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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: Twitter: Dereklowe

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December 4, 2009

Caloric Restriction and Lifespan - Without the Caloric Restriction?

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Posted by Derek

If there's one thing that study-of-aging researchers can agree on, it's that caloric restriction seems to prolong lifespan in a number of different organisms. The jury is still out on whether this extends all the way up to humans - people are giving it a try, with varying degrees of dedication and experimental rigor, but it takes quite a while for the results to come in.

One thing that stands out from experiments in small organisms is that cutting back on food intake seems to increase lifespan at the expense of fertility. That makes sense in a sort of three-laws-of-robotics way: the first task is to survive. The second task is to reproduce, as long as that doesn't interfere too much with survival. . .so under very tight energy restrictions, the organism doesn't have enough overhead to move on to the reproduction side of things. (On the other hand, under abundant food conditions, it may be that for some organisms reproduction moves up into first place, depending on what kind of ecological niche they're trying to fill).

This usual thinking here has been that it's total availability of food that throws these switches, through pathways that are sensitive to metabolic flux. There's now a paper out in Nature that makes this model harder to stick with. The researchers look at fruit flies, Drosophila, the very pest that I'm trying to evict from my kitchen at home (thanks to a recent contaminated package of plantains). As it turns out, it's known that these flies don't eat fruit so much as they eat yeast, which accounts for their attraction to bread, vinegar, beer, and overripe produce. This paper tries to pin down which nutrients, exactly, in yeast have effects on fecundity and lifespan, and whether they really are mutually exclusive.

A good way to search for those effects is to take a population of calorically-restricted fruit flies and add nutrients back to their diet to see if anything shows up in lifespan or egg-laying behavior. Vitamins, lipids, and carbohydates were soon ruled out as entire classes - none of the ones found in yeast seemed to have much of an effect either way when they were added back to the diet. That's an interesting result right there - the flies were now getting more food, but their lifespans did not decrease, suggesting that it's not just calories per se that have the effect.

That leaves proteins, and their constituent amino acids. And there things started to get interesting. Adding an amino acid mixture recapitulated the effect of full feeding: lifespans went down, and reproduction went back up. After looking for possible general non-nutritional effects of amino acids (effects on pH, osmotic strength of the food solution, and so on - nothing meaningful found), the team then narrowed things down, trying mixtures of the ten amino acids that are known to be essential for Drosophila versus the ten that aren't. (It's pretty much the same list as for humans, actually).

Adding back the non-essential ones slightly decreased lifespan, with no effect on reproduction. Adding back the essential amino acids (EAAs), though, had substantial effects on both. Now things are getting close to the payoff: amino acids seem to be behind basically all of the caloric restriction effect, and the ten essential ones account for almost all of that. What about looking at them one by one? (I really love science, I have to tell you).

I'll take you right to the end, although plenty of experimentation was needed to get there: it comes down to methionine. Tryptophan has some effect, but methionine alone is sufficient to bring reproduction back to the levels seen in full feeding when you start with calorically restricted flies that are getting the other essential amino acids. It works in a dose-dependent manner, too: if you take restricted-nutrient flies and start putting methionine back into their diet, the fecudity comes up in tandem, eventually plateauing out to a level that you can only raise by giving them more of the other essential amino acids (which are presumably now the things in short supply). That makes it seems as if methionine isn't some signal that it's time to lay eggs - its effects depend on the concentration of the other nine essential amino acids.

Now here's the really neat part: adding methionine back to the diet did not decrease lifespan. So lifespan and reproduction are not always coupled. I'll let the authors lay it out (I've stripped out the references to other papers and to figures that are found in the original text):

Adding back each EAA individually did not decrease lifespan, although, again, methionine alone increased fecundity. Adding back all EAAs except methionine restored lifespan to the level corresponding to dietary restriction, whereas omission of tryptophan had no effect. Notably, restriction of methionine alone also increases lifespan in rodents. Methionine thus acts in combination with one or more other EAAs to shorten lifespan with full feeding. Full feeding thus increases fecundity and decreases lifespan through the effects of different nutrients in Drosophila, the fecundity increase through methionine alone and the lifespan decrease through a combination of methionine and other EAAs. There is thus an imbalance in the ratio of amino acids in yeast relative to the ratio the fly requires for the high fecundity from full feeding, and some consequence of this imbalance decreases lifespan. . .

. . .The mechanisms that influence lifespan are conserved over the large evolutionary distances between invertebrates and mammals, and our results hence imply that in mammals also the benefits of dietary restriction for health and lifespan may be obtained without impaired fecundity and without dietary restriction itself, by a suitable balance of nutrients in the diet.

Now that's going to set off the nutrional supplement industry, for sure, although the lack of effect of vitamins and various lipids will put a crimp into some sections of it. But I find this a fascinating result, and believe that it's probably only the beginning of a long, interesting, and important field of study.

