Systematic Review Calls for Overhaul in Biological Aging Measurement Paradigms

A recent systematic review advocates for a fundamental reassessment of the methodologies used to quantify biological aging, arguing that current proxies often mix genuine age-related changes with physiological effects unrelated to the aging process itself. The analysis, conducted by Dr. Dan Ehninger of the German Center for Neurodegenerative Diseases and Dr. Maryam Keshavarz, targets established metrics including lifespan extension data, epigenetic clocks, and the widely cited 'hallmarks of aging' framework.

The central contention is that many existing measures capture age-independent physiological shifts rather than the intrinsic rate of senescence. Experts frequently note that observed lifespan increases often result from successfully treating specific, life-limiting pathologies, not from a true deceleration of the overall aging process. This species-specific mortality bottleneck is evident across the animal kingdom: in humans, cardiovascular disease remains the leading cause of death, accounting for 35 to 70 percent of fatalities even among centenarians, suggesting death rarely results from 'pure' old age. This contrasts with mice, where neoplasia causes 84 to 89 percent of age-related deaths, and macaques, where cardiovascular disease accounts for over 60 percent of deaths in aged individuals, underscoring the need to distinguish between disease treatment and fundamental aging rate modification.

The review specifically scrutinizes aging clocks, noting their inherently correlational nature. While molecular tools like the epigenetic clocks, such as the Horvath clock introduced in 2013 based on nearly 8,000 samples, can accurately predict chronological age, their capacity to illuminate the causal mechanisms of aging remains debated. These tools, which utilize DNA methylation patterns across CpG sites, are valuable for risk stratification and tracking age acceleration, but interindividual variability stemming from confounding diseases and lifestyle factors can influence their predictive accuracy when compared to chronological age.

Furthermore, the evidentiary basis for the influential 'hallmarks of aging' framework, originally proposed by López-Otín and colleagues in 2013 and subsequently updated, is subjected to rigorous questioning. The analysis indicated that a substantial proportion of studies cited to support the roles of hallmarks like genomic instability (approximately 67% of cited studies) or cellular senescence (63%) were based on models that phenocopy aging manifestations but lack clear relevance to normal organismal aging. Many interventions show effects primarily in young animals, suggesting symptomatic improvement rather than a genuine modification of the intrinsic aging rate.

To advance the field beyond these limitations, researchers strongly recommend implementing new study designs that mandate the inclusion of both young and old treated cohorts. This comparative approach is essential to accurately distinguish between rate effects—a true slowing of aging—and baseline effects, which represent symptomatic improvement in physiological function. Such methodological rigor, alongside integrating composite clinical measures, is necessary to enhance the resolution of molecular markers and guide the development of effective geroprotective interventions aimed at improving healthspan.