Much of present research into longevity-enhancing genetic alterations is a matter of following the chains of association in protein machinery, looking for common mechanisms shared by different mutations. Since any given metabolic alteration that extends life can be induced or influenced by changing the levels of numerous different proteins, it is expected that (a) researchers will find many different longevity mutations beyond those already known, and (b) most of these will act through a much smaller number of common mechanisms. Identifying those common mechanisms is one path towards greater understanding of the way in which natural variations in longevity are determined by genes and the operation of metabolism.
While numerous life-extending manipulations have been discovered in the nematode Caenorhabditis elegans, one that remains most enigmatic is disruption of oxidative phosphorylation. In order to unravel how such an ostensibly deleterious manipulation can extend lifespan, we sought to identify the ensemble of nuclear transcription factors that are activated in response to defective mitochondrial electron transport chain (ETC) function.
Using a feeding RNAi approach, we targeted over 400 transcription factors and identified 15 that, when reduced in function, reproducibly and differentially altered the development, stress response, and/or fecundity of isp-1(qm150) Mit mutants relative to wild-type animals. Seven of these transcription factors - [including HIF-1 and] the CREB homolog-1 (CRH-1)-interacting protein TAF-4 - were also essential for isp-1 life extension.
When we tested the involvement of these seven transcription factors in the life extension of two other Mit mutants, namely clk-1(qm30) and tpk-1(qm162), TAF-4 and HIF-1 were consistently required. Our findings suggest that the Mit phenotype is under the control of multiple transcriptional responses, and that TAF-4 and HIF-1 may be part of a general signaling axis that specifies Mit mutant life extension.