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Studies in mice suggest that rapamycin has a negative impact on glucose homeostasis by inducing insulin resistance. However, results have been inconsistent and difficult to assess because the strains, methods of treatment, and analysis vary among studies. Using a consistent protocol, we surveyed nine inbred strains of mice for the effect of rapamycin on various aspects of glucose metabolism. Across all strains, rapamycin significantly delayed glucose clearance after challenge. However, rapamycin showed no main effect on systemic insulin sensitivity. Analysis of individual strains shows that rapamycin induced higher glucose values at 15 minutes post-challenge in 7/9 strains. However, only three strains show rapamycin-induced reduction in glucose clearance from 15 to 120 minutes. Although pancreatic insulin content was reduced by rapamycin in seven strains, none showed reduced serum insulin values. Although one strain showed no effects of rapamycin on glucose metabolism (129), another showed increased systemic insulin sensitivity (B6). We suggest that rapamycin likely inhibits insulin production and secretion in most strains while having strain-specific effects on glucose clearance without altering systemic insulin sensitivity. This strain survey indicates that genetic differences greatly influence the metabolic response to rapamycin. [ABSTRACT FROM AUTHOR]

We previously reported that insulin-like growth factor 1 (IGF1) was involved in coregulating female sexual maturation and longevity. To understand the underlying genetic mechanisms, based on the strain survey assays of development and aging traits, we crossed two mouse strains, KK/HIJ and PL/J, and produced 307 female F2 mice. We observed the age of vaginal patency (AVP) and the life span of these females. We also measured circulating IGF1 level at 7, 16, 24, 52, and 76 weeks. IGF1 level at 7 weeks significantly correlated with AVP. IGF1 levels at ages of 52 and 76 weeks negatively correlated with longevity (p ≤ .05). A gene mapping study found 22, 4 ,and 3 quantitative trait loci for IGF1, AVP, and life span, respectively. Importantly, the colocalization of IGF1, AVP, and life span quantitative trait loci in the distal region of chromosome 2 suggests this locus carries gene(s) that could regulate IGF1, AVP, and life span. In this region, proprotein convertase subtilisin/kexin type 2 has been found to be associated with female sexual maturation in a human genome-wide association study. We verified the roles of proprotein convertase subtilisin/kexin type 2 in regulating IGF1 and AVP by showing that depletion of proprotein convertase subtilisin/kexin type 2 significantly reduced IGF1 and delayed AVP in mice, suggesting that it also might be involved in the regulation of aging. [ABSTRACT FROM AUTHOR]

The National Institute on Aging Interventions Testing Program (ITP) was established to evaluate agents that are hypothesized to increase life span and/or health span in genetically heterogeneous mice. Each compound is tested in parallel at three test sites. It is the goal of the ITP to publish all results, negative or positive. We report here on the results of lifelong treatment of mice, beginning at 4 months of age, with each of five agents, that is, green tea extract (GTE), curcumin, oxaloacetic acid, medium-chain triglyceride oil, and resveratrol, on the life span of genetically heterogeneous mice. Each agent was administered beginning at 4 months of age. None of these five agents had a statistically significant effect on life span of male or female mice, by log-rank test, at the concentrations tested, although a secondary analysis suggested that GTE might diminish the risk of midlife deaths in females only. [ABSTRACT FROM PUBLISHER]

Quantitative trait loci (QTL) of longevity identified in human and mouse are significantly colocalized, suggesting that common mechanisms are involved. However, the limited number of strains that have been used in mouse longevity studies undermines the ability to identify longevity genes. We crossed C57BL/6J mice with a new wild-derived strain, Pohn, and identified two life span QTL—Ls1 and Ls2. Interestingly, homologous human longevity QTL colocalize with Ls1. We also defined new QTL for metabolic heat production and body weight. Both phenotypes are significantly correlated with life span. We found that large clone ratio, an in vitro indicator for cellular senescence, is not correlated with life span, suggesting that cell senescence and intrinsic aging are not always associated. Overall, by using Pohn mice, we identified new QTL for longevity-related traits, thus facilitating the exploration of the genetic regulation of aging. [ABSTRACT FROM PUBLISHER]

