Date Published: November 30, 2012
Publisher: Impact Journals LLC
Author(s): Gary Landis, Jie Shen, John Tower.
Gene expression changes in response to aging, heat stress, hyperoxia, hydrogen peroxide, and ionizing radiation were compared using microarrays. A set of 18 genes were up-regulated across all conditions, indicating a general stress response shared with aging, including the heat shock protein (Hsp) genes Hsp70, Hsp83 and l(2)efl, the glutathione-S-transferase gene GstD2, and the mitochondrial unfolded protein response (mUPR) gene ref(2)P. Selected gene expression changes were confirmed using quantitative PCR, Northern analysis and GstD-GFP reporter constructs. Certain genes were altered in only a subset of the conditions, for example, up-regulation of numerous developmental pathway and signaling genes in response to hydrogen peroxide. While aging shared features with each stress, aging was more similar to the stresses most associated with oxidative stress (hyperoxia, hydrogen peroxide, ionizing radiation) than to heat stress. Aging is associated with down-regulation of numerous mitochondrial genes, including electron-transport-chain (ETC) genes and mitochondrial metabolism genes, and a sub-set of these changes was also observed upon hydrogen peroxide stress and ionizing radiation stress. Aging shared the largest number of gene expression changes with hyperoxia. The extensive down-regulation of mitochondrial and ETC genes during aging is consistent with an aging-associated failure in mitochondrial maintenance, which may underlie the oxidative stress-like and proteotoxic stress-like responses observed during aging.
Heat shock protein (Hsp) genes are induced in response to stresses that cause protein denaturation, through activation of the heat shock factor (HSF) . Up-regulation of Hsp genes is also observed during normal aging . For example, both Hsp70 and Hsp22 are up-regulated during normal Drosophila aging, and this up-regulation requires functional HSF binding sites (Heat Shock Elements, or HSEs) in the promoters of these genes [3-5]. Genome-wide studies of gene expression changes during Drosophila aging have revealed additional features of a stress response, including the up-regulation of additional oxidative stress-response genes, and the dramatic up-regulation of innate immune response genes [6-8]. In addition, Drosophila aging is characterized by a small but across-the-board down-regulation of mitochondrial metabolism and electron transport chain (ETC) genes [6, 8], and this pattern is also observed in aging mammalian tissues , and at early adult ages in both Drosophila and C. elegans , indicating a conservation of aging mechanisms across species. Both innate immune response genes  and Hsp genes [11, 12] have been shown to be predictive biomarkers of individual animal life span when the gene promoters are fused to GFP to create transgenic reporters, thereby supporting the significance of the identified gene expression changes. Here normal aging was compared with multiple stressors to provide further insight into common and unique features.