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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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August 15, 2011

mINDY Mice - No Obesity, No Diabetes?

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Posted by Derek

Caloric restriction increases healthy lifespan. That's true in a range of organisms, and probably in humans. But it's never going to be popular - and what's more, it's not going to be feasible, either, given how clearly people like to eat. So the search has been on for just how it exerts its effects, with a number of interesting clues turning up.

And now there's another one. There's a longevity gene in fruit flies known as INDY (short for, I fear, "I'm Not Dead Yet", and if you don't get that reference, you should probably turn in your geek license. This would be a good time to note, as required by law, that the fruit fly people are a longstanding and apparently endless fountain of weird nomenclature). Reducing INDY expression definitely lengthens lifespan in flies and in the nematode C. elegan.

A recent paper in Cell Metabolism, from a large-multicontinent team involving the Shulman group at Yale and many others, explores the effects of the mammalian homolog, mINDY, in mice. The knockout mice are smaller, although they take in the same number of calories. They are much leaner, though, with remarkable less fat. Their metabolism seems to be ramped up, as you might figure from that situation, and they're especially good at fat oxidation in the liver. Very interestingly, they maintain this phenotype as they age, while normal mice tend to put on more fat. They have lower basal glucose and insulin levels, and are better at clearing glucose, apparently through better uptake in skeletal muscle. They also seem resistant to the bad effects of a high-fat-chow diet, show a much reduced tendency to putting on weight and developing insulin resistance. All in all, this is what you'd call a desirable metabolic phenotype, and it fits in very well with what has been worked out in the fruit flies.

So what does this gene code for? Turns out that it's a citrate transporter, which might not be the most obvious thing at first, but it makes sense. Citrate is converted to acetylCoA, which is the building block for fatty acid synthesis. Cutting down its availability basically starves the liver tissue, which depends on fatty acids for a good part of its energy needs, and causes it to efficiently burn off whatever fatty acids it can acquire. And this effect might just be one of the things that produce the benefits of caloric restriction - in other words, you might not have to deprive your whole body of calories, just the key parts of it. To show that I'm not overinterpreting here, I'll let the authors say it:

These data suggest that mIndy may be a key mediator of the beneficial effects of dietary energy restriction. Since prolonged caloric restriction is very difficult to achieve in humans, our observations raise the tantalizing possibility that modulating the levels or function of mIndy could lead to some of the health-promoting effects of calorie restriction, without requiring severe caloric restriction.

And as they go on to suggest, this makes for a very interesting target for obesity, diabetes, and fatty liver disease. What about extending lifespan? Well, I've dug through the paper several time, and can find no mention of mice older than 8 months, and no numbers on their longevity. I assume that this will be the subject of another paper as the rodents get older - it's too big an issue to ignore, and this paper seems determined not to say a word about it.

Comments (26) + TrackBacks (0) | Category: Aging and Lifespan | Diabetes and Obesity


COMMENTS

1. Anonymous on August 15, 2011 10:53 AM writes...

Who is developing the drugs against this target?

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2. DCRogers on August 15, 2011 11:04 AM writes...

OT: the perils of outsourcing

http://www.fda.gov/Drugs/DrugSafety/ucm265559.htm

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3. MTK on August 15, 2011 11:27 AM writes...

Interesting.

Being completely ignorant in this area I'd like to ask a few questions:

a) Did the knockout mice live longer?

b) I thought the whole caloric reduction leading to increased lifespan was due to a slow down in metabolism rather than a ramp up? Basically, we only have a finite number of turns on the crank and that by slowing down the rate of turns life span in increased? Incorrect?

c) Wasn't obesity one of those areas that lots of folks wish they'd never heard of?

Just wondering.

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4. zensci on August 15, 2011 11:56 AM writes...

Just FYI, the paper is published in Cell Metabolism. Cool paper.

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5. Anonymous on August 15, 2011 12:00 PM writes...

Well, it doesn't matter about the aging effects since Sirtris and GSK are all over that with their sirtuin pipeline. Moncef and Patrick are going to live forever!

