Calorie Restriction Plus Longevity Genes, Both At Once

Calorie restriction with optimal nutrition is known to extend healthy life span in mammals - this from the wait and see method of study, meaning that all we can say for sure today for humans is that it does great things for your long-term health. Researchers have been digging into the mechanisms of calorie restriction more energetically in recent years, hoping to find the keys that change metabolism to slow aging.

The other side of the metabolic approach to intervening in the aging process is the search for longevity genes - mutations or changes in gene expression that change the processes of metabolism to slow down the accumulation of age-related damage. Scientists have been turning up a handful of new longevity genes every year in the recent past, many connected to the mechanisms of calorie restriction, many not.

After studies demonstrating extended life span through single gene mutations, and studies demonstrating extended life span through calorie restriction, why not studies of both at once? There's a lot of that going on at the moment, as researchers attempt to understand just how many distinct ways exist to improve metabolism and slow aging.

How diet interacts with longevity genes:

In laboratory mice, suppression of growth hormone (GH) signaling by spontaneous mutations or targeted disruption of GH- or IGF1-related genes can lead to an impressive increase of longevity. Hypopituitary Ames dwarf (Prop1 df) and GH receptor knockout (GHRKO) mice live 35-70% longer than their normal littermates.

Many phenotypic characteristics of these long-lived mutants resemble findings in genetically normal animals subjected to calorie restriction (CR). Microarray and RT-PCR studies of gene expression suggest that effects of the "longevity assurance genes " (Prop1 df or Ghr-/-) and CR are overlapping but not identical.

Subjecting Ames dwarf mice to 30% CR starting at 2 months of age leads to a further significant extension of their average and maximal lifespans. In contrast, identical CR regimen has either no or very little effect (depending on gender) on longevity of GHRKO mice. We suspect that this difference in response is related to the fact that CR improves insulin sensitivity in Ames dwarfs but does not further increase the extreme insulin sensitivity of GHRKO mice.

To search for effects of CR associated with extension of longevity, we are studying expression of insulin and IGF1-related genes in the liver, skeletal muscle and heart of normal and GHRKO mice.

Researchers will be working on the mechanisms of metabolic longevity for many years to come - it's a rich vein. It does seem plausible, however, that the biomechanisms of calorie restriction could be completely uncovered and understood within the next five years. The present pace is fast, and a great deal of funding is available in that part of the field.

For all that, if you're one of those folk holding out for a good calorie restriction mimetic (a drug to trigger all the same controlling gene expression changes without the need to diet), it's worth bearing in mind that a fair chunk of the benefits of calorie restriction seems to stem from cutting down visceral fat mass and not triggering an insulin resistance feedback loop through chronic overeating.

Meanwhile, we should all recall that slowing aging buys us little in comparison to methods to repair aging, and that those repair methods will likely be easier to develop in any case. It's a big leap to build a better metabolism when we're so far from fully describing the one we have. A far smaller leap to undo the known changes that turn a young metabolism into an aged, damaged metabolism.


Interesting study. What I would like to see is a study comparing caloric restriction (normal diet), caloric restriction (low-carb) and low-carb without caloric restriction. Does the longevity effect have more to do with calorie intake or weight gain? For example, you could eat 5,000 calories of fat and protein and lose weight, but you'd gain weight with 3,000 calories of carbs.

Posted by: JLL at April 17th, 2008 6:18 AM
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