Tag Archives: rapamycin

We Can Learn a Lot from Yeast How to Slow Down Aging

Valter Longo's lecture

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.

Advertisements

1 Comment

Filed under genomics

Successful Results of Aging Research According to the Washington Post

It is always nice to see articles about fighting aging in the major press sources. This article in Washington Post sums the most promising results in aging research so far. The most successful interventions include caloric restriction, metformin, acarbose, rapamycin, genetic modification and GDF11/parabiosis. I would say that the author has left out some things like melatonin and aspirin, for example. Also I wouldn’t suggest parabiosis as an intervention, sure it’s good for the old, but what about the young organisms? Some of their biological parameters become worse as a result of parabiosis. We wouldn’t want that effect in people, would we?)) However, pharmacological intervention based on the GDF11 is another thing that may work.

I was very pleased to see that gene therapy was among the proposed solutions. In my opinion it has enormous potential. We now know about 100 longevity-associated genes. Why not use gene therapy to either bring these genes into the organism, or increase their efficiency if they already exist. We could try various combinations of those genes and maybe the combinations can lead to synergistic rather than additive effect. But who am I kidding, additive effect would also be amazing if proven safe and efficient in humans.

1 Comment

Filed under Life Extension

Dave Sharp: Study shows Rapamycin extends life in mice

A year ago the Methuselah Foundation presented a special Mprize Lifespan Achievement Award to Dave Sharp for his work with rapamycin. Science, Nature and TIME magazines each featured rapamycin – an antibiotic used in transplant patients that extended the life span of aged mice – as a significant and exciting scientific breakthrough.

More recently, Dave Sharp has announced that a second replication of the life span study has been repeated with the same results.

The drug, called rapamycin or sirolimus and marketed under the brand name Rapamune by Wyeth, suppresses the immune system but also fights inflammation, which underlies cancer, heart disease, Alzheimer’s disease and a range of other ills.

“Rapamycin may extend lifespan by postponing death from cancer, by retarding mechanisms of aging, or both,” David Harrison of The Jackson Laboratory in Bar Harbor, Maine and colleagues wrote in their report, published in the journal Nature.

The researchers at several U.S. centers fed rapamycin capsules to the mice daily starting at the age of 600 days, an age equivalent to 60 years old in humans.

All the mice lived longer, they reported. Some lived as much as 55 per cent longer, but the effects varied.

“We believe this is the first convincing evidence that the aging process can be slowed and lifespan can be extended by a drug therapy starting at an advanced age,” said Randy Strong, of the University of Texas Health Science Center at San Antonio, who worked on the study.

Read more about the findings that could help researchers find better ways to fight the diseases of aging and perhaps the process itself.

Here is a video presentation of Dave Sharp receiving his MPrize award for rapamycin.

1 Comment

Filed under Drug design, Life Extension, Science