Cautionary Data on IGF-1 Involvement in Longevity in Mammals

Metabolism is complex - very, very complex. In areas that have been well studied for more than a decade, researchers are still pushing back and forth on whether well known genes and pathways are actually important in longevity. In this sort of environment a single study in a few dozen mice isn't worth much, as the results from these various studies are either are all over the map, or prone to being overturned by a more careful, well-funded, and larger research project. That is what seems to have happened here for IGF-1 and longevity:

One of the major discoveries in aging during the past decade has been the observation that mutations in insulin/IGF-1 signaling led to increased longevity in various invertebrate models.

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The most direct evidence that mutations affecting the insulin/IGF-1 signaling pathway lead to increased longevity in mammals has come from studies with Igf1r+/− mice ... i.e., mice lacking one copy of the gene coding for IGF-1 receptor ... In 2003, Holzenberger et al. reported that female Igf1r+/− mice exhibited a 33% increase in lifespan. ... However, the lifespan data in the Holzenberger study are problematic because of the small sample size and the very short lifespan of both the wild type (WT) and Igf1r+/− mice studied.

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therefore, we have reassessed the effect of reduced expression of the IGF-1R on lifespan using the rigorous criteria recommended by Ladiges et al., e.g., lifespan and end-of-life pathology were assessed using large sample sizes and husbandry conditions that permitted the control lifespan to approach its full potential, which are necessary if the longevity differences in the experimental group are to be relevant to healthy aging.

In agreement with Holzenberger et al., we found that the female Igf1r+/− mice were more resistant to the oxidative stress than were WT female mice while no difference was observed between the male Igf1r+/− and WT mice. However, there was only a modest increase in the mean lifespan (4.7%) of female Igf1r+/− mice compared to their WT littermates and no significant change in end-of-life pathology. Thus, our data show [that] reduced IGF-1R signaling in mammals does not play the same major role in aging that is observed in invertebrates.

And so it goes - sometimes the early results achieved in small, prospective studies with small budgets don't hold up to closer inspection. Some fundamental processes relating to the link between operation of metabolism and longevity are very similar between lower animals (like worms) and higher animals (like mammals). You might think of the effects of calorie restriction, for example. But clearly other processes are significantly different between species, and this is one more layer of complexity that will increase the cost and slow the progress of efforts to slow aging by manipulating metabolism - such as by altering IGF-1.

Comments

I still think we need more data on igf1 mammal applicability. The recent TED talk by cynthia kenyon, hinted that igf1 receptor mutations were common in centenarian populations, correlated with smaller sizes even.

The laron dwarf mutant humans appear to exhibit extraordinary resistance to cancer and diabetes, and feature very low igf1.

QUOTE:"In nature, dwarf models live longer," he says. "Ponies live longer than horses, small dogs live longer than large dogs. It's a very fascinating field in aging."

QUOTE:Dr. Longo said he believed that having very low levels of IGF-1 was the critical feature of the Laron patients’ freedom from age-related diseases. In collaboration with Dr. Guevara-Aguirre, he exposed human cells growing in a laboratory dish to serum from the Laron patients. The cells were then damaged with a chemical that disrupts their DNA. The Laron serum had two significant effects, the two physicians reported on Wednesday in Science Translational Medicine.

First, the serum protected the cells from genetic damage. Second, it spurred the cells that were damaged to destroy themselves, a mechanism the body uses to prevent damaged cells from becoming cancerous. Both these effects were reversed when small amounts of IGF-1 were added to the serum.- http://www.nytimes.com/2011/02/17/science/17longevity.html

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IF IIRC the methuselah record was achieved by growth hormone knockout with CR combination achieving 100% lifespan increase, again iirc.

Human centenarian children are said to have increased protection from cardiovascular disease but not much else, according to one study. CR already confers peak human cardiovascular parameters, as seen in CR society member blood analysis, that likely match or exceed the centenarian benefits.

If igf1 can be lowered and it confers virtual cancer immunity, it would bode well for increased lifespan beyond that of centenarians.

Posted by: steampowered god at December 3rd, 2011 5:38 AM

we already have large scale date on billions of people over centuries from the longer lifespan of vegetarians who likely have lower IGF levels.

Posted by: seer at December 4th, 2011 8:27 PM

Perhaps a diet low in methionine, which reduces IGF-1 signaling, may increase lifespan. Some educated speculations:

"The low-methionine content of vegan diets may make methionine restriction
feasible as a life extension strategy"
http://www.oasisofhope.com/media/pdf/met_vegan.pdf

Posted by: Lou Pagnucco at December 5th, 2011 11:22 AM

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