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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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In the Pipeline: Don't miss Derek Lowe's excellent commentary on drug discovery and the pharma industry in general at In the Pipeline

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November 20, 2005

Sir2 Surprise

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Posted by Derek

I've written before about the gene known as SIR2. Overexpression of it (or its homologs in different animals) extends lifespan in a range of organisms, and there's been a tremendous amount of research on these over the last few years. A good deal of evidence has linked them to the known life-extending effects of caloric restriction. In mice, for example, Sirt1 is involved in nutrient sensing and fat mobilization.

It suggests a pretty neat package, but the ribbon on it is unraveling. I wrote about Sir2/Sirt1 here a couple of years ago, where I said "An extra copy of the gene lengthens life; deletion shortens it." Well, in yeast cells that appears to be true, when you measure lifespan by how many times the cells can divide before burning out.

But what if you measure lifespan by the amount of time the cells can live when they're not dividing? That's the subject of a new paper in Cell from Valter Longo's group at USC, which they have given the provocative title "Sir2 Blocks Extreme Life-Span Extension." Yep, deleting it actually extends the non-dividing lifespan of the yeast, and combining that with caloric restriction increases it even more. These yeast cells have some problems, though, some of which can be ameliorated by further mutations in the IGF-1 pathway (itself heavily implicated in metabolic rate and lifespan). Yeast with combined Sir2 and IGF mutations, under caloric restriction, live longer by up to sixfold, a startling increase.

So what about higher organisms? Well, there appear to be some very similar findings in mice - maybe. Earlier this year, Frederick Alt's lab at Children's Hospital in Boston deleted Sirt1 in mouse cells and found, quite to their surprise, that the cells were extremely vigorous indeed. Such cell lines start to break down after a certain number of passages (cell divisions), but the Sirt1 knockouts just keep rolling along.

They then tried growing the cells under oxidative stress, but they plowed right through that, too. That led to the thought that Sirt1 might be some sort of checkpoint, which would normally limit cell division under such DNA-damaging conditions. But the Sirt1-deleted cells showed no signs of greater DNA degradation than normal lines. They're quite robust.

This is all extremely interesting, but you may have noticed that I pulled a fast one here. In these mouse cell lines, it appears that replicative life span has increased when Sirt1 is taken out - but with Sir2 deletion in yeast that's not the case at all. There it's replicative life span that takes the hit, and non-replicating (chronological) life span that's increased. How do we reconcile these blatantly contradictory findings? I've no idea, but it's a safe bet that several high-powered labs are currently working overnight shifts to answer that question.

So much for mouse cells - how about whole mice? Well, as hardy as some of their cells may be, the Sirt1 knockout is a pretty hard animal to prepare, because most of the mice don't survive. The ones that do appear fairly normal, but have a complex phenotype, which includes decreased fat mass and body weight. (Alt's group is also trying to interfere with Sirt1 in adult animals, bypassing all the developmental roles that make the standard knockouts so hard to work with).

The big question now, given all these divergent cell findings, is: will these guys live longer, or not? And what happens to them when you put them on a limited-calorie diet? Are they going to act like the replicative-aging models, or the chronological aging ones? (We'll leave the yeast-mouse contradiction out of it for a while). Perhaps the two mechanisms will fight each other to a standstill, leaving the animals with plain ol' normal lifespans, but with some tissues acting much younger than the whole-body age and some acting much older. Mice generally live around two years. I wonder just how many months ago these lifespan studies started. . .

Comments (7) + TrackBacks (0) | Category: Aging and Lifespan


COMMENTS

1. tom bartlett on November 21, 2005 9:32 AM writes...

I just wish somebody would work out a decent formula for immortality; I'm pushing 50. Time is short.

Permalink to Comment

2. Derek Lowe on November 21, 2005 10:21 AM writes...

Be careful what you wish for - remember the Cumaean Sibyl. (See the epigraph to Eliot's "The Waste Land" for a summary.)

Permalink to Comment

3. JSinger on November 21, 2005 10:34 AM writes...

Mice generally live around two years. I wonder just how many months ago these lifespan studies started. . .

Yeah, I continue to *not* recommend this as a postdoc project.

In general, all this caloric restriction stuff seems quixotic to me, except as an entry point into the underlying biochemistry. OK, it works for rodents living under lab conditions. What will it do for animals or people living in non-sterile environments?

Permalink to Comment

4. tom bartlett on November 21, 2005 10:49 AM writes...

"remember the Cumaean Siby"

I recall a similar theme in the story of Tithonus. I have found Greek mythology a more entertaining read than the Christian variety-- and about equally plausible.

Permalink to Comment

5. Alleria on November 21, 2005 7:56 PM writes...

What's the strategy for examining the gene in adult mice? Cre-LoxP under the control of a promoter dependent on something like tet?

Permalink to Comment

6. Derek Lowe on November 21, 2005 9:34 PM writes...

Alleria, that's something I was wondering about, too. I assume that it's some sort of workaround knockout like you describe - I can't imagine that they're going to try to do it with RNA interference

Permalink to Comment

7. Jerry Snyder on December 23, 2005 8:32 PM writes...

"Ya gotta live," that's what I tell them. Jerry.

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