This open access paper showcases a significant amount of scientific research. Scientists delved into transcriptomics data from the Interventions Testing Program (ITP) mouse studies, involving a vast number of mice across various tissues, to create clocks for aging and mortality. They integrated single cell transcriptomics and human data to validate these clocks for broader applicability and examined their effectiveness in cases of progeria and rejuvenation through reprogramming. The coming decade holds immense potential for the expansion of data related to biological age clocks. Progress in linking specific clock components to aging mechanisms is crucial for accelerating the evaluation of potential rejuvenation therapies.
The development of mortality transcriptomic clocks based on gene expression profiles holds promise in unveiling universal and specific molecular mechanisms underlying healthspan regulation, rejuvenation, and aging models. Through an RNA-seq analysis of mice subjected to 20 compound treatments in the ITP, and integrating data from diverse rodent tissues, this study generated robust multi-tissue transcriptomic biomarkers of mortality that quantify aging and lifespan changes in various models. These tools were extended to single-cell and human data, revealing common molecular aging mechanisms across cell types and species. Network analysis identified 26 co-regulated aging and longevity modules across tissues, leading to the creation of interpretable module-specific clocks that capture aging- and mortality-related phenotypes of functional components. These clocks showcased biological age acceleration induced by progeria models, chronic diseases, rejuvenation methods like heterochronic parabiosis, early embryogenesis, and cellular reprogramming. They highlighted universal mortality signatures shared among rejuvenation and age-related disease models, including notable markers like Cdkn1a and Lgals3 with strong associations with mortality, disease incidence, and risk factors. This study unveils molecular hallmarks of mammalian mortality that transcend organs, cell types, species, diseases, and rejuvenation models, shedding light on fundamental aging and longevity mechanisms.
