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.
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.
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.
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. —
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
Holzenberger, et al. Nature 2003
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.)
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.
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.
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