Prolonging healthy aging: Longevity vitamins and proteins

Ames, Bruce N.

doi:10.1073/pnas.1809045115

Cited by 188 publications

(155 citation statements)

References 140 publications

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“…A triage hypothesis has been proposed for the systemic control of micronutrients. It distinguishes allocation to proteins necessary for immediate survival and reproduction from that to proteins important for long-term health [144].…”

Section: Zinc Deficiency a Pro-oxidant Condition Causing Oxidative Smentioning

confidence: 99%

The redox biology of redox-inert zinc ions

Maret

2019

Free Radical Biology and Medicine

172

124

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Zinc(II) ions are redox-inert in biology. Yet, their interaction with sulfur of cysteine in cellular proteins can confer ligandcentered redox activity on zinc coordination sites, control protein functions, and generate signalling zinc ions as potent effectors of many cellular processes. The specificity and relative high affinity of binding sites for zinc allow regulation in redox biology, free radical biology, and the biology of reactive species. Understanding the role of zinc in these areas of biology requires an understanding of how cellular Zn2+ is homeostatically controlled and can serve as a regulatory ion in addition to Ca2+, albeit at much lower concentrations. A rather complex system of dozens of transporters and metallothioneins buffer the relatively high (hundreds of micromolar) total cellular zinc concentrations in such a way that the available zinc ion concentrations are only picomolar but can fluctuate in signalling. The proteins targeted by Zn2+ transients include enzymes controlling phosphorylation and redox signalling pathways. Networks of regulatory functions of zinc integrate gene expression and metabolic and signalling pathways at several hierarchical levels. They affect enzymatic catalysis, protein structure and protein-protein/biomolecular interactions and add to the already impressive number of catalytic and structural functions of zinc in an estimated three thousand human zinc proteins. The effects of zinc on redox biology have adduced evidence that zinc is an antioxidant. Without further qualifications, this notion is misleading and prevents a true understanding of the roles of zinc in biology. Its antioxidant-like effects are indirect and expressed only in certain conditions because a lack of zinc and too much zinc have pro-oxidant effects. Teasing apart these functions based on quantitative considerations of homeostatic control of cellular zinc is critical because opposite consequences are observed depending on the concentrations of zinc: pro-or anti-apoptotic, pro-or anti-inflammatory and cytoprotective or cytotoxic. The article provides a biochemical basis for the links between redox and zinc biology and discusses why zinc has pleiotropic functions. Perturbation of zinc metabolism is a consequence of conditions of redox stress. Zinc deficiency, either nutritional or conditioned, and cellular zinc overload cause oxidative stress. Thus, there is causation in the relationship between zinc metabolism and the many diseases associated with oxidative stress. Highlights• Redox-inert zinc ions regulate some aspects of redox biology and the biology or reactive species.• Control of cellular zinc homeostasis determines antioxidant-like or pro-oxidant effects.• Zinc deficiency and overload cause oxidative stress.• Disorders of zinc metabolism are a cause or consequence of diseases associated with oxidative stress.Abbreviations ER, endoplasmic reticulum; GCL, glutamate cysteine ligase; MT, metallothionein; MTF-1, metal regulatory element (MRE)-binding transcription factor-1; NOS, nitric oxide syntha...

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Section: Zinc Deficiency a Pro-oxidant Condition Causing Oxidative Smentioning

confidence: 99%

The redox biology of redox-inert zinc ions

Maret

2019

Free Radical Biology and Medicine

172

124

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“…Astaxanthin has been implicated in numerous health benefits in humans, including reduction in cardiovascular diseases, enhancement of the immune response and reduction in the occurrence of various cancers. (Ames 2018, Zhang and Wang 2015, Zhang et al . 2016).…”

Section: Introductionmentioning

confidence: 99%

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

hoffman

Sultan

Saada

et al. 2019

Preprint

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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.

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“…Ergothioneine is an antioxidant with many potential health benefits (Cheah and Halliwell, 2012, Ames, 2018; Halliwell et al, 2018). Furthermore, the interaction of ERG with metal ions (Hanlon, 1971) could conceivably play a role in the intracellular chaperoning of trace elements.…”

Section: Discussionmentioning

confidence: 99%

Engineering the yeastSaccharomyces cerevisiaefor the production of L-(+)-ergothioneine

Hoek

Darbani

Zugaj

et al. 2019

Preprint

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20 cerevisiae, yeast, nutraceutical 21 22 Abbreviations: ERG L-(+)-ergothioneine, HCO S-(hercyn-2-yl)-L-cysteine S-oxide, PBS 23 phosphate-buffered saline, PI propidium iodide, PLP pyridoxal 5'-phosphate, SAM S-adenosyl-24 L-methionine 25 26Abstract 27 L-(+)-Ergothioneine is an unusual, naturally occurring antioxidant nutraceutical that has been 28 shown to help reduce cellular oxidative damage. Humans do not biosynthesise it, so can acquire 29 it only from their diet; it exploits a specific transporter (SLC22A4) for its uptake. ERG is 30 considered to be a nutraceutical and possible vitamin that is involved in the maintenance of 31 health, and seems to be at too low a concentration in several diseases in vivo. Ergothioneine is 32 thus a potentially useful dietary supplement. Present methods of commercial production rely on 33 extraction from natural sources or on chemical synthesis. Here we describe the engineering of 34 the baker's yeast Saccharomyces cerevisiae to produce ergothioneine by fermentation in defined 35 media. After integrating combinations of ERG biosynthetic pathways from different organisms, 36 we screened yeast strains for their production of ERG. The highest-producing strain was also 37 engineered with known ergothioneine transporters. The effect of amino acid supplementation of 38 the medium was investigated and the nitrogen metabolism of S. cerevisiae was altered by knock-39 out of TOR1 or YIH1. We also optimized the media composition using fractional factorial 40 methods. Our optimal strategy led to a titer of 598 ± 18 mg/L ergothioneine in fed-batch culture 41 in bioreactors. Because S. cerevisiae is a GRAS ('generally recognised as safe') organism that is 42 2 widely used for nutraceutical production, this work provides a promising process for the 43 biosynthetic production of ERG. 44 45

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Prolonging healthy aging: Longevity vitamins and proteins

Cited by 188 publications

References 140 publications

The redox biology of redox-inert zinc ions

The redox biology of redox-inert zinc ions

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

Engineering the yeastSaccharomyces cerevisiaefor the production of L-(+)-ergothioneine

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