HIF-1–dependent regulation of lifespan in Caenorhabditis elegans by the acyl-CoA–binding protein MAA-1

Abstract

In yeast, the broadly conserved acyl-CoA-binding protein (ACBP) is a negative regulator of stress resistance and longevity. Here, we have turned to the nematode <i>C. elegans</i> as a model organism in which to determine whether ACBPs play similar roles in multicellular organisms. We systematically inactivated each of the seven <i>C. elegans</i> ACBP paralogs and found that one of them, <i>maa-1</i> (which encodes membrane-associated ACBP 1), is indeed involved in the regulation of longevity. In fact, loss of <i>maa-1</i> promotes lifespan extension and resistance to different types of stress. Through genetic and gene expression studies we have demonstrated that HIF-1, a master transcriptional regulator of adaptation to hypoxia, plays a central role in orchestrating the anti-aging response induced by MAA-1 deficiency. This response relies on the activation of molecular chaperones known to contribute to maintenance of the proteome. Our work extends to <i>C. elegans</i> the role of ACBP in aging, implicates HIF-1 in the increase of lifespan of <i>maa-1</i>-deficient worms, and sheds light on the anti-aging function of HIF-1. Given that both ACBP and HIF-1 are highly conserved, our results suggest the possible involvement of these proteins in the age-associated decline in proteostasis in mammals.