title: 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.
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/Université Louis Pasteur, Illkirch, France.
authors.forename: Carmen
authors.initials: C
authors.lastname: Argmann
authors.forename: Radu
authors.initials: R
authors.lastname: Dobrin
authors.forename: Sami
authors.initials: S
authors.lastname: Heikkinen
authors.forename: Aurélie
authors.initials: A
authors.lastname: Auburtin
authors.forename: Laurent
authors.initials: L
authors.lastname: Pouilly
authors.forename: Terrie-Anne
authors.initials: TA
authors.lastname: Cock
authors.forename: Hana
authors.initials: H
authors.lastname: Koutnikova
authors.forename: Jun
authors.initials: J
authors.lastname: Zhu
authors.forename: Eric E
authors.initials: EE
authors.lastname: Schadt
authors.forename: Johan
authors.initials: J
authors.lastname: Auwerx
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D005786:Gene Expression Regulation; D008136:Longevity / Q000235:genetics*; D008297:Male; D051379:Mice; D047495:PPAR gamma / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D047495:PPAR gamma