Christina Curtis 1 , Gary N Landis 1 , Donna Folk 2 , Nancy B Wehr 3 , Nicholas Hoe 1 , Morris Waskar 1 , Diana Abdueva 1 , 4 , Dmitriy Skvortsov 1 , Daniel Ford 1 , Allan Luu 1 , Ananth Badrinath 1 , Rodney L Levine 3 , Timothy J Bradley 2 , Simon Tavaré 1 , 5 , John Tower , 1
9 December 2007
Transcriptional profiling of MnSOD-mediated life-span extension in Drosophila identifies a set of candidate biomarkers of aging, consisting primarily of carbohydrate metabolism and electron transport genes.
Several interventions increase lifespan in model organisms, including reduced insulin/insulin-like growth factor-like signaling (IIS), FOXO transcription factor activation, dietary restriction, and superoxide dismutase (SOD) over-expression. One question is whether these manipulations function through different mechanisms, or whether they intersect on common processes affecting aging.
A doxycycline-regulated system was used to over-express manganese-SOD (MnSOD) in adult Drosophila, yielding increases in mean and maximal lifespan of 20%. Increased lifespan resulted from lowered initial mortality rate and required MnSOD over-expression in the adult. Transcriptional profiling indicated that the expression of specific genes was altered by MnSOD in a manner opposite to their pattern during normal aging, revealing a set of candidate biomarkers of aging enriched for carbohydrate metabolism and electron transport genes and suggesting a true delay in physiological aging, rather than a novel phenotype. Strikingly, cross-dataset comparisons indicated that the pattern of gene expression caused by MnSOD was similar to that observed in long-lived Caenorhabditis elegans insulin-like signaling mutants and to the xenobiotic stress response, thus exposing potential conserved longevity promoting genes and implicating detoxification in Drosophila longevity.
The data suggest that MnSOD up-regulation and a retrograde signal of reactive oxygen species from the mitochondria normally function as an intermediate step in the extension of lifespan caused by reduced insulin-like signaling in various species. The results implicate a species-conserved net of coordinated genes that affect the rate of senescence by modulating energetic efficiency, purine biosynthesis, apoptotic pathways, endocrine signals, and the detoxification and excretion of metabolites.