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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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« A Reply on Academic Alzheimer's Research | Main | Alnylam Makes It (As Does RNAi?) »

January 13, 2014

Boost Your NAD And Fix It All?

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Posted by Derek

Here's a paper from a few weeks back that I missed during the holidays: work from the Sinclair labs at Harvard showing a new connection between SIRT1 and aging, this time through a mechanism that no one had appreciated. I'll appreciate, in turn, that that opening sentence is likely to divide its readers into those who will read on and those who will see the words "SIRT1" or "Sinclair" and immediate seek their entertainment elsewhere. I feel for you, but this does look like an interesting paper, and it'll be worthwhile to see what comes of it.

Here's the Harvard press release, which is fairly detailed, in case you don't have access to Cell. The mechanism they're proposing is that as NAD+ levels decline with age, this affects SIRT1 function to the point that it no longer constains HIF-1. Higher levels of HIF-1, in turn, disrupt pathways between the nucleus and the mitochondia, leading to lower levels of mitochondria-derived proteins, impaired energy generation, and cellular signs of aging.

Very interestingly, these effects were reversed (on a cellular/biomarker level) by one-week treatment of aging mice with NMN (nicotine mononucleotide edit: fixed typo), a precursor to NAD. That's kind of a brute-force approach to the problem, but a team from Washington U. recently showed extremely similar effects in aging diabetic rodents supplemented with NMN, done for exactly the same NAD-deficiency reasons. I would guess that the NMN is flying off the shelves down at the supplement stores, although personally I'll wait for some more in vivo work before I start taking it with my orange juice in the mornings.

Now, whatever you think of sirtuins (and of Sinclair's work with them), this work is definitely not crazy talk. Mitochondria function has long been a good place to look for cellular-level aging, and HIF-1 is an interesting connection as well. As many readers will know, that acronym stands for "hypoxia inducible factor" - the protein was originally seen to be upregulated when cells were put under low-oxygen stress. It's a key regulatory switch for a number of metabolic pathways under those conditions, but there's no obvious reason for it to be getting more active just because you're getting older. Some readers may have encountered it as an oncology target - there are a number of tumors that show abnormal HIF activity. That makes sense, on two levels - the interiors of solid tumors are notoriously oxygen-poor, so that would at least be understandable, but switching on HIF under normal conditions is also bad news. It promotes glycolysis as a metabolic pathway, and stimulates growth factors for angiogenesis. Both of those are fine responses for a normal cell that needs more oxygen, but they're also the behavior of a cancer cell showing unrestrained growth. (And those cells have their tradeoffs, too, such as a possible switch between metastasis and angiogenesis, which might also have a role for HIF).

There's long been speculation about a tradeoff between aging and cellular prevention of carcinogenicity. In this case, though, we might have a mechanism where our interests on on the same side: overactive HIF (under non-hypoxic conditions) might be a feature of both cancer cells and "normally" aging ones. I put that word in quotes because (as an arrogant upstart human) I'm not yet prepared to grant that the processes of aging that we undergo are the ones that we have to undergo. My guess is that there's been very little selection pressure on lifespan, and that what we've been dealt is the usual evolutionary hand of cards: it's a system that works well enough to perpetuate the species and beyond that who cares?

Well, we care. Biochemistry is a wonderful, heartbreakingly intricate system whose details we've nowhere near unraveled, and we often mess it up when we try to do anything to it, anyway. But part of what makes us human is the desire (and now the ability) to mess around with things like this when we think we can benefit. Not looking at the mechanisms of aging seems to me like not looking at the mechanisms of, say, diabetes, or like letting yourself die of a bacterial infection when you could take an antibiotic. Just how arrogant that attitude is, I'm not sure yet. I think we'll eventually get the chance to find out. All this recent NAD work suggests that we might get that chance sooner than later. Me, I'm 51. Speed the plow.

Comments (17) + TrackBacks (0) | Category: Aging and Lifespan | Biological News | Diabetes and Obesity


COMMENTS

1. Bruce Hamilton on January 13, 2014 10:45 AM writes...

Awesome, bonus points for the mention of "Speed the Plough" on Plough Monday, the traditional start of the English agricultural year.

Plough Monday is also known for early 19th century "trick or treat" extortion celebrations, whereby farm boys would pull a plough around and request donations from home owners and plough up the front gardens if no donation was forthcoming.

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2. Virgil on January 13, 2014 11:07 AM writes...

The paper has already attracted some attention on PubPeer (https://pubpeer.com/publications/A367937A1FE47F62833BCA961CA087) on account of having some rather creative looking western blots.

Assuming the data check out, I'm not sure I agree this is all working through SIRTs, given all the other anti-damage pathways that use NAD as a substrate. Key examples would be aldehyde dehydrogenase and PARP - boosting both of those would be expected to have a general detoxifying effect on nasty things like electrophilic aldehydes and DNA damage. It's obvious why Sinclair went after the SIRTs, but is he missing the bigger picture that NAD in general is beneficial, and SIRT is only part of the mechanism.

My other concern would be what are the projected side effects of long-term supplementation with NMN? I would imagine after some time then messing with NAD would disrupt redox set-points in an unfavorable manner. It's also surprising that it's bioavailable at all - probably gut bacteria would have a big impact on how it gets absorbed.

