Dr. Valter Longo hold the record of yeast lifespan extension. He was able to increase longevity of this species 10 fold. This a one of the most remarkable results in longevity science. Here Dr. Longo is giving us a lecture on yeast genetics. Let me summarize what he told us.
Yeast are unicellular organisms. They have 6,000 genes packed in 16 chromosomes. They divide every 90 minutes. They are one of the widely used model animals for research, and not only aging research, because they are safe, quite easy to handle and inexpensive. One of the best feature for aging research is that their lifespan is really short. I will use a vague term – about a week, because it depends on the way how you measure their longevity.
There are two major methods to see how long yeast live – replicative and chronological lifespan analyses. The first one looks at the dividing mother cell and determines how many times the division happened. People can distinctly distinguish the newly formed daughter cell and the mother cell, because daughter cells are smaller in size. This work is really tedious, because it relies on manual sorting of the cells. None the less, this is how we can measure the yeast health span – the period of time when the cell is able to give progeny. After it has no more “babies” it doesn’t die though immediately (humans don’t too), however this assay doesn’t include the time when the cell remains alive.
The chronological lifespan analysis looks at how long the non-diving colony of cells live. The number of cells alive at each particular moment is estimated by the number of colonies that they form on a plate with nutrients that allows growth so the colonies can be visible. In order to bring the yeast to a non-diving state, they are stripped of nutrients in the medium, so they switch to a growth arrest state to ensure survival rather than reproduction. This is called a post-diauxic phase. Their survival is approximately 6 days in this state. And the metabolic rates are very high.
One of the ways to extend yeast lifespan is to remove all nutrients from the medium and simply substitute it with water. They will then enter a stationary phase when their metabolic rate is reduced, which allows better stress resistance and longer survival, about 17 days.
There is an even great lifespan extension mode that allow yeast cells live years – spore state. If you put the cells in 1% potassium acetate, the cells will convert into spores and will be able to live several year. They will be dormant and highly stress resistant. I can’t say anything about their metabolic rate though, and do you know why? Because nobody in the world in studying that. Can you believe it? I was so surprised. The reason why is I guess because of lack of funding. So, there is no person or agency in the world that is interesting in learning how an organism that normally lives just 6 days can manage to stay alive for several years. This is just so hard to grasp for me.
In yeast the best gene found so far for longevity interventions is Sch9. It is an analog of the S6 kinase that mammalian cells have to sense nutrients and respond in growth and division. Sch9 is more central in nutrient signaling than tor1. This is probably true for all eukaryotes. We know interventions for mTOR, which is a drug that suppresses mTOR activity, called rapamycin. Apparently, there maybe even more potent drugs that slow down aging that work on the S6 kinase. They haven’t been identified yet.
Another very interesting genes in yeast is rash. It senses glucose. Mutant yeast that don’t have this gene also live longer, but not as long as the “top record holder” Sch9 mutants. Sch9 can be seen as a conductor that orchestrates what is happening in the cell. I loved this beautiful analogy that Dr. Longo used, because it really makes you understand why sometimes if a trumpet plays really loud (and a trumpet is a very nice instrument), the whole orchestra doesn’t sound better. It’s the same when you activate one thing, one very good thing on its own, but all together you don;t see an improvement in life extension. The reason is because you need to influence the “conductor”, a gene like Sch9 in yeast.
Sch9 operates through msn2 and msn4 genes that pass on the orders of the “conductor” and activate various genes like cytoplasmic catalase T (anti-oxidative stress gene), DNA damage response genes, heat shock protein 12, trehalose phosphate phosphatase (stress protectant) and others. Also MnSOD (superoxide dismutase, anti-oxidant enzyme) is required for the longevity effect of switching off Sch9 to take place. This effect is 3 times lifespan extension, by the way. Over expressing SOD can only give 10-30% lifespan extension, so it’s crucial when it works together with the “conductor”.
Mutations in tor1 and school that delay aging cause a metabolic shift from the catabolism of glucose and ethanol to respiration and production of glycerol. Glycerol for yeast appears to be a neutral carbon course that does not promote pro-aging phenotype. It’s kind of like “good fat”, like olive oil. Mitochondrial superoxide is a major mediator of DNA mutations, aging, death, and the release of nutrients. Mutations in the Sch9 or Ras pathways extend life span in part by increasing protection against mitochondrial superoxide.