Our understanding of aging in animals owes a great debt to a large body of careful work in a single-celled organism, the brewer’s yeastSaccharomyces cerevisiae. Indeed, as I’ve arguedbefore, yeast is one of the two organisms with the strongest credible claim to have started modern biogerontology. An unusually large crop of yeast aging papers have appeared over the last few months, and I thought it would be appropriate to spent a few paragraphs describing them — in honor of this humble organism that rises our bread, ferments our beer, and has done so much to open our eyes to the fundamental mechanisms of aging.
For those unfamiliar with the yeast field or simply wishing a clearly written and nearly comprehensive summary,Steinkrauset al.provide the historical perspective. The piece thoroughly reviews the development of yeast as a model system in aging, as well as the arguments in favor of a connection between results in yeast and well-established (but sometimes hard-to-test) hypotheses in animals.
Based on the influence that yeast has already had on biogerontology as a whole, it seems fair to claim that it will continue to reveal fundamentals of aging that are conserved across evolution. Now, however, there is quantitative evidence to back up that claim:Smithet al.have used bioinformatic and genomic approaches to study the conservation between known longevity genes in yeast and worm, and they show that yeast mutants in worm longevity genes are significantly more likely to be long-lived than randomly chosen mutants — suggesting that
genes that modulate aging have been conserved not only in sequence, but also in function, over a billion years of evolution.
Given this functional conservation, it is reasonable to use yeast to help answer questions about aging in general, so long as these questions as cell-biological in scope.
For instance: NAD+/NADH ratios are thought to be an important metric of the cellular energy balance, and appear to have effects both within the mitochondria and the cytosol. The mitochondrial inner membrane, however, is impermeable to both NAD+ and NADH. How, then, is information about energy balance communicated between the two cellular compartments?Easlonet al.report that two components of the malate-aspartate NADH shuttle (which transports metabolites across the mitochondrial membrane, resulting in equilibration of the cytosolic and mitochondrial NAD+/NADH pools) are involved in controlling longevity. The two proteins, Mdh1 and Aat1, are required for longevity enhancement by calorie restriction (CR), and overexpression of both proteins can increase lifespan independent of caloric conditions (but in a Sir2-dependent manner, about which see more below).
Another outstanding question involves how cellular energy balance is coordinated with the rates of catabolic and anabolic processes, and how this coordination impinges on regulation of longevity. We know that in yeast, the effects of CR are mediated by pathways involving thenutrient sensor TOR and the kinase Sch9. (Brief aside: longevity-enhancing mutations of Sch9 can alsosuppress genomic instability; new results fromQinet al.show that genomic instability is also associated with lifespan variation in yeast). Sch9 regulates, among other things, ribosome biogenesis; both CR and Sch9 mutation cause ribosome synthesis to decrease — but are the ribosome and longevity phenotypes related? Very likely yes:Steffenet al.report that multiple means of downregulating ribosome synthesis all extend lifespan, implying that reducing production of ribosomes is essential in order to reap the benefits of CR.
As the tools of biology have adapted, so has the yeast field (sometimes leading the charge, as in the case of the earliest microarray-based expression profiling experiments).Murakamiet al.have developed a high-throughput method for measuring yeast lifespan. In this first report, the authors primarily demonstrate the use of their method on known mutants, arguing that their results are similar but with lower variance. (Brief aside: they also demonstrate that CR-induced lifespan extension does not require SIR2 or any other yeast sirtuin, adding fuel to the controversy about whether sirtuins play any role in CR in yeast; for more, seehereandhere.) The increased precision of their technique will allow detection of subtler aging-related phenotypes than were previously detectable, very likely allowing us to add to the list of genes known to regulate lifespan. The high-throughput aspects of the method, of course, open the door to testing small-molecule drugs that could delay aging in yeast —historicallya fruitful approach though not without itspotential pitfalls.
If you’ve made it this far, feel free to toastS. cerevisiae, perhaps with a beer.
(Before I depart, I just want to mention — since it’s not necessarily clear from the first authors’ names — that four of the papers mentioned above, as well as many of the papers described in earlier Ouroboros posts linked above, are the result of the combined work of theKaeberleinandKennedylabs at U-Wash Seattle. Both of them worked together in theGuarente labback in the day, and they’ve been in the yeast aging field from its very beginning. Clearly, their combined work is continuing to advance the field.)
