Deep Phenotyping and Lifetime Trajectories Reveal Limited Effects of Longevity Regulators on the Aging Process in C57BL/6J Mice
Authors: Xie Kan , Fuchs Helmut , Scifo Enzo , Liu Dan , Aziz Ahmad , Aguilar-Pimentel Juan Antonio , Amarie Oana Veronica , Becker Lore , da Silva-Buttkus Patricia , Calzada-Wack Julia , Cho Yi-Li , Deng Yushuang , Cole Edwards A. , Garrett Lillian , Georgopoulou Christina , Gerlini Raffaele , Hölter Sabine M. , Klein-Rodewald Tanja , Kramer Michael , Leuchtenberger Stefanie , Lountzi Dimitra , Mayer-Kuckuk Phillip , Nover Lena L. , Oestereicher Manuela A. , Overkott Clemens , Pearson Brandon L. , Rathkolb Birgit , Rozman Jan , Russ Jenny , Schaaf Kristina , Spielmann Nadine , Sanz-Moreno Adrián , Stoeger Claudia , Treise Irina , Bano Daniele , Busch Dirk H. , Graw Jochen , Klingenspor Martin , Klopstock Thomas , Mock Beverly A. , Salomoni Paolo , Schmidt-Weber Carsten , Weiergräber Marco , Wolf Eckhard , Wurst Wolfgang , Gailus-Durner Valérie , Breteler Monique M.B. , de Angelis Martin Hrabě , Ehninger Dan 
Published: March 2022

Current concepts regarding the biology of aging are based on studies aimed at identifying factors regulating natural lifespan. However, lifespan as a sole proxy measure for aging can be of limited value because it may be restricted by specific sets of pathologies, rather than by general physiological decline. Here, we employed large-scale phenotyping to analyze hundreds of phenotypes and thousands of molecular markers across tissues and organ systems in a single study of aging male C57BL/6J mice. For each phenotype, we established lifetime profiles to determine when 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; the following PAAIs were examined: mTOR loss-of-function, loss-of-function in growth hormone signaling, dietary restriction) for a possible countering 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 detectable age-dependent phenotypic change. In parallel to our studies in mice, we assessed genetic variants for their effects on age-sensitive phenotypes in humans. We observed that, surprisingly, many PAAI effects influenced phenotypes long before the onset of detectable age-dependent changes, rather than altering the rate at which these phenotypes developed with age. Accordingly, this subset of PAAI effects does not reflect a targeting of age-dependent phenotypic change. Overall, our findings suggest that comprehensive phenotyping, including the controls built in our study, is critical for the investigation of PAAIs as it facilitates the proper interpretation of the mechanistic mode by which PAAIs influence biological aging.

Highlights

Phenotyping at scale defines lifetime trajectories of age-dependent changes in C57BL/6J mice

Central genetic and environmental lifespan regulators (putative anti-aging interventions; PAAIs) influence age-sensitive phenotypes (ASPs) often long before the appearance of age-dependent changes in these ASPs

Corresponding genetic variants in humans also have age-independent effects

Many PAAI effects shift the baseline of ASPs rather than slowing their rate of change