Pick your aminoacids carefully

[Guest guest]

I would like to point to a very interesting and thorough study that has just

been published in the Dec 9 issue of Nature

R. Grandison, M. Piper and L. Partridge. Amino-acid imbalance explains

extension of lifespan by dietary restrictions in Drosophila.

The study is quite complex but I will try to summarize the main points:

1-Background

As all readers of this group already know, dietary restrictions without

malnutrition extends lifespan across the board, from yeast to mammals.

An important caveat is that reduction of caloric intake, by itself does not

consitently provide life extension in all organisms tested: it appears that the

restriction of specific nutrients is the key, more so than low caloric intake.

Also, it has been consistently observed that dietary restriction reduces

fertility and reproduction rates. This can make sense from a biological and

evolutionary perspective. The theory is that during times of food shortage

reproduction can be dangerous for the parents and the offspring has low survival

rates; mechanisms are then switched on to extend the life of the individuals

until food is abundant again and reproduction success can be maximized.

The work of Partridge and colleagues addresses 3 questions:

-are the lifespan and fertility effects of dietary restriction rigorously

inversly related, or do specific nutrients affect the two parameters?

-If the two effect can be uncoupled, which nutrients are primarily controlling

fertility and which ones are controlling lifespan

-What is the role of glucose metabolism, and in particular, the role of the

insulin pathway?

2-Findings

At least in Drosophila, it is confirmed that caloric intake per se is a poor

predictor of longevity or fertility. When specific sets of nutrients were

individually added back to a restricted diet, lipids, charbohydrates or vitamins

had no effect (that is, restricted diets with added back lipids or carbs or

vitamins, still showed prolonged lifespan and low fertility). However, when a

restricted diet was supplemented with all aminoacids, the flies had a short

lifespan and high fertility. By testing the effects of individual aminoacids,

the Partridge team found that Methionine alone could account for the fertility

effect: when Methionine is absent from the diet the fertility is reduced and

when Methionine is the only aminoacid in the diet fertility goes back to normal

levels. What about longevity? Surprisingly the Methionine effect uncouples

reproduction and longevity. Methonine per se can alter fertility but it has no

effect on lifespan. Flies on restricted diet live longer and reproduce poorly,

flies on restricted diet supplemented with Methionine reproduce normally and

still have longer lifespan! Adding back all aminoacids except Methionine reduced

the lifespan. since none of the aminoacids was able to decrease lifespan when

added alone to the restricted diets, the conclusion is that some combination of

the other (non-Met) aminoacids is responsible for the shortening of lifespan.

What about glucose and the insulin pathway? When the experiments where conducted

in mutant flies in which the insulin pathway is inactivated, the lifespan

reached the highest levels: these mutants lived even significantly longer than

normal flies on restricted diet. Interestingly feeding these flies with a

restricted diet supplemented with all aminoacids did not reduce their lifespan

(which is what happens in the normal flies). Similarly, the deficient insulin

signalling, abolished the response of the reproductive system to Methionine.

Very interesting work overall, although it raises lots of questions. One I find

particularly intriguing is why carbs have no effect on longevity in Drosophila

but the modulation of the insulin pathway is perhaps the strongest predictor of

the flies lifespan? Is this true in other organisms and humans?

In summary, protein quality, the precise balance of different aminoacids in the

diet and limited activation of the insulin pathway, will likely turn out to be

critical.

Andre