Comments (30) + TrackBacks (0) | Category: Aging and Lifespan


1. SP on December 4, 2009 10:46 AM writes...

How long until foods are advertised as, "Low in Methionine!"
Met might imply there's something about epigenetics, SAM being the source of the methyl group for all methyltransferases, including histone and DNA methyltransferases.

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2. alig on December 4, 2009 11:03 AM writes...

But now supplements of SAM-e and Met will advertise that they increase fecundity along with curing arthitis and all other ills.

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3. HelicalZz on December 4, 2009 11:49 AM writes...

Well color me surprised. I only follow this stuff on the periphery, but also find it really interesting. As I read Derek's piece, I immediately thought 'methionine' would be key, but would have perhaps expected the opposite result, with Met being key to longevity.

Methionine, free or incorporated into proteins, has long been associated (along with methionine sulfoxide reductase) with oxidative stress signaling. So I would have thought the lack of Met would be detrimental to longevity. Things never really are that simple though are they when dealing with biology.


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4. RTW on December 4, 2009 11:51 AM writes...

Need to do the reverse experiment now. Take short life span, normal reproductives, and adjust these same parameters and see if lifespand increases without dietary restriction? Can life span be increased? We might end up with a new and improved food pyrimide!

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5. anony on December 4, 2009 12:12 PM writes...

I'm too lazy to go back and see if this reference also shows up on the paper but it's very interesting. It's from 1992!

It's titled: "Low Methionine Ingestion by Rats Extends Life Span"

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6. anony on December 4, 2009 12:40 PM writes...

ok, somebody has to say so i'll just come out and be the one.

these studies basically mean that vegetarians had it right all along... plant protein (except for seeds) seems to be very low in methionine when compared to animal protein.

and... if you look at the combination of rice and beans, you end up with a diet very low in methionine!

And all of these nutjobs that keep drilling the message of "protein protein protein" (when they always mean animal protein), should all go hide in a cave

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7. alig on December 4, 2009 12:57 PM writes...

Read the article. It says you need methionine for normal reproduction rates (fecundity). And that adding methionine into a CR diet maintained the long life spans. Therefore a diet high in methionine but low in another, yet to be identified, amino acid could lead to a high fertility rate and long life. This seems to indicate that if this translates to humans (a big if) vegetarians would have a lower fertility rate.

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8. barry on December 4, 2009 1:04 PM writes...

is there any evidence that S-adenosyl-methionine (SAM, SAMe, etc) has non-zero oral bioavailability? I can see it doing all sorts of noxious things, but crosssing biological membranes isn't among them.

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9. anchor on December 4, 2009 1:24 PM writes...

#5 this reference (Journal of Nutrition, 1993, 123, 269) was right on target and the current paper in circulation in Nature, did not even bother to mention the previous work form the Cold Spring labs. Interstingly, the rat study in that work had more weightage in that we are closer to rat! The conclusions are very similar for both papers. The eggregious ommision of the previous work by the Nature article is highly regretable.

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10. barry on December 4, 2009 2:12 PM writes...

fertility is an inconvenience to most people, most of the time. Even if we couldn't dissociate infertility from longevity, we might add amino acid supplements to our diets for a few years out of a lifetime.

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11. Cloud on December 4, 2009 2:43 PM writes...

Fascinating. It will be interesting to see how this all relates to humans, although that will pretty difficult to figure out.

I'm on a pretty high protein diet right now, because I'm breastfeeding and protein is one component of milk that my body can't make from the fat stores it put on during pregnancy. I've wondered whether supplementing with the EAAs would have a similar effect, but I enjoy eating hamburgers too much to do the experiment.

Derek- the best way we've found to control the fruit fly infestations endemic in our kitchen: a little bit of red wine under a fly strip. They love red wine.

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12. Philip on December 4, 2009 2:57 PM writes...

To Cloud

We recently had the same problem and found the same solution. We have a small compost bucket under the sink and recently a banana peel stayed a bit too long before going to the big compost bin outside. We soon had a number of new house guests. One night during the infestation, I left a wine glass on the counter with a bit of red wine remaining. An hour or so later it had about 15 fruit flies in the glass. I put my hand over the top and carried them outside and blew them out. After about four more trips outside over the next two days, the flies were gone.

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13. PJ Hansen on December 4, 2009 3:21 PM writes...

To Philip

Did you sing "Born Free" as you released those little buggrs back into the wild?


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14. Bored on December 4, 2009 3:24 PM writes...

Actually, I had read last summer about getting rid of fruit flies with red wine. I didn't have any red wine in the house at the time. Out of curiosity, I went out in the garage and got some denatured alcohol, and put about an inch in a tall glass. After about an hour, there were dozens of fruit flies in the glass, and some who had commited suicide in the alcohol.

Maybe they are attracted to ethanol. Sounds like a good high school science project.

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15. SP on December 4, 2009 4:01 PM writes...

