Ppargamma2 is a key driver of longevity in the mouse

Abstract

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 Ppargamma 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 Ppargamma2 as one of the determinants of longevity and suggest that lifespan may be rather determined by a purposeful genetic program than a random process.

Figure 1. A subnetwork of likely longevity genes in mouse adipose tissue.

(A) Longevity-related subnetwork of 775 genes, extracted from the mouse adipose transcriptional network of 13,088 genes. The 33 “known” longevity genes used as a seed set are depicted as green diamonds, and the 213 genes overlapping from the mouse WAT rosiglitazone signature in blue circles. The 5 gene overlap of “known” longevity genes and rosiglitazone signature is shown as blue diamonds. Pparg, shown as a red circle, is part of the rosiglitazone signature. (B) The distribution of mean shortest path lengths (μ) for the set of 33 “known” longevity genes and 10⁶ randomly selected sets of 33 genes within the mouse consensus network. Red arrow marks the mean shortest path (μ = 6.7102) for the “known” longevity genes.

Figure 2. Pparg determines longevity.

(A) Lifespan of hypomorphic (hyp) Pparg deficient mice (n = 38 wild type and 24 Pparγ^hyp/hyp mice). ** p = 0.003. (B) Lifespan of Pparg2 knock-out mice (n = 25 wild type and 26 Pparg2^−/− mice). * p = 0.020 when mice >120 weeks were excluded from the test.