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<p>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 <i>C. elegans</i> 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<sup>ER</sup>). This UPR<sup>ER</sup> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月16日

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

摘要

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 (UPRER). This UPRER 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.