Rethinking the heritability of aging
The genetic contribution to human longevity is greater than previously thought
The shapes of aging
Life span varies strikingly across the tree of life. Baker’s yeast survive for days, fruit flies for weeks to months, bowhead whales for more than two centuries, and bristlecone pines for millennia (1). Comparative studies have uncovered conserved biological mechanisms that regulate aging (2), leaving little doubt that genetics places strong constraints on how long organisms live. Nevertheless, classical aging experiments in animals show that there is considerable variability in life span, even among isogenic littermates, indicating that there’s more to aging than genetics (3). Indeed, population-level studies on twins estimate that the heritability of human life span may be as little as 10 to 25% (4, 5), as do studies on pedigrees (6, 7). The prevailing view is that individual longevity is influenced largely by environmental factors and lifestyle. On page 504 of this issue, Shenhar et al. (8) challenge this notion, reporting that human heritability is 55%, considerably higher than previous estimates.
Shenhar et al. reexamined how mortality is conceptualized and quantified. In their framework, life span reflects the combined influence of intrinsic mortality, which is driven by biological aging processes, and extrinsic mortality, which arises from external hazards such as infections or accidents. Because extrinsic deaths may occur independently of inherited differences in the rate of biological aging, the causes of extrinsic death introduce variance unrelated to genetic contributions to intrinsic aging. As a result, the authors conclude that analyses that do not distinguish intrinsic from extrinsic mortality tend to systematically underestimate the heritability of aging, even when substantial genetic differences in intrinsic aging processes are present. Across human twin-cohort datasets, Shenhar et al. found that heritability estimates increased as extrinsic mortality declined and rose further when extrinsic deaths were mathematically removed from their model. Accordingly, they found that birth cohorts with progressively lower extrinsic mortality showed a parallel increase in estimated life-span heritability. Taking these observations into consideration, Shenhar et al. arrived at an intrinsic heritability of 55%.
Why might previous estimates be wrong? Although susceptibility to external hazards can be genetically influenced, mortality in historical human populations was largely dominated by variation in exposure, medical care, and chance. Many classical life-span studies therefore rely on cohorts born during periods when premature death from external causes was common. Such early deaths truncate survival independently of biological aging, reducing similarity among genetically related individuals and suppressing heritability estimates. Further, some studies have also relied on data spanning several hundred years with potentially poor data quality. The effect is that additional variance is introduced that masks correlations.
These considerations carry important implications. If life span is largely fixed by genetics, then the scope for influencing the rate of aging is limited, particularly for lifestyle interventions. Conversely, if genetic contributions are minimal, efforts to understand aging through genetic approaches are difficult to justify. Clarifying the role of inherited variation in aging-related mortality is therefore central to both biological understanding and societal expectations.
Several observations suggest that inherited factors make a meaningful contribution to the rate of aging. Rare genetic disorders marked by accelerated aging lead to early onset of multiple age-associated pathologies and markedly shortened life span, demonstrating that perturbations in single genes can substantially alter the rate of aging (9). Individuals with exceptionally long-lived relatives tend to experience lower mortality across adulthood, indicating that inherited factors contribute to such longevity (10). Consistent with this, twin studies have shown greater similarity in life span between identical twins than between fraternal twins, pointing to a genetic contribution to longevity (11). Genome-wide association studies have identified numerous variants associated with human life span and age-related traits, yet their combined explanatory power remains limited (12).
Another interesting finding of Shenhar et al. is that different diseases show different levels of heritability. They note that cardiovascular disease and dementia display higher heritability than cancer, an observation previously described in other patient cohorts (13, 14). A key ramification of this finding is that cancer is either more extrinsically influenced or more stochastic than other chronic diseases. Indeed, it makes sense that stochastic processes could drive rare cellular events leading to malignant transformation.
By reframing life-span heritability through the lens of intrinsic mortality, the study of Shenhar et al. has important consequences for aging research. A substantial genetic contribution strengthens the rationale for large-scale efforts to identify longevity-associated variants, refine polygenic risk scores, and link genetic differences to specific biological pathways that regulate aging. It also suggests that the limited success of previous genome-wide association studies may reflect phenotypic noise introduced by extrinsic mortality rather than inherently weak genetic effects. Further, the findings of Shenhar et al. agree with the observed 50% heritability of other complex traits (15). Perhaps this means that intrinsic rates of aging are tightly optimized through evolution, in line with other traits such as cognitive function and metabolism.
In Summary. Only about 50% of aging is heritable. Our next post will cover extrinsic causes for biological aging
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