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Developmental programming of late-life proteostasis and longevity by NuA4 complex activity in early life [RNA-Seq]

ABSTRACT: Maintaining proteostasis is essential for healthy aging and preventing neurodegenerative diseases like Alzheimer's disease, yet its collapse in late life leads to irreversible pathologies. It is unknown if there exists an early-life window where proteostasis can be programmed to confer lasting resilience, offering a preventative approach against these conditions. Leveraging short life cycle and the genetical tractability of Caenorhabditis elegans, we discover that inhibition of the TIP60/NuA4 acetyltransferase complex in early life can enhances late-life proteostasis and extends lifespan. We found that reducing early-life NuA4 activity diminishes epigenetic priming of H4K16ac, triggering compensatory activation of the XBP-1-mediated unfolded protein response (UPRER). This early-life-predominant XBP-1 activation remodels ER structure and reprograms lipid metabolism. Crucially, early-life NuA4/H4K16ac suppression boost oleic acid accumulation, which confers late-life health benefits. Overall, our study demonstrates the principle of developmental plasticity in shaping late-life proteostasis and reveals the potential for early interventions to combat neurodegeneration and aging.

ORGANISM(S): Caenorhabditis elegans

PROVIDER: GSE300492 | GEO | 2026/07/07

REPOSITORIES: GEO

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Developmental programming of late-life proteostasis and longevity by NuA4 complex activity in early life [CUT&Tag]

Project description:Maintaining proteostasis is essential for healthy aging and preventing neurodegenerative diseases like Alzheimer's disease, yet its collapse in late life leads to irreversible pathologies. It is unknown if there exists an early-life window where proteostasis can be programmed to confer lasting resilience, offering a preventative approach against these conditions. Leveraging short life cycle and the genetical tractability of Caenorhabditis elegans, we discover that inhibition of the TIP60/NuA4 acetyltransferase complex in early life can enhances late-life proteostasis and extends lifespan. We found that reducing early-life NuA4 activity diminishes epigenetic priming of H4K16ac, triggering compensatory activation of the XBP-1-mediated unfolded protein response (UPRER). This early-life-predominant XBP-1 activation remodels ER structure and reprograms lipid metabolism. Crucially, early-life NuA4/H4K16ac suppression boost oleic acid accumulation, which confers late-life health benefits. Overall, our study demonstrates the principle of developmental plasticity in shaping late-life proteostasis and reveals the potential for early interventions to combat neurodegeneration and aging.

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