Genetics of Longevity Webcast Transcript Arrives

After long aeons of waiting, the SAGE Crossroads Genetics of Longevity webcast transcript has now arrived - and there was much rejoicing. You'll be hearing a lot about the merits of yeast as a platform for aging research:

It really wasn't a good model for eukaryotic aging at all at the time we started. Yeast is the simplest eukaryote you can work on. And by that I mean, it's a cell that's related to the type of cells we have in our body.

I felt like at the time that even if we didn't learn anything that directly applied to human aging, we would at least set a paradigm for how aging might occur. I think that it's still not entirely clear how related the two species are in terms of aging by any means. But there is accumulating evidence that there are going to be some things that are in common.

Not to mention yeast and sirtuins, the latter being a hot topic elsewhere in aging research (in relation to calorie restriction):

But so - I mean, and this sort of gets back to what you asked - what limits the replicative life span of a yeast cell? We don't completely know the answer. We know that one thing that limits how many times a cell can divide is the accumulation of these extra chromosomal RDNA circles, which some people call ERCs, and SIR2 inhibits that process.

We now think that that's not the whole story, that there are other things going on. So the real question is - one thing that's interesting about these ERCs is that they seem to be specific to yeast. People have looked and there's no evidence that these circles accumulate or cause aging in other organisms. Yet it's very clear in yeast that that's how [SIR2] is acting. So it's a burning question - [SIR2] seems to regulate aging at least in yeast and worms and flies, apparently by different mechanisms. So that's one of the questions, how could such a system have evolved, and is there something else going on that we don't completely understand?

Yeast, like the nematode worm, is a fairly simple organism - this opens up the doors to some methodical approaches that would be unfeasible in more complex life:

In the meantime, the yeast community has gone and made a deletion of every single gene, each in one strain. So there are 5,000 strains now that all have a deletion of each nonessential gene in yeast. What we're doing now is scanning through those, just randomly looking for ones that are long-lived. We're finding that there are a lot of other pathways in addition to [SIR2] that are regulating aging.

As with so much of funded aging research at the moment, the primary focus is the biochemical and genetic processes governing the regulation of metabolism. This is all useful work, but Strategies for Engineered Negligible Senescence it isn't - tinkering with our metabolism is never going to give us radically extended healthy life spans. But back to the topic at hand: as in other laboratories, calorie restriction is a big part of that picture.

The question about how it's activated, I think, gets to the point of calorie restriction or dietary restriction. One of the clues that aging is conserved in different organisms is that if you reduce caloric intake - and that's done in different ways in different organisms. But if you reduce caloric intake, do you extend life span? That works in yeast and flies and mice and monkeys, presumably. And maybe even us.

There is a big question: what is calorie restriction doing? One model that was put forth was that calorie restriction was leading to the activation of [SIR2]. At least in the strains we work in, we think it is a lot more complicated than that, and that [SIR2] may not be the link for calorie restriction. That doesn't mean it is not regulating aging, but we think that there are other pathways that calorie restriction are affecting that are causing aging.

That's just for starters - there's a good deal more, covering telomeres, other prospective aging-related genes and processes, and half a dozen other interesting topics in passing. Go and read the whole thing.

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