Nucleosome stability safeguards cell identity, stress resilience and healthy aging.

The Information Theory of Aging (ITOA) proposes that aging results from the progressive loss of epigenetic information. As the repeating units of the epigenome, nucleosomes are considered pivotal for its stability. Accordingly, the ITOA predicts that destabilization of nucleosomes will accelerate aging. However, this causal link has not been directly tested. Here, we addressed this through histone mutants that weaken histone-histone interactions. Without broadly perturbing steady-state chromatin accessibility, DNA damage, cell proliferation or viability, nucleosome instability compromised cell identity maintenance, altered lineage specification and activated intrinsic inflammatory and stress pathways in a manner reminiscent of aging in mouse tissues and human cells. Consistently, nucleosome instability accelerated age-associated transcriptional alterations and functional decline in Caenorhabditis elegans and Drosophila melanogaster, and reduced cellular resilience to exogenous perturbations-including environmental, epigenetic and mitotic stress-in human cells and Saccharomyces cerevisiae. These cross-species findings establish nucleosome stability as a fundamental requirement for preserving cell identity and stress resilience, thereby safeguarding organismal longevity.