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Abstract

Caloric restriction reduces metabolic disease and associated comorbidities. Yet, the molecular mechanisms encoding cellular memory of these benefits remain unclear. Here, we use a functional genomics approach to integrate evolutionary cues, single-cell sequencing, and metabolomics, identifying convergent signals that encode epigenetic memory of adaptive states in visceral adipose tissue natural killer (NK) cells. Cross-species analysis shows that genomic hubs linked to human accelerated regions (HARs) are conserved and active during dietary restriction, forming transcriptional compartments that regulate oxidative stress response and DNA repair genes. Targeted screens and multimodal profiling across human data and mouse models reveal convergent signals needed for persistent adaptation: cooperative transcriptional regulators (NRF2, CIRBP, NR4A2) at key HAR-linked genomic hubs, innate immune mediators (IL15-IL2RB), and metabolic cofactors from linoleic acid oxidation. Activity of these convergent signals reduces DNA damage and methylation and enhances epigenetic plasticity and cytotoxic functions, thereby decreasing tissue fibrosis and senescence while maintaining both local and systemic metabolic plasticity. Mechanistically, linoleic acid metabolism supplies acetyl-CoA to sustain H3K27ac epigenetic marks that maintain coordinated repair and cytotoxic programs after programming. IL15-IL2RB signaling links tissue metabolic state to NK cell function for coherent adaptive responses. We show that engineering of NK cells with this multimodal programming leads to long-term preservation of therapeutic phenotypes in metabolic aging models, rescuing systemic dysfunction through damaged cells clearance and leptin sensitivity. Overall, these findings establish that convergent signals encode persistent cellular phenotypes linked to metabolic plasticity, suggesting design principles for engineering therapeutic memory of cell function. One-Sentence SummaryA multimodal approach reveals how dietary and evolutionary cues can be harnessed to engineer resilient phenotype memory.

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