Aging in male primates: reproductive decline, effects of calorie restriction and future research potential.
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ABSTRACT:
SUBMITTER: Sitzmann BD
PROVIDER: S-EPMC2527629 | biostudies-other | 2008 Sep
REPOSITORIES: biostudies-other
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Project description:Calorie restriction (CR) is the most widely studied intervention protecting from the adverse effects of aging. Almost all prior studies have examined the effects of CR initiated in young animals. Studies examining the effects of CR on development of aging cardiomyopathy found only partial prevention. The major goal of this study was to determine whether CR initiated after aging cardiomyopathy developed could reverse the cardiomyopathy. Aging cardiomyopathy in 2-year-old mice was characterized by reduced left ventricular (LV) function, cardiac hypertrophy, and increased cardiac apoptosis and fibrosis. When short-term (2 months) CR was initiated after aging cardiomyopathy developed in 20-month-old mice, the decrease in cardiac function, and increases in LV weight, myocardial fibrosis and apoptosis were reversed, such that the aging hearts in these mice were indistinguishable from those of young mice or mice where CR was initiated in young mice. If apoptosis was the mechanism for protecting against aging cardiomyopathy, then total myocyte numbers should have reverted to normal with CR, but did not. However, the alterations in cytoskeletal proteins, which contribute to aging cardiomyopathy, were no longer observed with CR. This is the first study to demonstrate complete prevention of aging cardiomyopathy by CR and, more importantly, that instituting this intervention even later in life can rapidly correct aging cardiomyopathy, which could have important therapeutic implications.
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Project description:Calorie restriction (CR) is the only intervention known to extend lifespan in a wide range of organisms, including mammals. However, the mechanisms by which it regulates mammalian aging remain largely unknown, and the involvement of the TOR and sirtuin pathways (which regulate aging in simpler organisms) remain controversial. Additionally, females of most mammals appear to live longer than males within species; and, although it remains unclear whether this holds true for mice, the relationship between sex-biased and CR-induced gene expression remains largely unexplored.We generated microarray gene expression data from livers of male mice fed high calorie or CR diets, and we find that CR significantly changes the expression of over 3,000 genes, many between 10- and 50-fold. We compare our data to the GenAge database of known aging-related genes and to prior microarray expression data of genes expressed differently between male and female mice. CR generally feminizes gene expression and many of the most significantly changed individual genes are involved in aging, hormone signaling, and p53-associated regulation of the cell cycle and apoptosis. Among the genes showing the largest and most statistically significant CR-induced expression differences are Ddit4, a key regulator of the TOR pathway, and Nnmt, a regulator of lifespan linked to the sirtuin pathway. Using western analysis we confirmed post-translational inhibition of the TOR pathway.Our data show that CR induces widespread gene expression changes and acts through highly evolutionarily conserved pathways, from microorganisms to mammals, and that its life-extension effects might arise partly from a shift toward a gene expression profile more typical of females.
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Project description:Mice and diets. One-month-old male mice of the long-lived B6C3F1 strain were purchased from Harlan (Indianapolis, IN) and maintained as described after weaning (15). Mice were housed in groups of 4 per cage and fed a non-purified diet, PMI Nutrition International Product #5001 (Purina Mills, Richmond, IN). At 5 months of age, the mice were individually housed, and randomly assigned to one of two groups, control (CON) or long-term CR (LTCR). CON mice were fed 93 kcal per week of a defined control diet (AIN-93M, Diet No. F05312, BIO-SERV). LTCR mice were fed 52.2 kcal per week of a defined CR diet (AIN-93M 40% Restricted, Diet No. F05314, BIO-SERV). The LTCR mice consumed approximately 40% fewer calories than mice in the CON mice. The CR diet was enriched so that the CR mice consumed approximately the same amount of protein, vitamins, and minerals per gram body weight as the control mice. Experimental design. At 20 months of age, cohorts of mice in the CON group were randomly assigned to one of 7 experimental groups (Fig. 1). A CON group continued to be fed 93 kcal per week of control diet for 8 weeks. A CR8 group was fed 77 kcal per week of CR diet for 2 weeks, followed by 52.2 kcal per week of CR diet for 6 weeks. The remaining dietary groups were fed the control diets containing, respectively, metformin (MET; Sigma, St. Louis, MO), glipizide (GLIP; Sigma), GLIP plus MET (GM), rosiglitazone (ROS; Avandia, SmithKline Beecham) or soy isoflavone extract (SOY; NOVASOY 400, Life Extension Foundation) for 8 weeks at the dosages indicated in Table 1. The drugs were mixed with powdered control diet and cold-pressed into one gram pellets (BIO-SERV Inc.). At 0900, all mice were fed 2/7 of the weekly allotment of food on Monday and Wednesday and 3/7 on Friday. The mice had free access to acidified tap water. They were fasted for 48 hours and killed by cervical dislocation at 22 months of age. No signs of pathology were detected in the animals used for the studies reported (n=4 per group). Organs were removed rapidly, flash frozen, and stored in liquid nitrogen. The weights of the mice were monitored bi-weekly. Mouse weights are given in Table 1. Measurement of specific mRNA levels. Liver total RNA was isolated as described from livers of pathology-free mice in each group (n=4 per group) (13). mRNA levels were measured using Affymetrix mouse U74Av2 arrays according to standard Affymetrix protocols (Affymetrix). Probe set expression measurement and normalization. After hybridization and scanning, raw image files were converted to probe set data (*.CEL files) using Microarray Suite (MAS 5.0). Probe set data from all 32 arrays were simultaneously analyzed with the Robust multichip Average (RMA) method to generate normalized expression measures for each probe set (Fig. 2; Ref. 24) The data were further filtered to exclude probe data sets that were “Absent” across all 32 arrays according to the MAS 5.0 detection algorithm (1,47). Keywords = CR mimetics Keywords = microarray profiling Keywords = drug discovery Keywords = gene-expression biomarkers Keywords: other
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