Not so fast, daf-2: IGF-I is all kinds of good for you

Insulin-like Growth Factor-I (IGF-I) and insulin itself have been convincingly implicated in the genetic control of lifespan. Mutants in the worm gene DAF-2 (a homolog of IGF-I receptor) are long-lived, and disruptions in insuling signaling also boost longevity in mammals. It’s not yet clear whether IGF-I mutations extend lifespan via the same mechanisms as calorie restriction (CR); the evidence is piling up in favor of independent mechanisms with some degree of convergence (q.v. this excellent recent paper from Iser and Wolkow, a careful genetic dissection of the phenotypic interactions between daf-2 and CR in the worm). Regardless of mode of action, biogerontologists widely accept that loss of function in insulin and insulin-like pathways increases lifespan in a wide range of organisms.

It is therefore troubling that the outcome of decreased IGF-I levels on specific organ systems is so uniformly negative: low IGF-I seems to slow down brain activity; high IGF-I paradoxically seems to delay cardiac aging even as it shortens the lifespan of a particular heart’s owner. To this list of perplexities add a recent report that IGF-I supplementation in elderly rodents cures a whole host of metabolic ills. From García-Fernández et al.:

Low Doses of Insulin-Like Growth Factor I improve insulin resistance, lipid metabolism, and oxidative damage in Aging Rats

Growth Hormone (GH) and Insulin-like Growth Factor I (IGF-I) concentrations decline with age. Age-related changes appear to be linked to decreases in the anabolic hormones, GH and IGF-I.

The aim of this study was to investigate the antioxidant, anabolic and metabolic effects of the IGF-I replacement therapy, at low doses, in aging rats. …

Compared with young controls, untreated aging rats showed a reduction of IGF-I and testosterone levels and a decrease of serum total antioxidant status, which were corrected by IGF-I therapy. In addition, untreated old rats presented increased levels of serum glucose with hyperinsulinemia, cholesterol and triglycerides and a reduction of free fatty acid concentrations. IGF-I therapy was able to revert insulin resistance and to reduce cholesterol and triglycerides levels increasing significantly free fatty acid concentrations.

Old rats showed higher oxidative damage in brain and liver tissues associated with alterations in antioxidant enzyme activities. IGF-I therapy reduced oxidative damage in brain and liver, normalizing antioxidant enzyme activities and mitochondrial dysfunction.

In conclusion, low doses of IGF-I restore circulating IGF-I, improve glucose and lipid metabolism, increase testosterone levels and serum total antioxidant capability and reduce oxidative damage in brain and liver associated with a normalization of antioxidant enzyme activities and mitochondrial function.

This is exasperating: Why should a hormone that is neuroprotective and cardioprotective, and that prevents oxidative damage, insulin resistance and mitochondrial dysfunction, shorten the overall lifespan?

I’m tempted to suspect that the answer lies in developmental timing. The IGF-I mutants studied thus far in lifespan studies have been non-conditional hypomorphs, hemizygotes or full knockouts — in other words, the mutations were present over the entire lifespan of the organism. (Note that the brain study cited above used an adult-onset model of IGF-I deficiency, confounded somewhat by a simultaneous adult-onset loss of growth hormone, GH.)

If IGF-I has some effect in early life that sets the body on a course for a short lifespan, but is beneficial at all other times, then it might be possible to reconcile the seemingly paradoxical observations that IGF-I both accelerates aging and mitigates age-related disease. This is not as much of a stretch as it might first appear: we already know that that early-life gene expression can control late-life outcomes (q.v. McCarroll et al., who demonstrated that most of the evolutionarily conserved transcriptional program of aging is implemented in early adulthood).

Both for the fundamental science of biogerontology and for the human health implications, it seems essential to parse the contributions of IGF-I to programming short lifespans on the one hand, and protecting against age-related decline on the other.


  1. I thought that Cynthia Kenyon had done the adult daf2 knockdown and extended lifespan. I could be mistaken.

  2. > Mutants in the worm gene DAF-2 (a homolog
    > of IGF-I)

    Correction: the gene daf-2 (its protein product is DAF-2) is a homolog of the mammalian receptors for insulin and IGF-1, not of IGF-1 itself. I stopped reading about there.

  3. Joe —

    Thanks for the correction; I’ve amended the article to reflect the actual homology relationship.

    Sorry that a typo convinced you the rest of the article wasn’t worth reading. I hope you’ll deign to reconsider.


Comments are closed.