Astaxanthin extends lifespan via altered biogenesis of the mitochondrial respiratory chain complex III

Abstract

Astaxanthin is a keto-carotenoid produced in some bacteria and algae, which has very important industrial applications (i.e., in cosmetics, coloring additive in aquaculture and as a dietary supplement for human). Here, we analyzed the molecular basis of Astaxanthin-mediated prolongevity in the model organism, Caenorhabditis elegans. The increased lifespan effects of Astaxanthin are restricted in C. elegans to the adult phase and are uninfluenced by various other carotenoids tested. Genetic analyses indicated that the Astaxanthin-mediated life-extension relies on mitochondria activity, via the Rieske iron-sulfur polypeptide-1 (ISP-1), but is not influenced by the functions of other known longevity-related gene-loci, including CLK-1, DAF-2, DAT-16, EAT-2, GAS-1 GLP-1 or MEV-1. Biochemical analyses of native respiratory complexes showed that Astaxanthin affects the biogenesis of holo-complex III (and likely supercomplex I+III, as well). Effects on holo-CIII assembly and activity were also indicated by in-vitro assays, with mitochondria isolated from worms, rodents, human and plants, which were treated with Astaxanthin. These data indicated a cross-species effect on the oxidative phosphorylation (OXPHOS) machinery by the carotenoid, and provide with further insights into the molecular mechanism of animals longevity extension by Astaxanthin. Significance Statement Astaxanthin is a widely consumed pigment by animals and human. In this study we find that Astaxanthin, but not other tested carotenoids, significantly extends the lifespan of animals by affecting respiratory complex III (CIII) biogenesis of the mitochondria, in plants, C. elegans, rodents and human. We further propose a model to try explaining this effect of astaxanthin on animals’ longevity.

Terpenoids as Potential Geroprotectors

“…Carotene lycopene had no effects on C. elegans lifespan parameters [ 348 ]. At the same time, pure synthesized lycopene at a dose of 7.5 ppm increased the mean lifespan of both D. melanogaster males and females by 4.8–8.1% as well as the maximum lifespan of females by 4.8% [ 345 ].…”

“…Astaxanthin in concentrations 0.1–1 mM also increased the mean lifespan of wild-type C. elegans up to 31% [ 351 ]. It was shown that the positive effects on C. elegans lifespan parameters were observed only if the compound was fed to animals throughout their entire life or only at adult stage [ 348 ]. No effects were found, when astaxanthin has been fed to worms only from the larval L1 stage until adulthood.…”

“…The effects on flies’ females were not studied. Zeaxanthin had no effects on C. elegans lifespan parameters [ 348 ].…”

“…The effects of astaxanthin were also associated with decreased ROS production in mitochondria. However, in another study, it was shown that the effects of astaxanthin on C. elegans were independent of the insulin/IGF-1 signaling pathway as the positive effects of the compound were also present in experiments with daf-2(e1370) and daf-16(mu86) strains [ 348 ]. Experiments with eat-2 (ad1116) mutants revealed that they were also independent of the dietary restriction mechanism.…”

“…Experiments with eat-2 (ad1116) mutants revealed that they were also independent of the dietary restriction mechanism. The main mechanism of astaxanthin proposed by the authors is that the compound affects biogenesis and activity of the mitochondrial respiratory chain complex III, which possibly results in decreased mtROS production due to the decreased electron leakage [ 348 ].…”