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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.

Methionine residues are susceptible to oxidation, but this damage may be reversed by methionine sulfoxide reductases MsrA and MsrB. Mammals contain one MsrA and three MsrBs, including a selenoprotein MsrB1. Here, we show that MsrB1 is the major methionine sulfoxide reductase in liver of mice and it is among the proteins that are most easily regulated by dietary selenium. MsrB1, but not MsrA activities, were reduced with age, and the selenium regulation of MsrB1 was preserved in the aging liver, suggesting that MsrB1 could account for the impaired methionine sulfoxide reduction in aging animals. We also examined regulation of Msr and selenoprotein expression by a combination of dietary selenium and calorie restriction and found that, under calorie restriction conditions, selenium regulation was preserved. In addition, mice overexpressing a mutant form of selenocysteine tRNA reduced MsrB1 activity to the level observed in selenium deficiency, whereas MsrA activity was elevated in these animals. Finally, we show that selenium regulation in inbred mouse strains is preserved in an outbred aging model. Taken together, these findings better define dietary regulation of methionine sulfoxide reduction and selenoprotein expression in mice with regard to age, calorie restriction, dietary Se, and a combination of these factors.

Objective: The aim of this study was to test dietary restriction (DR) as an intervention to alleviate senescence-associated functional defects in hematopoietic stem cells (HSCs)., Materials and Methods: BALB/cByJ (BALB) mice were fed ad libitum (AL) or were diet restricted (DR) to 75% of the AL food intake after 1 month of age. Peripheral blood and bone marrow cell compositions were compared in 3- and 25-month-old AL (AL-3, AL-25) mice and in 25-month-old DR (DR-25) mice using fluorescence-activated cell staining. Relative HSC functions in vivo were compared using competitive repopulation, and were also tested in 6-month-old BALB mice to measure the effects of short-term DR., Results: Compared to AL-3, AL-25 blood had significantly lower levels of red blood cells and hemoglobin. AL-25 marrow contained less than half the concentration of Lin(-)CD34(-)Sca1(+)CD117(+) HSCs and showed only half the in vivo functional ability of AL-3 marrow. In vivo, AL-25 HSCs failed to produce the strong correlations over time that demonstrate clonal stability during competitive repopulation. These correlations were shown in AL-3 HSCs. DR for 24 months alleviated hematopoietic deficiencies in the blood, increased concentrations of bone marrow Lin(-)CD34(-)Sca1(+)CD117(+) HSCs and improved HSC functional abilities in DR-25 mice to values far greater than those in normally aged mice. Surprisingly, HSC function in 25-month-old DR mice was better than that in young adults. Degrees of recipient repopulation by HSCs from DR-25 mice also correlated well over time, demonstrating clonal stability. Short-term DR for 5 months also improved HSC function, but to a much smaller degree., Conclusions: Aged BALB mice show hematopoietic and HSC senescence and clonal succession. Lifelong DR slows hematopoietic senescence and prevents HSC aging.

Inhibition of the TOR signalling pathway by genetic or pharmacological intervention extends lifespan in invertebrates, including yeast, nematodes and fruitflies; however, whether inhibition of mTOR signalling can extend lifespan in a mammalian species was unknown. Here we report that rapamycin, an inhibitor of the mTOR pathway, extends median and maximal lifespan of both male and female mice when fed beginning at 600 days of age. On the basis of age at 90% mortality, rapamycin led to an increase of 14% for females and 9% for males. The effect was seen at three independent test sites in genetically heterogeneous mice, chosen to avoid genotype-specific effects on disease susceptibility. Disease patterns of rapamycin-treated mice did not differ from those of control mice. In a separate study, rapamycin fed to mice beginning at 270 days of age also increased survival in both males and females, based on an interim analysis conducted near the median survival point. Rapamycin may extend lifespan by postponing death from cancer, by retarding mechanisms of ageing, or both. To our knowledge, these are the first results to demonstrate a role for mTOR signalling in the regulation of mammalian lifespan, as well as pharmacological extension of lifespan in both genders. These findings have implications for further development of interventions targeting mTOR for the treatment and prevention of age-related diseases.

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]