But do the flies live longer after release due to the resveratrol in the wine?

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16. Cloud on December 4, 2009 4:57 PM writes...

Philip, you're nicer than we are. We just let them drown.

During fruit fly season here (who says Southern California doesn't have seasons?) we have to cover all red wine glasses or risk getting some extra protein....

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17. Cloud on December 4, 2009 5:15 PM writes...

Oh, and Bored- we see a noticeable difference in the effect of red and white wine, and have never noticed them to be attracted to beer at all despite ample opportunity. I've never tried other types of alcohol. And I haven't set up a controlled experiment.

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18. barry on December 4, 2009 6:59 PM writes...

fertility is an inconvenience to most people, most of the time. Even if we couldn't dissociate infertility from longevity, we might add amino acid supplements to our diets for a few years out of a lifetime.

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19. Morten G on December 5, 2009 8:27 AM writes...

Cloud - they definitely like beer. Whenever we get fruit flies in the lab lunch room it's time to take the empty bottles to recycling. But our fruit flies seem a lot more timid than yours - they would never attack a glass that was standing next to a live human.

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20. Arnd on December 5, 2009 9:58 AM writes...

I see a world where after marriage there would be an ┬┤official diet┬┤ for couples for at least couple of years.

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21. milkshake on December 5, 2009 1:07 PM writes...

I see a world where mothers in law are served methionine-enriched diet

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22. RKN on December 5, 2009 3:30 PM writes...

Curious that Trp gave some effect, as it and Met are the only two amino acids encoded by a single codon. Probably just a coincidence.

Cool result but I'm not surprised by the apparent uncoupling of survival from fecundity. Organisms ostensibly selected for "reproductive success" might well be expected to value reproduction over their own survival, or so the theory goes.

Might be interesting to feed one DR group heavy Met and another regular (unlabeled) Met, then compare by differential proteomics to tease out what pathways may have a role in the phenotype.

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23. Sili on December 6, 2009 5:18 AM writes...

I good time I chose to finally learn the AAs, I see.

(I really love science, I have to tell you).
I do believe that why we're here, and why you get to write in Chem. World.

I take your personal observation as yet more evidence that bananas are the disgusting fruit of the devil, though.

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24. Morten G on December 6, 2009 2:57 PM writes...

"Adding back all EAAs except methionine restored lifespan to the level corresponding to dietary restriction, whereas omission of tryptophan had no effect"
I don't get this sentence. Is there a "no" omitted before dietary restriction? Or is "restored" just the wrong choice of words? It really makes no sense to me.

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25. Bob on December 6, 2009 5:12 PM writes...

Off topic, but laughed when I saw the below picture. It hurts because it's true.

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26. Patrick on December 6, 2009 7:44 PM writes...

Morten, this may help... from the abstract: "Adding essential amino acids to the dietary restriction condition increased fecundity and decreased lifespan, similar to the effects of full feeding, with other nutrients having little or no effect. However, methionine alone was necessary and sufficient to increase fecundity as much as did full feeding, but without reducing lifespan."

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27. puff65537 on December 6, 2009 8:36 PM writes...

I wonder if ripping up amino acids for nonEAA synthesis and/or using them for energy and the resulting ammonia release is what causes the lifespan decrease. Anyone know offhand if there is a cheap and bioavailable NH3/NH4+ scavenger?

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28. dddddddd on December 7, 2009 6:52 AM writes...


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29. InfMP on December 8, 2009 6:04 PM writes...

Derek, my apt was infested this summer and i tried all the tricks on the internet with no luck. there were hundreds in my small bachelor apt.

A regular spray bottle (mist) available at most groceries stores in the plant section with regular dish soap heavily diluted with water was the trick.

It was very fun, you can even shoot them out of the air while they are flying. They die in a matter of seconds from the soap water.

I thought about getting a holster.

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30. dill on August 10, 2012 1:49 AM writes...

hi, this is really late and i cant tell if you've got new research but basically can this conclusion be summed up from CR and meth experiments? (although i understand we probably cant ever sum up anything biological):

1. CR (proportionate decrease in meth) => infertility => increased lifespan.

2. No CR + meth restriction => infertility => increased lifespan

3. CR + higher ratios of meth compared to other EEAs - non EEAs => fertility + increased lifespan.

by my understanding this means 1. & 2. would actually be the same method; decreasing fertility to prolong lifespan, while 3. would be a whole new ballgame, and apparently better from an evolutionary point of view, being fecund + longer lifespan.

just some other questions;

contemporary CR studies usually indicate mild hypothyroidism, which would make sense if meth is significantly involved in our metabolism. Yet the animals can still be fit with low bf% from sheer caloric deficits?

with CR+meth, are the animals closer in bf% and health with CR groups or normal+restricted meth groups?

if my post makes you bang your head against the screen in horror, my apologies, non-science major here.

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