Insulin Levels and Life Span Studies

Sci. Aging Knowl. Environ., 4 August 2004
Vol. 2004, Issue 31, p. re5
[DOI: 10.1126/sageke.2004.31.re5]


Murine Models of Life Span Extension

Jason K. Quarrie, and Karl T. Riabowol

The authors are in the Department of Biochemistry and Molecular Biology at the University of Calgary, Calgary, Alberta, Canada, T2N 4N1. E-mail: (K.T.R.)

Key Words: life span extension • mouse models • growth hormone • insulin-like growth factor • oxidative damage • caloric restriction

Abstract: Mice are excellent experimental models for genetic research and are being used to investigate the genetic component of organismal aging. Several mutant mice are known to possess defects in the growth hormone/insulin-like growth factor 1 (GH/IGF-1) neurohormonal pathway and exhibit dwarfism together with extended life span. Their phenotypes resemble those of mice subjected to caloric restriction. Targeted mutations that affect components of this pathway, including the GH receptor, p66Shc, and the IGF-1 receptor (IGF-1R), also extend life span; mutations that affect IGF-1R or downstream components of the pathway decouple longevity effects from dwarfism. These effects on life span may result from an increased capacity to resist oxidative damage.

Citation: J. K. Quarrie, K. T. Riabowol, Murine Models of Life Span Extension. Sci. Aging Knowl. Environ. 2004 (31), re5 (2004)


Mammalian life-span determinant p66shcA mediates obesity-induced insulin resistance

1. Sofia Chiatamone Ranieria,
2. Salvatore Fuscoa,
3. Emiliano Panieria,
4. Valentina Labatea,
5. Marina Melea,
6. Valentina Tesoria,
7. Anna Maria Ferraraa,
8. Giuseppe Mauluccib,
9. Marco De Spiritob,
10. Giuseppe Ettore Martoranac,
11. Tommaso Galeottia, and
12. Giovambattista Pania,1

+ Author Affiliations

Institutes of aGeneral Pathology, Laboratory of Cell Signaling,
bPhysics, and
cBiochemistry and Clinical Biochemistry, Università Cattolica Medical School, 00168 Rome, Italy


Communicated by Louis Siminovitch, Samuel Lunenfeld Research Institute, Toronto, Canada, June 18, 2010 (received for review September 12, 2009)


Obesity and metabolic syndrome result from excess calorie intake and genetic predisposition and are mechanistically linked to type II diabetes and accelerated body aging; abnormal nutrient and insulin signaling participate in this pathologic process, yet the underlying molecular mechanisms are incompletely understood. Mice lacking the p66 kDa isoform of the Shc adaptor molecule live longer and are leaner than wild-type animals, suggesting that this molecule may have a role in metabolic derangement and premature senescence by overnutrition. We found that p66 deficiency exerts a modest but significant protective effect on fat accumulation and premature death in lepOb/Ob mice, an established genetic model of obesity and insulin resistance; strikingly, however, p66 inactivation improved glucose tolerance in these animals, without affecting (hyper)insulinaemia and independent of body weight. Protection from insulin resistance was cell autonomous, because isolated p66KO preadipocytes were relatively resistant to insulin desensitization by free fatty acids in vitro. Biochemical studies revealed that p66shc promotes the signal-inhibitory phosphorylation of the major insulin transducer IRS-1, by bridging IRS-1 and the mTOR effector p70S6 kinase, a molecule previously linked to obesity-induced insulin resistance. Importantly, IRS-1 was strongly up-regulated in the adipose tissue of p66KO lepOb/Ob mice, confirming that effects of p66 on tissue responsiveness to insulin are largely mediated by this molecule. Taken together, these findings identify p66shc as a major mediator of insulin resistance by excess nutrients, and by extension, as a potential molecular target against the spreading epidemic of obesity and type II diabetes.

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Sci. Aging Knowl. Environ., 9 June 2004
Vol. 2004, Issue 23, p. pe25
[DOI: 10.1126/sageke.2004.23.pe25]


Inside Insulin Signaling, Communication Is Key to Long Life

Adam Antebi

Adam Antebi is in the Max-Planck-Institut für Molekulare Genetik, Ihnestrasse 73, D-14195 Berlin, Germany. E-mail:

Key Words: insulin/IGF signaling • fat body • Drosophila • oxidative stress

Abstract: In a recent Nature paper (1), Tatar and colleagues show that inhibition of insulin/insulin-like growth factor (IGF) signaling specifically in the adipose tissue of Drosophila melanogaster retards organismal aging, increases resistance to oxidative stress, augments lipid deposition, and restricts insulin signaling in peripheral tissues by a cell-non-autonomous mechanism. Consistent with recent work in the worm, these results suggest that insulin/IGF signaling itself may mediate communication among various tissues to influence organismal longevity.

Citation: A. Antebi, Inside Insulin Signaling, Communication Is Key to Long Life. Sci. Aging Knowl. Environ. 2004 (23), pe25 (2004).

Science 299 (5606): 572-574

Extended Longevity in Mice Lacking the Insulin Receptor in Adipose Tissue

Matthias Blüher,1 Barbara B. Kahn,2 C. Ronald Kahn1*

Caloric restriction has been shown to increase longevity in organisms ranging from yeast to mammals. In some organisms, this has been associated with a decreased fat mass and alterations in insulin/insulin-like growth factor 1 (IGF-1) pathways. To further explore these associations with enhanced longevity, we studied mice with a fat-specific insulin receptor knockout (FIRKO). These animals have reduced fat mass and are protected against age-related obesity and its subsequent metabolic abnormalities, although their food intake is normal. Both male and female FIRKO mice were found to have an increase in mean life-span of ~134 days (18%), with parallel increases in median and maximum life-spans.

Thus, a reduction of fat mass without caloric restriction can be associated with increased longevity in mice, possibly through effects on insulin signaling.

1 Joslin Diabetes Center and Department of Medicine, Harvard Medical School, One Joslin Place, Boston, MA, 02215 USA.
2 Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, 02215 USA.
* To whom correspondence should be addressed. E-mail:;299/5606/572

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