Mapping the Genes that Increase Lifespan

Comprehensive study finds 238 genes that affect aging in yeast cells.

The work was described as “exhaustive” but Buck postdoctoral fellow Mark McCormick managed to make it out the other side– after compiling and analyzing lifespan data from 4,698 yeast strains, each with a single gene deletion.  The project was 10 years in the making and McCormick spent five years on the effort (which was just one of his projects in the Kennedy lab). The study, which he also wrote, published in Cell Metabolism last month and is sure to be a career-boosting addition to his resume. After the study published he wrote a blog post about the work for SAGE.  This is an excerpt:

Why do we age?  Can this process be altered in any way, perhaps even delayed?  These are questions that have fascinated people for millennia. We have tried to answer these questions in increasingly sophisticated ways, made possible by our rapidly growing understanding of biology.

Work in many labs, here at the Buck Institute and elsewhere, has led to important discoveries that help us better understand how we age.  From previous work we know that making changes to a single gene can dramatically alter lifespan and aging in laboratory organisms.  We know that many of these gene changes do not simply extend the tired existence of unhealthy organisms; instead these changes can greatly delay many of the problems that arise with age.  Finally, we know that many genes first found to affect aging in simple organisms such as yeast, worms, and fruit flies have been shown to affect aging in mice, and even humans.

All of this previous knowledge has led to the design of our most recent study in the Kennedy lab to better understand and discover additional genes involved in healthy aging.  To do this we used the single-celled eukaryote Saccharomyces cerevisiae, or Baker's yeast. It's the same species of yeast used to make bread and beer, and many of the most important advances in our understanding of human biology have originated from experiments first performed in this powerful workhorse lab organism. 

We (a huge “we” that involved at least 50 undergraduates both at the Buck and the University of Washington) worked with a collection of yeast strains that had single genes deleted from their genome.  It was painstaking microscopic work that involved using a small needle to tease out daughter cells away from the mother every time it divided, logging how many daughter cells a mother produced before it stopped dividing.  

Of the 6000 or so genes in yeast, many of which have a human counterpart, about 1000 are necessary for survival under lab conditions, leaving about 5000 non-essential genes to test.  For each of these strains with one single gene deleted, we asked how long the strain lived, or more specifically how many times the cells divided, on average.  We were especially interested in long-lived yeast that divided many more times than the normal 26-27 divisions. This is in part because previous work has shown that this type of yeast can point to genes that affect aging in more complex organisms, like humans.

We identified 238 genes whose deletion caused the yeast to live significantly longer.  Some of these were already known, but many were not.  Interestingly, these genes did not represent a random assortment; many of them clustered together into groups of

genes th

at function in a single biological process.  This suggests that we are finding meaningful results, and that the biological processes identified by these clusters of genes are important modifiers of aging. 

Finally, we found many genes that did not cluster into one of these groups, including genes about which almost nothing is known.  Each of these categories represents an area of ongoing work, as we try to further unravel these results moving forward.

One gene that we picked up in this screen and focused on in detail was LOS1, a tRNA exporter.  Deletion of LOS1 extends yeast

lifespan by 60 percent.  We were able to show that two previously known methods of extending yeast lifespan, dietary restriction and inhibition of TOR, both cause Los1 protein to be excluded from the yeast nucleus.  Additionally, many of the genes whose mRNA levels change upon LOS1 deletion are targets of a transcription factor called Gcn4.  This is noteworthy because previous work has shown that Gcn4 plays an important role in aging in multiple organisms. 

We still have much work remaining to truly understand the basic biology of aging.  Even fully understanding the role of LOS1 in aging will require further study.  Many additional studies will be needed to fully understand the significance of the genes we have identified.  As we work to build a clearer picture of the overall regulation of aging, in yeast and in more complex organisms, these newly identified genes will help us.  Single genes identified in yeast have previously pointed the way to drugs that extend the lifespan of many lab organisms, including mice, and some of these will eventually be tested in humans.  We are hopeful that each new gene identified in this study is one more potential avenue that could lead to a discovery that could slow aging in humans.

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