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6. Curious Wavefunction on August 15, 2011 12:40 PM writes...

Not directly related but I couldn't help but note; apparently Starbucks just came out with a new super size 916 ml drink, a "Trenta" cup that's larger than your stomach. Another milestone on the highway of caloric restriction.

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7. In Vivo Veritas on August 15, 2011 1:15 PM writes...

Shulman? Longevity? Novel target?
Metabolic Disease discovery organizations of big pharma, start your engines. This paper will haunt groups like mine for the next year at least, wether it gets replicated or not.

I wonder how many folks wasted time looking for the target of Shulmans last big find, NAPE....

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8. MoMo on August 15, 2011 2:23 PM writes...

You sure you have the biochemistry straight? I thought oxaloacetic acid condenses with acetyl CoA to form citric acid, etc etc. But they do things differently in Cambridge I guess.

But I wonder what happens when you deprive cells and mitochondria of citric acid transporters, which are everywhere?

ACCase is a much better target and more directly involved in FA biosynthesis.

Don't waste your time here drug designers-Get It?

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9. milkshaken on August 15, 2011 2:45 PM writes...

"prolonged caloric restriction is very difficult to achieve in humans"...
Not in North Korea - they successfully tested it on the entire population (the dear leader and his family serve as controls)

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10. Jon on August 15, 2011 3:05 PM writes...

916 mL? That's nothing. I used to drink a Double Gulp fairly often in high school. That's 1.9 L of soda goodness (diet, so it's not as bad as it sounds.) Heck, a large soda at most fast food places is either 950 mL or 1.3 L.

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11. Virgil on August 15, 2011 3:09 PM writes...

Dare I say it, but there's at least the beginnings of a mechanistic link to sirtuins here...

The enzymatic activity of sirtuins (well, one of them) is the removal of acetyl groups from lysine residues on a multitude of different proteins (mostly metabolic enzymes). This is how they supposedly act as master regulators of metabolism. Thing is, the acetyl groups are put there in the first place by acetylases (in the same way that kinases and phosphatases antagonize each other), and there's some pretty nice work showing that the proximal source of the acetyl-CoA used for acetylation is ATP-Citrate lyase, which of course uses... you guessed it... citrate as a substrate.

So, messing with citrate metabolism might be expected to have an impact on protein acetylation levels, which conveniently is the same mechanism by which sirtuins are proposed to work. Personally, I'd love to see some acetyl-lysine proteomics in the mINDY knockout mice. It would also be pretty easy in the model organism systems to see if the mutations in SIRTs and INDY are epistatic.

(one last point - the name of those pesky worms is C. elegans, with an S on the end, not elegan)

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12. OHNOO- on August 15, 2011 3:11 PM writes...

@ In Vino Veritas: As someone who was (gulp, intimately) involved in the NAPE work, I'm sorry this brought you grief; it brought me grief too. If you had asked (yes, we will communicate with the fearsome pharmateriat) I would have advised you to work with the aqueophile glycerophospo NAPE metabolites (GP-NAEs), which are what's really active it turns out. Buy some from Cayman and inject it in mice (say 1-100 mg/kg). If you're not completely impressed/weirded out by what happens, I'll buy you a bottle of Vino. Can't help you with how they lower food intake yet but they do light up GPR119's fatty little world.

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13. Anonymous on August 15, 2011 3:43 PM writes...

What's the Shulman NAPE story?

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14. Liz on August 15, 2011 3:57 PM writes...

Ok, a few random questions (yes, I s'pose I ought read the original paper, huh?)-

To what degree is INDY expressed in humans versus the species tested? It is comparable? More to the point, is it druggable?

If hINDY is inhibited, what other feedback loops are involved?
It sounds as though the pathway is in the early phases of investigation and thus, still under heavily scrutiny. I'm curious to see what is downstream from INDY as well as what measures aside from those initially observed are employed by the body.