Our understanding of aging in animals owes a great debt to a large body of careful work in a single-celled organism, the brewer’s yeastSaccharomyces cerevisiae. Indeed, as I’ve arguedbefore, yeast is one of the two organisms with the strongest credible claim to have started modern biogerontology. An unusually large crop of yeast aging papers have appeared over the last few months, and I thought it would be appropriate to spent a few paragraphs describing them — in honor of this humble organism that rises our bread, ferments our beer, and has done so much to open our eyes to the fundamental mechanisms of aging.
For those unfamiliar with the yeast field or simply wishing a clearly written and nearly comprehensive summary,Steinkrauset al.provide the historical perspective. The piece thoroughly reviews the development of yeast as a model system in aging, as well as the arguments in favor of a connection between results in yeast and well-established (but sometimes hard-to-test) hypotheses in animals.
Based on the influence that yeast has already had on biogerontology as a whole, it seems fair to claim that it will continue to reveal fundamentals of aging that are conserved across evolution. Now, however, there is quantitative evidence to back up that claim:Smithet al.have used bioinformatic and genomic approaches to study the conservation between known longevity genes in yeast and worm, and they show that yeast mutants in worm longevity genes are significantly more likely to be long-lived than randomly chosen mutants — suggesting that
Given this functional conservation, it is reasonable to use yeast to help answer questions about aging in general, so long as these questions as cell-biological in scope.
For instance: NAD+/NADH ratios are thought to be an important metric of the cellular energy balance, and appear to have effects both within the mitochondria and the cytosol. The mitochondrial inner membrane, however, is impermeable to both NAD+ and NADH. How, then, is information about energy balance communicated between the two cellular compartments?Easlonet al.report that two components of the malate-aspartate NADH shuttle (which transports metabolites across the mitochondrial membrane, resulting in equilibration of the cytosolic and mitochondrial NAD+/NADH pools) are involved in controlling longevity. The two proteins, Mdh1 and Aat1, are required for longevity enhancement by calorie restriction (CR), and overexpression of both proteins can increase lifespan independent of caloric conditions (but in a Sir2-dependent manner, about which see more below).
Another outstanding question involves how cellular energy balance is coordinated with the rates of catabolic and anabolic processes, and how this coordination impinges on regulation of longevity. We know that in yeast, the effects of CR are mediated by pathways involving thenutrient sensor TOR and the kinase Sch9. (Brief aside: longevity-enhancing mutations of Sch9 can alsosuppress genomic instability; new results fromQinet al.show that genomic instability is also associated with lifespan variation in yeast). Sch9 regulates, among other things, ribosome biogenesis; both CR and Sch9 mutation cause ribosome synthesis to decrease — but are the ribosome and longevity phenotypes related? Very likely yes:Steffenet al.report that multiple means of downregulating ribosome synthesis all extend lifespan, implying that reducing production of ribosomes is essential in order to reap the benefits of CR.
As the tools of biology have adapted, so has the yeast field (sometimes leading the charge, as in the case of the earliest microarray-based expression profiling experiments).Murakamiet al.have developed a high-throughput method for measuring yeast lifespan. In this first report, the authors primarily demonstrate the use of their method on known mutants, arguing that their results are similar but with lower variance. (Brief aside: they also demonstrate that CR-induced lifespan extension does not require SIR2 or any other yeast sirtuin, adding fuel to the controversy about whether sirtuins play any role in CR in yeast; for more, seehereandhere.) The increased precision of their technique will allow detection of subtler aging-related phenotypes than were previously detectable, very likely allowing us to add to the list of genes known to regulate lifespan. The high-throughput aspects of the method, of course, open the door to testing small-molecule drugs that could delay aging in yeast —historicallya fruitful approach though not without itspotential pitfalls.
If you’ve made it this far, feel free to toastS. cerevisiae, perhaps with a beer.
(Before I depart, I just want to mention — since it’s not necessarily clear from the first authors’ names — that four of the papers mentioned above, as well as many of the papers described in earlier Ouroboros posts linked above, are the result of the combined work of theKaeberleinandKennedylabs at U-Wash Seattle. Both of them worked together in theGuarente labback in the day, and they’ve been in the yeast aging field from its very beginning. Clearly, their combined work is continuing to advance the field.)