Midlife gene expressions identify modulators of aging through dietary interventions

Bing Zhou; Liu Yang; Shoufeng Li; Jialiang Huang; Haiyang Chen; Lei Hou; Jinbo Wang; Christopher D. Green; Zhen Yan; Xun Huang; Matt Kaeberlein; Li Zhu; Huasheng Xiao; Yong Liu; Jing-Dong J. Han

doi:10.1073/pnas.1119304109

New Research In

Edited by Valter D. Longo, University of Southern California, Los Angeles, CA, and accepted by the Editorial Board March 20, 2012 (received for review November 23, 2011)

Abstract

Dietary interventions are effective ways to extend or shorten lifespan. By examining midlife hepatic gene expressions in mice under different dietary conditions, which resulted in different lifespans and aging-related phenotypes, we were able to identify genes and pathways that modulate the aging process. We found that pathways transcriptionally correlated with diet-modulated lifespan and physiological changes were enriched for lifespan-modifying genes. Intriguingly, mitochondrial gene expression correlated with lifespan and anticorrelated with aging-related pathological changes, whereas peroxisomal gene expression showed an opposite trend. Both organelles produce reactive oxygen species, a proposed causative factor of aging. This finding implicates a contribution of peroxisome to aging. Consistent with this hypothesis, lowering the expression levels of peroxisome proliferation genes decreased the cellular peroxide levels and extended the lifespan of Drosophila melanogaster and Caenorhabditis elegans. These findings show that transcriptional changes resulting from dietary interventions can effectively reflect causal factors in aging and identify previously unknown or under-appreciated longevity pathways, such as the peroxisome pathway.

Footnotes

↵¹B.Z. and L.Y. contributed equally to this work.
↵²To whom correspondence may be addressed. E-mail: liuy{at}sibs.ac.cn or jdhan{at}genetics.ac.cn.

Author contributions: Z.Y., Y.L., and J.-D.J.H. designed research; B.Z., L.Y., S.L., J.H., H.C., L.H., J.W., L.Z., and H.X. performed research; B.Z., L.Y., S.L., C.D.G., X.H., M.K., Y.L., and J.-D.J.H. analyzed the data; and B.Z., L.Y., S.L., C.D.G., X.H., M.K., Y.L., and J.-D.J.H. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission. V.D.L. is a guest editor invited by the Editorial Board.
Data deposition: The microarray data reported in this paper have been deposited in the Gene Expression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession nos. GSE36836 and GSE36838).
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1119304109/-/DCSupplemental.