Mice homozygous for the targeted disruption of the growth hormone (GH) receptor (Ghr) gene (GH receptor knockout; GHRKO; KO) are hypoinsulinemic, highly insulin sensitive, normoglycemic, and long-lived. Visceral fat removal (VFR) is a surgical intervention which improves insulin signaling in normal (N) mice and rats and extends longevity in rats. We have previously demonstrated decreased expression level of certain pro-apoptotic genes in skeletal muscles and suggested that this may contribute to the regulation of longevity in GHRKO mice. Alterations in apoptosis-related genes expression in the kidneys also may potentially lead to lifespan extension. In this context, we decided to examine the renal expression of the following genes: caspase-3, caspase-9, caspase-8, bax, bad, bcl-2, Smac/DIABLO, Apaf-1, p53, and cytochrome c1 (cyc1) in male GHRKO and N mice subjected to VFR or sham surgery, at approximately 6 months of age. The kidneys were collected 2 months after VFR. As a result, caspase-3, caspase-9, and bax expressions were decreased in KO mice as compared to N animals. Expressions of Smac/DIABLO, caspase-8, bcl-2, bad, and p53 did not differ between KOs and N mice. VFR did not change the expression of the examined genes in KO or N mice. In conclusion, endocrine abnormalities in GHRKO mice result in decreased expression of pro-apoptotic genes and VFR did not alter the examined genes expression in N and KO mice. These data are consistent with a model in which alterations of GH signaling and/or insulin sensitivity lead to increased lifespan mediated by decreased renal expression of pro-apoptotic genes.

Earlier, we showed that the offspring from exceptionally long-lived families have a more favorable glucose metabolism when compared with controls. As chronic low-grade inflammation has been regarded as a strong risk factor for insulin resistance, we evaluated if and to what extent the favorable glucose metabolism in offspring from long-lived families could be explained by differences in subclinical inflammation, as estimated from circulating levels of C-reactive protein. We found no difference between the two groups in C-reactive protein levels or in the distribution of C-reactive protein haplotypes. However, among controls higher levels of C-reactive protein were related to higher glucose levels, whereas among offspring levels of C-reactive protein were unrelated to glucose levels. It is a limitation of the current study that its cross-sectional nature does not allow for assessment of cause–effect relationships. One possible interpretation of these data is that the offspring from long-lived families might be able to regulate glucose levels more tightly under conditions of low-grade inflammation. To test this hypothesis, our future research will be focused on assessing the robustness of insulin sensitivity in response to various challenges in offspring from long-lived families and controls.

The single gene mutation of Ames dwarf mice increases their maximum longevity by around 40% but the mechanism(s) responsible for this effect remain to be identified. This animal model thus offers a unique possibility of testing the mitochondrial theory of aging. In this investigation, oxidative damage to mitochondrial DNA (mtDNA) was measured for the first time in dwarf and wild type mice of both sexes. In the brain, 8-oxo,7,8-dihydro-2′-deoxyguanosine (8-oxodG) in mtDNA was significantly lower in dwarfs than in their controls both in males (by 32%) and in females (by 36%). The heart of male dwarfs also showed significantly lower mtDNA 8-oxodG levels (30% decrease) than the heart of male wild type mice, whereas no differences were found in the heart of females. The results, taken together, indicate that the single gene mutation of Ames dwarfs lowers oxidative damage to mtDNA especially in the brain, an organ of utmost relevance for aging. Together with the previous evidence for relatively lower level of oxidative damage to mtDNA in both long-lived and caloric restricted animals, these findings suggest that lowering of oxidative damage to mtDNA is a common mechanism of life extension in these three different mammalian models.

The potential usefulness of growth hormone (GH) as an anti-aging therapy is of considerable current interest. Secretion of GH normally declines during aging and administration of GH can reverse age-related changes in body composition. However, mutant dwarf mice with congenital GH deficiency and GH resistant GH-R-KO mice live much longer than their normal siblings, while a pathological elevation of GH levels reduces life expectancy in both mice and men. We propose that the actions of GH on growth, development, and adult body size may serve as important determinants of aging and life span, while the age-related decline in GH levels contributes to some of the symptoms of aging.