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 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.

Transcriptomic profiling of long- and short-lived mutant mice implicates mitochondrial metabolism in ageing and shows signatures of normal ageing in progeroid mice

“…Confirming our predictions, C. elegans carrying a loss of function allele of ahr-1 (Ahr in mice), display extended lifespan and increase motility and stress resistance (Eckers et al, 2016). Similarly in worms, knockdown of either acpb-1 or acbp-3 (Dbi in mice), extends lifespan (Shamalnasab et al, 2017). Among the interventions with a more positive correlation with short-lived mice and ageing, we found evidence of premature death in 6 cases, including Sirt7, Dicer1, Pdss2, Rb1 and Sgpl1 knockout mice (Frezzetti et al, 2011;Lin et al, 2011;Lyon and Hulse, 1971;Schmahl et al, 2007;Vakhrusheva et al, 2008).…”

New Strains for Tissue-Specific RNAi Studies in Caenorhabditis elegans

“…The ne219 allele was used as the RNAi deficient genetic background for tissue specific rescue of RNAi function (Qadota et al 2007). This technique of tissue-specific RNAi has been cited in over 70 publications, including these recent studies (Shamalnasab et al 2017;Liu et al 2017;Jeong et al 2017;Chun et al 2017;Han et al 2017). Our findings indicate that the results of these studies must be carefully interpreted, and future studies of gene knockdowns in specific tissues should not use the rde-1(ne219) background, because this strain is not completely RNAi deficient.…”

The Target of Rapamycin Signalling Pathway in Ageing and Lifespan Regulation

“…HIF-1 is required for the anti-ageing response induced by MAA-1 deficiency. This response relies on the activation of molecular chaperones known to contribute to maintenance of the proteome [ 102 ]. The discrepancy between studies could be explained through temperature.…”