Why do we age, and why do some interventions appear to slow aging or extend lifespan? These questions have challenged scientists for decades. While researchers know that aging affects nearly every tissue in the body, the molecular changes that drive aging and mortality are still being uncovered.

Researchers from Harvard Medical School and Brigham and Women’s Hospital analyzed more than 11,000 transcriptomes collected from over 25 tissues across four mammalian species, including mice, rats, macaques, and humans. By examining these large-scale gene expression datasets, the team identified common molecular signatures associated with aging and mortality.

The researchers used RNA sequencing and transcriptomic analysis to develop biomarkers capable of predicting chronological age, mortality risk, chronic disease burden, and even the effects of lifespan-extending interventions. Remarkably, many of these aging-related molecular patterns were conserved across species, suggesting that fundamental biological mechanisms of aging are shared among mammals.

Among the most significant findings was the identification of common gene expression changes involving genes such as CDKN1A and LGALS3. Protein levels associated with these genes were also linked to mortality risk and the presence of multiple chronic diseases in participants from the UK Biobank.

The analysis showed that aging-related molecular signatures appeared in a variety of biological conditions associated with cellular damage, including inflammation, cellular senescence, metabolic stress, and radiation exposure. Conversely, these signatures were reduced or reversed by interventions known to promote cellular rejuvenation, including cellular reprogramming, heterochronic parabiosis, and early embryonic development.

The researchers also discovered that aging is not driven by a single process. Instead, it involves multiple interconnected biological pathways. Network analysis revealed distinct aging modules involving inflammation, interferon signaling, mitochondrial function, chromatin regulation, and extracellular matrix organization.

To better understand these processes, the team developed pathway-specific aging clocks. These clocks allowed them to measure aging in individual cellular systems rather than treating aging as a single biological event. For example, chronic diseases primarily accelerated inflammatory aging pathways, while caloric restriction affected mitochondrial and metabolic aging pathways.

Another notable finding was the relationship between transcriptomic aging clocks and DNA methylation clocks. The two approaches showed correlated patterns of age acceleration in human blood samples, particularly within chromatin-associated pathways, providing additional evidence that multiple molecular mechanisms contribute to biological aging.

The findings suggest that aging can be measured and potentially targeted at the level of specific cellular processes. By identifying conserved molecular signatures across species, researchers may gain new tools for evaluating anti-aging interventions and understanding the biological mechanisms that influence lifespan and healthspan.