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3. biologist on January 13, 2014 11:36 AM writes...

Derek, you wrote "My guess is that there's been very little selection pressure on lifespan"

My gues is the opposite. Human life span is very long compared to other mammals of similar body size. For example, gorillas have larger body mass than humans, therefore one would expect a longer lifespan. However, gorillas live only 40 years in the wild to 50 years in captivity. Humans who have survived childhood live up to 70 years "in the wild" and up to 100 "in civilization".

Actually, this is bad news. It's likely that in humans, all the easy ways to extend lifespan have already been implemented by evolution. Our animal models, on the other hand, are usually the shortest-lived in their taxonomic group: mice 2 years, Drosophila 2 weeks etc.

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4. NJBiologist on January 13, 2014 12:26 PM writes...

@3 biologist--Don't forget, in addition to the correlation with body size, there's also a correlation with metabolic rate. This could tie in with the latter.

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5. anon the II on January 13, 2014 12:28 PM writes...

Derek,

You wrote "nicotine adenine mononuculeotide". Did you mean "nicotine mononuculeotide"?

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6. Morten G on January 13, 2014 12:30 PM writes...

Bowhead whales seem to live ~200 years. Possibly longer.
And there was that paper in Nature also in December about diversity of ageing http://www.nature.com/nature/journal/v505/n7482/full/nature12789.html
There are many animals that age in a similar manner to humans both there are also plenty that don't.

There's a lot of biochemistry in this paper but it also seems a bit "It must have something to do with these 10-20 proteins that I am familiar with". There could be many factors at play. But I like the animal results. And I think there was a fair bit of research looking at nicotinamide / niacin which never really panned out. But if the rate-limiting step is the synthesis of NMN then that might explain it.

I'm only 33 but I get the "please let this work"-feeling too. Unfortunately, they administered the NMN intraperitoneally and I'm not keen to start injecting various supplements ;) Maybe in the future we'll all end up with an insulin-style pen in our bathroom cupboards.

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7. watcher on January 13, 2014 12:33 PM writes...

Interesting observation, but the interpretation being so specific regarding pathway seems dubious. Way too early to mean anything substantive in terms of new human treatments. And that's the main goal here, right?

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8. HP on January 13, 2014 1:57 PM writes...

NMN is nicotinamide mononucleotide (nicotine mononucleatide usually refers to NaMN, nicotinic acid mononucleotide)

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9. Erebus on January 13, 2014 3:15 PM writes...

@6: From what I understand, i.p. injections are often 'close enough' to oral administration. I.p. administration doesn't avoid the first-pass effect. Of course, absorption is total, and the deleterious effects of stomach acid are sidestepped, but... close enough, perhaps. Needless to say that enteric-coated dosage forms can also protect against stomach acids, if and when necessary.

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10. MTK on January 13, 2014 4:13 PM writes...

@3,

I would guess that selection pressure on longevity would be bifurcated. With little pressure to elongate life beyond useful childbearing age and quite a bit up to that point.

But hey, what do I know. I'm a chemist.

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11. Leperflesh on January 13, 2014 7:26 PM writes...

Humans have evolved as a communal-living species. We've lived in extended-family groups of maybe 10 to as many as 60 or 70 individuals, for at least the last two or three million years, and perhaps much longer.

In that context, the selective pressure is to live for as long as you can contribute to the health and success of your descendents, and then die only after you become a net burden on them.

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12. a. nonymaus on January 13, 2014 7:32 PM writes...

Re: 10
As an archetypal K-strategy species, in humans the selection pressure is to elongate life through (grand)childrearing age, not just childbearing.

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13. Leperflesh on January 13, 2014 7:34 PM writes...

Just to elaborate on that, though: our species spent a lot of time exploiting what may have been marginal ecological niches. In some cases, a given territory (defined by how much land the extended-family group can effectively traverse without getting too far from a reliable source of water, for example) might have only been capable of supporting X adults. Even if the older generation can still in theory exploit more food resources than they need to feed themselves, there might be an upper limit on how much food can be provided set by environmental factors. An excess of adults beyond X might limit the number of babies the group can support too much. So there might be a selective pressure for Grandpa and Grandma to die while their children or their grandchildren are still in their childbearing ages.

The point though, is that it's a complex question, and a simple "die when you can't make babies any more" explanation is far too simple. It immediately raises the question about selective pressure to extend fertility into older ages...

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14. Allchemistry on January 14, 2014 1:14 AM writes...

It is also possible that selection pressure simply does not play a decisive role in determining human lifespan.

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15. a. nonymaus on January 14, 2014 10:52 AM writes...

It also doesn't take that long for selection to show effects, consider that the various mutations for adult lactose tolerance have spread widely in only a few thousand years.

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16. Oligofructan on January 14, 2014 8:51 PM writes...

@9: An interesting point. Have there been any studies regarding the equivalence of taking an enteric coated capsule to an intraperitoneal injection? How effective is the enteric coated route? I am curious.

Permalink to Comment

17. Allchemistry on January 15, 2014 3:47 AM writes...

@9. I do not think that intraperitoneal administration of vitamin B3 (an NAD precursor IIRC) is absolutely required.

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