Rapamycin was administered in food to genetically heterogeneous mice from the age of 9 months and produced significant increases in life span, including maximum life span, at each of three test sites. Median survival was extended by an average of 10% in males and 18% in females. Rapamycin attenuated age-associated decline in spontaneous activity in males but not in females. Causes of death were similar in control and rapamycin-treated mice. Resveratrol (at 300 and 1200 ppm food) and simvastatin (12 and 120 ppm) did not have significant effects on survival in male or female mice. Further evaluation of rapamycin’s effects on mice is likely to help delineate the role of the mammalian target of rapamycin complexes in the regulation of aging rate and age-dependent diseases and may help to guide a search for drugs that retard some or all of the diseases of aging. [ABSTRACT FROM PUBLISHER]

We used a heterogeneous stock of mice-UM-HET3, the first generation offspring of CByB6F1/J and C3D2F1/J parents-to test effects of six antiaging treatments on life span. In the first report of diet restriction in a structured, segregating heterogeneous population, we observed essentially the same increases in mean and maximum life span as found in CByB6F1/J hybrid positive controls. We also report results of treatment with N-acetyl-L-cysteine started at 7 months, and aspirin, nitroflurbiprofen, 4-hydroxy phenyl N-tert-butyl nitrone, and nordihydroguaiaretic acid, all started at 16-18 months. Only male UM-HET3 mice receiving N-acetyl-L-cysteine had significantly increased life span, and this may have been due to treatment-related inadvertent diet restriction. The other agents had no significant effects on life span. The use of UM-HET3 mice helps assure that these results are not the result of unresponsiveness of a single genotype but that they more broadly represent laboratory mice. [ABSTRACT FROM AUTHOR]

In the search for novel genetic diversity that affects the timing of life history traits, we investigated a wild-derived stock of mice (Pohn). Early generations showed extended reproductive life span; however, this phenotype diminished with propagation of the stock. Out-crossing latter generation Pohn mice to C57BL/6J (B6) mice produced PohnB6F1 hybrids with remarkably extended reproductive life spans--mean age at last litter of 647 ± 32 days--longer than for the parental strains (70% longer than Pohn, 88% longer than B6) and longer than for highly heterogeneous crosses of laboratory mice. Litter size among young PohnB6F1 adults was similar to parental stocks, but their age-related decline in litter size was delayed by 150-200 days, resembling the earlier Pohn generations. Possibly, out-crossing Pohn mice unmasked cryptic alleles that promote extended female reproduction. This work establishes the PohnB6F1 hybrid as a new model for delayed reproductive aging. [ABSTRACT FROM AUTHOR]

Panel 5 focused on genetic factors that might mediate or moderate the effects of caloric restriction (CR) on longevity. Panel members stated that currently there is limited information directly addressing these issues. Therefore, they focused attention on what studies could be done. In addition, the panel believed that certain conceptual issues merited clarification and focused attention on this issue. Human studies and studies of nonhuman model organisms were discussed. The panel found at least three reasons why it would be valuable to find genes that influence the (putative) longevity-promoting effect of CR in humans. Such knowledge would offer: (a) the ability to predict individual responses to CR; (b) increased understanding of physiological mechanisms; and (c) the potential to develop mechanism-based interventions to promote longevity or healthy aging. In addition, the panel emphasized several macro-level recommendations regarding research strategies to avoid, research strategies to emphasize, and resources needing development. [ABSTRACT FROM AUTHOR]

