A groundbreaking revelation challenges the very foundation of how we measure biological aging, sparking a paradigm shift in the field. Dr. Dan Ehninger and Dr. Maryam Keshavarz, experts in biogerontology, have unveiled a critical flaw in our understanding of aging, one that could reshape the entire research landscape.
The paradox of lifespan extension is a key insight. While interventions may extend life, they don't necessarily slow down the aging process itself. This is evident across species, from humans where cardiovascular disease is the primary killer, to mice where neoplasia dominates, and even in invertebrates like Drosophila and C. elegans where specific failures determine lifespan.
The historical epidemiologic transition further underscores this point. The dramatic increase in human lifespan over the past two centuries was primarily due to advances in combating infectious diseases, not a fundamental slowing of aging. This distinction is crucial for interpreting pro-longevity effects and understanding the true nature of aging.
Aging clocks, such as those based on DNA methylation patterns, have become popular tools. However, the review raises concerns about their ability to truly measure biological age. The authors argue that these clocks may only capture correlation, not causation, and that they provide static snapshots rather than dynamic insights into the aging process.
Frailty indices face similar limitations. By summing diverse deficits into single scores, they may create misleading impressions of broad anti-aging effects.
The most provocative section of the review evaluates the hallmarks of aging framework. This framework, which has influenced research priorities and funding, may not be supported by the evidence. The authors found that most cited studies cannot distinguish between interventions that alter aging rates and those that produce age-independent baseline shifts.
The review proposes a conceptual framework to distinguish between rate effects, baseline effects, and mixed effects on age-sensitive phenotypes. This framework aims to provide a more rigorous understanding of genuine aging modulation.
Several critical questions emerge: Why do tissues age at different rates? Can cross-species translation succeed when life-limiting pathologies differ so fundamentally? These questions highlight the complexity of aging and the need for a more nuanced understanding.
The implications are far-reaching. If aging biomarkers and frameworks conflate baseline effects with genuine aging modulation, resources may be misdirected. The authors emphasize that geroscience aims to uncover mechanisms influencing age-related phenotypic change, not just regulate phenotypes.
The review concludes with practical recommendations for researchers, including building multitissue phenotype panels and including both young and old treatment groups in study designs.
This critical synthesis provides a comprehensive framework for understanding aging, offering both a historical perspective and a roadmap for future research. It reveals patterns and reconciles contradictions, showcasing the power of systematic literature analysis.
Source: Keshavarz, M. & Ehninger, D. (2025). Beyond the hallmarks of aging: Rethinking what aging is and how we measure it. Genomic Psychiatry. DOI: 10.61373/gp025w.0119
