Central longevity regulators have limited effects on age-dependent phenotypic changes assessed at scale. Aging interventions in mice

Most previous research aimed at identifying genetic and environmental factors regulating aging has largely relied on using lifespan as the sole proxy measure for aging or was restricted to the assessment of a small number of aging traits. Here, we introduce a new resource derived from a novel analytical approach to aging that offers the following major improvements compared to prior research. We employed large-scale phenotyping to analyze not only a few, but hundreds of phenotypes and thousands of molecular markers across tissues and organ systems in a single study in aging C57BL/6J mice. For each phenotype, we established lifetime profiles to determine at which age age-dependent phenotypic change is first detectable relative to the young adult baseline. We examined central genetic and environmental lifespan regulators (putative anti-aging interventions; PAAIs; targeting mTOR and growth hormone signaling; dietary restriction) for a possible amelioration of the signs and symptoms of aging. Importantly, in our study design, we included young treated groups of animals, subjected to PAAIs prior to the onset of age-dependent phenotypic change. This new study design allowed us to observe that most PAAI effects, surprisingly, influenced phenotypes long before the onset of age-dependent changes. Accordingly, many PAAI effects do not reflect a targeting of age-dependent phenotypic change, suggesting that the extent to which PAAIs influence the aging process has been overestimated.