Genome integrity, somatic mutation, and the N-of-1 imperative in aging research

Aging research has made remarkable progress in describing aging through the genetic architecture of longevity, epigenetic clocks, proteomic signatures, and systems-level analyses. Yet a critical dimension remains underrepresented: the role of genome integrity, germline and somatic mutation accumulation in individual-specific vulnerability, frailty, and multimorbidity across the life course. The need for individual-level thinking has deep roots, from Darwin's emphasis on individual variation in natural selection, to Garrod's chemical individuality, to Lewontin's genotype-phenotype (G-P) map and reaction norms. This tradition in evolutionary biology and medicine treats the individual as a primary unit of both selection and intervention. Here, we argue for an N-of-1 framework in aging research. Population-level epidemiology and genetics of aging based on means and variances can produce a "curse of the average," obscuring the individual genetic variation that impacts relative aging among individuals. The individual-centered N-of-1 framework would integrate longitudinal tracking of mutation accumulation ranging from individual cells, tissues, and organs into comprehensive individual aging profiles aligned with the G-P map concept. The emerging idea of "mosaic aging" further emphasizes that cells, cell types, tissues, organs, and organ systems within an individual reflect heterogeneous aging trajectories. We discuss how somatic mutations, operating through Muller's ratchet-like dynamics in stem cell populations, generate hierarchical vulnerabilities across biological scales. The extreme rarity of centenarians who may maintain superior genome integrity illustrates the relevance of this framework. We suggest that an integrated G-P map approach, grounded in evolutionary genetics, would advance both precision medicine and geroscience.