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

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

School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China. · pubmed

Paper

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

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Research summary

Reducing NuA4 complex activity during early development in C. elegans triggers a compensatory UPR(XBP-1) response that permanently enhances adult proteostasis and extends lifespan. This study provides mechanistic evidence for developmental programming of aging, linking early-life epigenetic regulation to late-life proteostatic capacity, which addresses a fundamental root cause of aging rather than just treating symptoms.

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