Genes and aging
Human Aging, Position Paper
Longevity of adults has changed little
Senior runners postponed disability 8.7 years
Estrogen with progesterone lengthens women lives
Testosterone and vascular functions in aging
estrogen and longevity
Free radicals part of aging process
FAD AGING CURES EXPOSED, by leading scientists
genes that slow aging
Genes and aging
Insulin's effect upon the SKN-1 gene and aging
Telemores, sexual size dimorphism and gender gap in life expectancy
SKIN AGING: causes & treatments
Carbohydrates and aging and age related diseases
Arthritis reduced with vigorous physical activity
Why Women Live Longer than Men

Genes are important.  However, the prospect of an intervention, given the complexity of their action and the state of the science, entails that commercial application is likely to be decades down the road.   



Role of insulin/insulin-like growth factor 1 signaling pathway in


Chun-Lei Cheng, Tian-Qin Gao, Zhen Wang, Dian-Dong Li


From the data presented, the insulin/IGF-1 pathway has the similar characters in C.elegans, D.melanogaster, rodents and humans, which include the constitution of the gene, the role in regulation of aging and longevity. All these can be concluded that the pathway exists long ago and the mechanism of aging is evolutionarily conserved. 


Reviewing the available data on the benefits and adverse effects of caloric restriction and genetic modifications Longo and Finch suggested three categories of drugs which may have the potential to prevent or postpone age-related diseases and extend life span: drugs that (1) stimulate dwarf mutations and therefore decrease pituitary production of GH; (2) prevent IGF-1 release from the liver, or (3) decrease IGF-1 signaling by the action on either extracellular or intracellular targets[18]. According to this, Anisimov concluded and reported that effects of antidiabetic biguanides seems to be more adequate in the prevention of age-related deteriorations in glucose metabolism and in insulin signaling pathway as well as in such important for longevity parameters as a fertility and a resistance to oxidative stress and tumorigenesis than those induced by caloric restriction and genetic manipulations[25]. 


Although, the insulin/IGF-1 pathway can regulate the life span in different species, the molecular mechanism largely remains unknown. The most possible is that the pathway can enhance the stress resistance. Murakami et al., reported that fibroblasts from Snell dwarf mice show resistance to a variety of forms of lethal injury, including ultraviolet light, heat, paraquat, H2O2, and the toxic metal cadmium. This cellular stress resistance may lead to resistance to late-life diseases and frailty, and thereby increase longevity[38]. Using DNA micro-array analysis, Murphy et al.[39],found the insulin/IGF-I pathway not only do cells function non-autonomously to regulate life span but also exert their effect on life span by up regulating a wide variety of genes, including cellular stress-response, antimicrobial and metabolic genes, and by down regulating specific life-shortening genes.  In human, Barbieri et al.[36], suggest that centenarians may have been selected for appropriate insulin regulation as well as for the appropriate regulation of tyrosine hydroxylase gene, whose product is rate limiting in the synthesis of catecholamines, stress-response mediators. It was shown that catecholamine may increase free radical production through induction of the metabolic rate and auto-oxidation in diabetic animals[25,40].


On the other hand, although the insulin/IGF-1 pathway is evolution conserved, the pathway in mammals is more complicated than other low animals. While disruption of the insulin/IGF-1 receptor in nematodes and flies increases lifespan significantly, mammals with genetic or acquired defects in insulin signaling pathway are at a risk for agerelated agerelated diseases and increased mortality. This contradiction can be explained by the acquisition of more complicated metabolic pathways in mammalians over evolution.  Mammals have insulin/IGF-1 receptors in many organs, but their functions are opposite if they are located in the central nervous system or in the periphery; whereas lower species have insulin/IGF-1 receptors signaling mainly through the nervous system. Furthermore, mammalians

have different and very specific receptors for insulin and IGF-1, with distinct pathways and diverse functions[41].


Human longevity is mysterious. Though we have found the role of insulin/IGF-1 pathway in regulation of longevity, further investigation would shed light on the molecular mechanism of the pathway so that we will get more methods to decrease the age-related diseases and everyone will be centenarians.


Association analysis between longevity in the Japanese population and polymorphic variants of genes involved in insulin and insulin-like growth factor 1 signaling pathways

Experimental Gerotolgy, Volume 39, Issues 11-12, November-December 2004, Pages 1595-98. 

Proceedings of the Seventh International Symposium on the Neurobiology and Neuroendocrinology of Aging, at http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T6J-4DGD4R7-1&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_version=1&_urlVersion=0&_userid=10&md5=b4a622a92f6e38fae3c9589fd1d5802c


Recent studies have demonstrated a significant association between mutations in genes involved in the insulin/IGF1 signaling pathway and extension of the life span of model organisms. In this study which compared 122 Japanese semisupercentenarians (older than 105) with 122 healthy younger controls, we examined polymorphic variations of six genes which are involved in insulin/IGF1 signaling. These genes were FOXO1A, INSR, IRS1, PIK3CB, PIK3CG, and PPARGC1A. We investigated the possible association of each gene locus and longevity by haplotype-based association analyses using 18 SNPs from public databases and the published literature. One INSR haplotype, which was comprised of 2 SNPs in linkage disequilibrium, was more frequent in semisupercentenarians than in younger controls.



other genes:

, PHA-4 is also involved in longevity of caloric restricted diet;    

  ^ "The gene for longevity, if you're a worm", ABC News (2007). Retrieved on 3 May 2007.


The activation of the Sirt1 gene is involved (work of David A. Sinclair).  Sir2 (in mammals known as the SIRT1), suppresses DNA instability   ^ Sinclair DA, Guarente L. Extrachromosomal rDNA circles--a cause of aging in yeast. Cell. 1997 Dec 26;91(7):1033-42. PMID: 9428525

Gene glitches may hold secret of a long life


Ian Sample, Science correspondent, The Gurardian, March 4 2008-03-05


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.


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. 

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