Date Published: July 27, 2017
Publisher: Impact Journals LLC
Author(s): Mehrnaz Shamalnasab, Manel Dhaoui, Manjunatha Thondamal, Eva Bang Harvald, Nils J. Færgeman, Hugo Aguilaniu, Paola Fabrizio.
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 C. elegans as a model organism in which to determine whether ACBPs play similar roles in multicellular organisms. We systematically inactivated each of the seven C. elegans ACBP paralogs and found that one of them, maa-1 (which encodes membrane-associated ACBP 1), is indeed involved in the regulation of longevity. In fact, loss of maa-1 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 C. elegans the role of ACBP in aging, implicates HIF-1 in the increase of lifespan of maa-1 –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.
Genome-wide screens in simple model organisms have identified a number of longevity genes with potentially conserved roles in aging in mammals. The validity of this approach is supported by work in the last two decades showing that the principal lifespan-regulating genes and pathways are conserved in species ranging from yeast to mice .
In this study, we report that the C. elegans ACBP MAA-1 shares a conserved role in longevity regulation and stress resistance with the yeast ortholog Acb1. While the mechanisms by which ACBP influences yeast lifespan are not yet known, we identified several genes involved in the novel MAA-1 pathway in C. elegans. We found that loss of MAA-1 prolongs lifespan and promotes resistance to heat, oxidative, and proteotoxic stress; identified HIF-1 as the principal transcriptional regulator of longevity; implicated an interaction between maa-1 and daf-16 in lifespan regulation; and showed that HIF-1–dependent activation of shsp gene expression plays a key role in lifespan extension.