2. Deleteriome: The Totality of Deleterious Change Associated with Life

The deleteriome includes molecular damage, all sorts of errors, by-products, dysregulation, maladaptive remodeling, and their downstream consequences (2, 5). It is best viewed as a latent, system-level residual burden remaining after maintenance, repair, renewal, and dilution have acted. It includes both primary damage (e.g., chemical modifications, mutations, crosslinks) and many other deleterious changes (e.g., inflammation, cellular senescence, compensatory responses that become costly or mistuned with time). Causality is unequally distributed among various components of the deleteriome: some damages, their locations and manifestations across the lifespan are more impactful, but no single damage component causes aging on its own. The deleteriome is distinct from entropy and excludes age-associated changes that are neutral or adaptive: its components are concrete biological changes that are deleterious in a given context, although their aggregate system-level burden is latent. Currently, methods do not exist to quantify the deleteriome. Aging is best tracked systemically and reasoned about at the level of the whole burden: different mechanisms dominate in different tissues, yet all contribute to a rise in vulnerability. The deleteriome framework rejects single-cause explanations (e.g., oxidative damage, telomere, epigenetic, mitochondrial, mutation) and focuses attention on composition (i.e., which components dominate and where), rate (i.e., how fast burden rises), and control (i.e., what biology can and cannot maintain) (2–5). Operationalizing the deleteriome will require direct or proxy measures of major damage classes and cell-, tissue-, organ-, and system-specific burden maps. In this sense, frailty and multimorbidity can be viewed as different projections of the same latent aging process, whereas the deleteriome represents the residual burden that links these projections to mechanisms and outcomes.