy aging and resilience to proteotoxic stress.

PMID:
42463911
Bibliographic data and abstract were imported from PubMed on 17 Jul 2026.

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