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. Previous work had systematically deleted every single gene in the entire yeast genome, one gene at a time. Of the 6000 or so genes in yeast, most of which have a human counterpart, about 1000 were necessary for survival under lab conditions, leaving about 5000 non-essential genes to test. For these genes, we asked how long each mutant 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 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 that 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. We found genes involved in the ribosome, which translates mRNA into protein, as well as genes involved in the mitochondrial ribosome, which translates a different smaller set of mitochondrial mRNAs. We also found a cluster of genes involved in the proteasome, which breaks down damaged proteins for recycling. Another cluster of genes was involved in protein mannosylation (a specific type of protein modification that takes place in the endoplasmic reticulum by adding a mannose to a serine or threonine amino acid), chromatin remodeling, and tricarboxylic acid metabolism (the cycle that creates energy through the oxidation of acetate, also commonly called the Krebs cycle). 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 greatly extends yeast lifespan. 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. As an example, Gcn4 is up-regulated in our long-lived ribosomal yeast deletions, and its up-regulation is required for these ribosomal deletion yeast strains’ extended lifespan.
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. Each of the newly identified genes here could potentially extend lifespan.