Expansive Development of Transcriptomic Clocks for Aging and Mortality
This open access paper represents a great deal of scientific work. Researchers analyzed transcriptomics from all of the successful Interventions Testing Program (ITP) mouse studies, a very large number of mice, in multiple tissues, to produce clocks for aging and mortality. They then pulled in single cell transcriptomics and human data to validate the clocks for broader use, and assessed the utility of these clocks in states of progeria and rejuvenation via reprogramming. The next decade is going to see the data associated with clock-like measures of biological age expand enormously. We might hope to also see meaningful progress toward connecting specific clock components with the underlying mechanisms of aging - this is much needed in order to be able to use aging clocks to speed up the assessment of potential rejuvenation therapies.
The development of mortality transcriptomic clocks based on gene expression profiles and their functional components across organs and mammalian species could reveal universal and specific molecular mechanisms of the established and novel models of healthspan regulation, rejuvenation and aging. Here, we conducted an RNA-seq analysis of mice subjected to 20 compound treatments in the Interventions Testing Program (ITP). By integrating it with the data from over 4,000 rodent tissues representing aging and responses to genetic, pharmacological, and dietary interventions with established survival data, we developed robust multi-tissue transcriptomic biomarkers of mortality, capable of quantifying aging and change in lifespan in both short-lived and long-lived models.
These tools were further extended to single-cell and human data, demonstrating common mechanisms of molecular aging across cell types and species. Via a network analysis, we identified and annotated 26 co-regulated modules of aging and longevity across tissues, and developed interpretable module-specific clocks that capture aging- and mortality-associated phenotypes of functional components, including, among others, inflammatory response, mitochondrial function, lipid metabolism, and extracellular matrix organization. These tools captured and characterized acceleration of biological age induced by progeria models and chronic diseases in rodents and humans. They also revealed rejuvenation induced by heterochronic parabiosis, early embryogenesis, and cellular reprogramming, highlighting universal signatures of mortality, shared across models of rejuvenation and age-related disease. They included Cdkn1a and Lgals3, whose human plasma levels further demonstrated a strong association with all-cause mortality, disease incidence and risk factors, such as obesity and hypertension.
Overall, this study uncovers molecular hallmarks of mammalian mortality shared across organs, cell types, species and models of disease and rejuvenation, exposing fundamental mechanisms of aging and longevity.