A series of rare genetic mutations that boost human lifespan have been discovered by a team of scientists studying centenarians and their elderly children.The genetic glitches are thought to interfere with the normal growth of cells, halting the ageing process.

The discovery mirrors similar findings from studies on animals, which have shown that certain variations of genes linked to an insulin-like growth hormone can extend animals' lives dramatically. Dr Nir Barzilai, director of the Institute for Ageing Research at Albert Einstein College of Medicine in New York, found a series of mutations exclusively among centenarians which affect sensitivity to "insulin growth factor 1", or IGF-1. This hormone influences the development of almost every cell in the body. It is crucial for children's growth and continues contributing to tissue generation throughout adulthood.Barzilai's team discovered the genetic markers after scanning the genetic codes of 384 participants whose ages ranged from 95 to 110, with an average age of 100. They were compared with 312 controls, who came from families with a typical life span, none of whom had lived to 95. Tests on cells taken from the elderly volunteers showed they were less sensitive to IGF-1, suggesting that the mutated genes were disrupting the body's ability to grow normally.

The study is published in the Proceedings of the National Academy of Sciences.

At PNAS (Proceedings of the National Academy of Sciences) March 4, 2008, vol 105, no. 9, 3171-72.

http://www.pnas.org/cgi/content/full/105/9/3171

Closing the circle of longevity In laboratory animals, from flies to worms to mice, the insulin-like growth factor (IGF-I) pathway is implicated in longevity. IGF-I levels are strongly linked to body size. In mammalian animal models, decreased levels of IGF-I predispose for short stature, but also increase longevity. To determine whether IGF-I plays a role in human longevity, Yousin Suh et al. looked for genetic variations in a cohort of Ashkenazi Jewish centenarians and their offspring. The authors used another group of Ashkenazi individuals with no history of familial longevity as controls. Comparing the two groups, the authors found that, although the IGF-I coding region was highly conserved, centenarians and their offspring were more likely to have a variety of mutations in the IGF-I receptor. The mutations, which led to a mild form of IGF-insensitivity, were more apparent in females and led to shorter stature in the offspring. The work shows that, even though specific mutations were relatively rare, those affecting the IGF-I signaling pathway play a role in human longevity. — T.H.D.

Extracted by jk from http://chusa.b3e.jussieu.fr/disc/bio_cell/Certificat/Docs/nature01298.pdf

IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice

Martin Holzenberger, et al. Nature 2003

The IFG-1 has been shown in mice to reguloat lifespan and rsistance to oxidative stress in mice.  An 03 study with mice showed that those with an active mutant (heterozygous knockout are not viable) do not develop dwarfism, their energy metabolism is normal, and their nutrient uptake, physical activity, fertility, and reproduction are unaffected.  There was a 6-8% reduction in growth.  Those with one active IGF1-1R allel outlived their wild-type littermates a mean of 26% longer.  Heterozoygotes develop half the insulin receptors coded for by that gene.  Serum IFG-1 levels were upregulated in alduts by about 20-30%. The IGFR^+1- receptor level was reduced by 50%.   Body temperature, which is indicative of metabolic acitivity, was reported to be lower (36.1 vs 37.4).  There was only marginal differences with food uptake thus eliminating this possible cause—lifespan is known to be extended on a severely restricted caloric diet.  (It is possible that caloric restriction results in decreaes in circulating IFG-1 levels, mimicking the IGF-1R produced here.)

These results differed from the long-lived C. elegans daf-2 mutants which displayed changes in fertility.  The IFG heterozygtes were for several sexual development parameters indistinguishable from the control group.  Oxidative stress is a principal cause ofaging in mice and fly mutants with enhanced resistance to oxidative stress being long lived.  To test this the grup injected paraquat, a herbicide (used in Vietnam jungles and to destroy crops there, and also to spray South American marijuana fields) that induces formation of reactive oxygen species.  The IGF-1R mutants resisted this challenge signficantly longer than controls.  This increase in stress resistance was more pronounced in female mutants. 

The IFG heterozyotes females live longer than the males possible because of a sex-related dimorphism were by in male mice there is reduced gl.ucose tolerance.

The p66 Shc^-1- is the only other targeted mutation in mamals described so far that lead to comparable increase in lifespan without inducing major side effects.  The p66 isoform of Shc mediates cellular responses to oxidative stress and is, together with IRS-1, a major cellular responses to oxidative stress and is together with IRS-1, a jajor cytoplasmic signal tranduction moluc le for IGF-1R.  Thus, the resistance of IfgIr^+1- mice to oxidative stress is of considerable interest, and by showing that the stress-regulating p66 Shc is underphosphorylated in IGF-1R deficency we found a plausible mechanism connecting IFG signalling to oxidative stress.   Caloric restriction and decreased in the response to oxidative stress and in insulin-like growth factor signalling all efficiently extend lifespan in mice.