Donor and host T cells were distinguished by T cell antigen marker Thy-1 isotype and cytoplasmic isozyme Gpi-1 in thisstudy of bone marrow transplantation between congenic mice. During the first 3–6 weeks after irradiation and marrowtransfer, percentages of cells bearing the donor Thy-1 isotype in the periphery are much lower than percentages of T cells bearing the donor Gpi-1 marker. Apparently a population of Thy-1− donor T cells exists for several weeks after bone marrow transplantation. Further study showed that this population of CD3+, Thy-1− donor T cells expressed CD4+ or CD8+ and was found in peripheral blood and spleen but not in the thymus. This finding suggests their extrathymic origin. [ABSTRACT FROM AUTHOR]

Mice of the C57BL/6J and CBA/HT6J inbred strains and their F hybrid were investigated at 67, 202, 463, and 711 days of age to determine how genetic differences affected aging patterns of renal function and morphology. The three genotypes differed significantly in their body and kidney weights and their kidney to body weight ratios. These differences reflected functional capacities, and renal hypertrophy appeared to be an attempt to compensate for functional losses with age. The glomerular filtration rate (GFR) decreased in both inbred strains with age but remained constant in the F hybrid mice. There was a significant strain difference in GFR, but this difference disappeared when the GFR was considered in relation to the kidney weight. Thus the strain difference appeared to reflect differences in ability to compensate for loss of function by increasing kidney size. Osmolarities and sodium clearances decreased with age and increased with renal hypertrophy, but plasma levels were constant. Histopathological changes with age appeared to be correlated with functional changes. [ABSTRACT FROM PUBLISHER]

Transplantation experiments indicated that losses with age in erythrocyte production were not intrinsically timed within marrow cell lines. In most cases marrow cell lines from old donors functioned as well as those from young donors after transplantation into either W/W anemic or lethally irradiated normal recipients. After normal marrow cells had been serially transplanted into successive W/W mice 5 times, both old and young cell lines began to fail; the old cell lines had produced erythrocytes normally for 77 to 84 mo. Transplanted old and young control marrow cell lines, identified by T6 chromosomes, saved the lives of lethally irradiated recipients; the oldest cell lines functioned normally for 54 mo. The hypothesis is suggested that senescence of an organism is caused by intrinsically timed functional declines in only a few vital cell types. In transplantation experiments to identify these cell types, four criteria—function, identification, control, and health—should be met. The marrow transplantation experiments led to and illustrate the hypothesis and the four criteria. [ABSTRACT FROM PUBLISHER]

Defective responses to severe bleeding in 25-mo.-old C57BL/6J mice were not improved by injections of 8-mo.-old marrow cells. Such injections greatly improved responses of genetically anemic W/W mice that have defective erythropoietic stem cells. Apparently the defective responses of old mice were not intrinsic to their erythropoietic Stem cells. [ABSTRACT FROM PUBLISHER]

A letter to the editor is presented in response to the article "Aging and Immune Function" by William Adler in the October 1975 issue.

Age-related changes in the cellular composition of the immune system that are associated with an impaired proliferate response to T-cell mitogens were identified for B6CBAF1 mice. The frequencies of precursors of Con Ainduced IL-2-secreting cells (pHTL) and of Con A-induced cytotoxic cells (pCTL), determined by limiting dilution analysis, were lower for splenocytes from old mice, as were the proliferative responses to con a andpha, determined in conventional high cell density cultures for the same mice. The pHTL frequency correlated with the proliferative response to con a (r = .94) and to pHA (r = .83) among old mice, but not among young; there were no correlations of pCTL frequency with proliferative responses. The reduced pHTL frequency in old mice resulted from: (a) an agerelated doubling of the number of splenic b cells that diluted T cells, and (b) a 67% decline in the absolute number of con A-reactive pHTL cells in the spleen that appeared despite the maintenance of normal numbers of total splenic CD4 and CD8 cells. Thus, both a decline in absolute pHTL numbers and an increase in the number of non-T cells in the spleen result in a diminished pHTL frequency that is closely linked to the impaired mitogen response observed for old B6CBAFL mice [ABSTRACT FROM PUBLISHER]