Rejuvenation strategies share gene expression programs of reduced inflammation and downstream restored fatty acid metabolism

Abstract

Mammalian aging is accompanied by low-grade chronic inflammation (CI), termed inflammaging, commonly regarded as a proximal cause of aging-related dysfunction. Inflammaging is thought to lie downstream of core drivers of aging consisting of cellular and molecular changes and damage forms, such as aberrant epigenomes and transcriptomes. Here we test the reverse hypothesis, that CI itself causes multiple aging-related changes at the transcriptional level - and thus that inflammation is a core driver of aging and some of the transcriptional changes are downstream of it. By analyzing bulk and single-cell RNA sequencing data, we find that interventions in lung, liver, and kidney that cause CI in young mice partially recapitulate the gene expression signature of aging mice in the same organs. This recapitulation occurs in most measured cell populations, including parenchymal, immune and stromal cells, and consists of both inflammation signals themselves and non-inflammation related genes. We find that senolytic treatment reverses the shared gene expression component of aging and CI. The results point to the potential role of age-dependent CI as a core driver of aging.