PparI32 Is a Key Driver of Longevity in the Mouse

Aging involves a progressive physiological remodeling that is controlled by both genetic and environmental factors. Many of these factors impact also on white adipose tissue (WAT), which has been shown to be a determinant of lifespan. Interrogating a transcriptional network for predicted causal regulatory interactions in a collection of mouse WAT from F2 crosses with a seed set of 60 known longevity genes, we identified a novel transcriptional subnetwork of 742 genes which represent thus-far-unknown longevity genes. Within this subnetwork, one gene was Pparg (Nr1c3), an adipose-enriched nuclear receptor previously not associated with longevity. In silico, both the PPAR signaling pathway and the transcriptional signature of PparI3 agonist rosiglitazone overlapped with the longevity subnetwork, while in vivo, lowered expression of Pparg reduced lifespan in both the lipodystrophic Pparg1/2-hypomorphic and the Pparg2-deficient mice. These results establish PparI32 as one of the determinants of longevity and suggest that lifespan may be rather determined by a purposeful genetic program than a random process. Author Summary The progression of aging is controlled by both genetic and environmental factors. Many of these factors are present also in adipose tissue, which itself has been shown to determine lifespan. Applying advanced bioinformatics methods on a large mouse gene expression data set, we identified Pparg (Nr1c3), an important metabolic controller that regulates the expression of many other genes particularly in adipose tissue, to be associated with longevity. This association was verified in experimental mouse models where the lowered expression of Pparg reduced lifespan. In addition to Pparg, our analysis identified >700 potential novel aging genes in mouse adipose tissue. More generally, these findings suggest that lifespan may not be a random process but controlled by a purposeful genetic program.