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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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September 24, 2007

More Sirtuins With More Effects

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Posted by Derek

It’s been a while since I talked about sirtuins, but the field has not been quiet. The latest data is a paper in Cell which set off a strong move in the stock of Sirtris, the company closely tied to the labs involved.

SIRT1 had already been the focus of a huge amount of attention in the aging/cancer field, but this paper seems to validate two other members of the family, SIRT3 and SIRT4. It’s mostly the story of NAD+, a very fundamental molecule indeed in cellular metabolism. There’s been some evidence (and a lot of speculation) that NAD+ levels are regulated quite differently in the mitochondria as opposed to the rest of the cell, but getting hard data on this pathway hasn’t been easy.

What is known is that apoptosis (programmed cell death) can depend on NAD+ levels. An enzyme called PARP-1 depletes NAD+ levels when it’s activated, and sets off a chain of events leading to apoptosis. Recently it was shown that there’s a PARP-1 fraction inside mitochondria, and given their central role in energy production, this gave room to wonder if an apoptosis signal could be set off from in there as well. On the flip side, NAD+ is synthesized (in mammals, anyway) though a pathway involving the enzyme Nampt. It’s also present in mitochondria, along with another NAD-pathway enzyme called Nnmat, so all the machinery is presumably there to up- and downregulate mitochondrial NAD+.

And so it does. The Cell paper looked at NAD+ levels inside mitrochondria for the first time, and found that they change greatly in response to nutrient levels. Fasted animals (and cells) greatly increased their mitrochondrial NAD+, which makes sense.

At first the authors were puzzled, when they found that although Nampt protected cells from genotoxic stress, it didn’t seem to affect how low the NAD+ levels in the cells went. Overexpression, underexpression – they all went down to the same low levels. It was only when the looked inside the mitochondria that they found where the NAD+ was being maintained.

So mitochondria can hold normal NAD+ levels even after they’ve fallen in other cell compartments. As far as the authors can tell, this is because of local synthesis, although it’s possible that the mitochondria also import all that they can get their hands on under such conditions. But the fact that levels of mitochondrial Nampt also rise along with the NAD+ argues for biosynthesis.

And the protective effects of all this NAD+ work through SIRT3 and SIRT4. Their activity is limited by the amount of NAD+ around, so it makes sense that they get more active under stress, when NAD+ levels are up. siRNA knockdowns of all seven sirtuins showed that only the 3 and 4 subtypes – which are localized in the mitochondria – are the players.

All this makes Nampt look like the yeast gene called PNC-1, which is on the yeast and roundworm pathway to make NAD+. PNC-1 has been shown to be involved in extending lifespan in such creatures, so if the human homolog has been found, the immediate question is whether it has the same effects. Its changes in fasting rats suggest a link with the caloric restriction route to lifespan extension. Overall, you have to think that if we’re not onto the relevant pathways, we’re very close indeed.

Thus the spike in Sirtris stock. It came back down as various analysts make cautious noises today, but until the company gets some Phase II data, publications like this one will be what moves things around. If you’re interested in a wild and speculative ride, they’re worth a look. Don’t expect a dull time, though – there’s an awful lot about this stuff that we don’t know.

Comments (1) + TrackBacks (0) | Category: Aging and Lifespan


COMMENTS

1. gene on September 25, 2007 11:30 AM writes...

Sounds like we all should be taking nicotinamide supplements. It would be funny if a highly abosorbed nicotinamide formulation greatly extended lifespan.
All the billions spent and the answer to long life found in the local vitamin shop.

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