While one can fantasize about taking an anti-hINDY pill then gobbling a 4-course dessert, it would still do us goo to remember that excessive caloric intact can lead to more than merely increased body fat. Cavities come to mind, among other things.

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15. watcher on August 15, 2011 5:03 PM writes...

Certainly, an interesting scientific finding and observation leading to extrapolated hypotheses as a potential target for medical intervention. Superficially, the science makes some sense. But, like so many previous genetic manipulations in rodents which have anticipated great impact for treatment of human health and improved well-being, it's just the beginning of a POTENTIAL story. Let's not get ahead of ourselves.

Oh but wait! Is there a biotech with sketchy data ready to be marketed for close to $1B? VCs----open your checkbooks and keep a generous line of credit.

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16. Greg Hlatky on August 15, 2011 5:21 PM writes...

Eat sensibly, exercise regularly, die anyway.

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17. Forming simulation on August 15, 2011 8:11 PM writes...

Hi Derek,
Thanks for your article..It was awesome.

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18. gippgig on August 15, 2011 8:42 PM writes...

This is probably just another way to activate AMPK, which is very promising but is old news. For a good recent review of AMPK see Biochemical Society Transactions vol. 39 p. 1.

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19. Handles on August 15, 2011 9:21 PM writes...

@Virgil

I think the link between sirtuins and metabolism is more direct than that. SIRT1 uses NAD+ as its deacetylation reagent. With no citrate to run the TCA cycle, the concentration of NAD+ is raised, and sirtuin activity increases.

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20. DCRogers on August 15, 2011 11:15 PM writes...

Wow, lots of miraculous discoveries this week. Here's another one, dispassionately titled "Scientists develop miracle drug that can cure any viral infection":

http://www.indianexpress.com/news/scientists-develop-miracle-drug-that-can-cure-any-viral-infection/830510/

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21. Anon 1 on August 16, 2011 3:10 AM writes...

If only all academic science were so easily transformed into useful applications for human use, consumption and well-being.

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22. sepisp on August 16, 2011 4:10 AM writes...

Just think about it: if caloric restriction was a drug, it wouldn't make it to the market. At least in the case if actual clinical outcome, not biomarkers were assessed. Poor efficacy, large part of the patient population being poor responders, very long and time-consuming treatment regime, persistent compliance problems. Active pharmaceutical ingredients poorly identified or disputed. Only minor cardiovascular and memory improvements, with significant clinical benefit only in the sickest part of the population (think of the "cherrypicking patients" accusations!). Risks: higher mortality (that one's a killer), muscle mass loss, malnutrition, cold sensitivity, menstrual irregularities, infertility, infections, anorexia, tiredness, weight loss, gallstones, constipation, inapplicability to the young (think of the children!). The only alternative is bariatric surgery.

With competing treatments like this, I very clearly see the point in developing new drugs.

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23. drug_hunter on August 16, 2011 4:27 AM writes...

@22 "sepisp" -- As Derek would say, a classic case of ignoratio elenchi. Pharma wastes its time on obesity drugs NOT to mimic the effects of a calorie restriction diet, but in a futile attempt to overcome the gluttony of the American public.

PS Wonder what else citrate is useful for and what danger there might be in blocking citrate transporters...

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24. johnnyboy on August 16, 2011 9:08 AM writes...

@20 DCRogers: to be fair, the news outlet you cite took its cues directly from the MIT PR office, whose press release was titled "New drug could cure nearly any viral infection".

Do I have to mention that the efficacy claims in question for this new 'drug' are almost entirely based on cell culture work ?

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25. sepisp on August 17, 2011 1:51 AM writes...

#23 drug_hunter: Then it's just a question of selecting the right target. Unfortunately it appears eating behavior in humans is no longer controlled by animal instinct, but the higher brain. We already know several drugs that knock the higher brain out or modify its behavior, for example amphetamine works wonders. Side effects, meh.

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26. Morten G on August 17, 2011 3:45 AM writes...

I thought it had already been shown that the positive effects of caloric restriction could be achieved with intermittent caloric restriction without having significantly reduced average calorie intake?

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