Genes, demography, and life span: the contribution of demographic data in genetic studies on aging and longevity.
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In population studies on aging, the data on genetic markers are often collected for individuals from different age groups. The purpose of such studies is to identify, by comparison of the frequencies of selected genotypes, "longevity" or "frailty" genes in the oldest and in younger groups of individuals. To address questions about more-complicated aspects of genetic influence on longevity, additional information must be used. In this article, we show that the use of demographic information, together with data on genetic markers, allows us to calculate hazard rates, relative risks, and survival functions for respective genes or genotypes. New methods of combining genetic and demographic information are discussed. These methods are tested on simulated data and then are applied to the analysis of data on genetic markers for two haplogroups of human mtDNA. The approaches suggested in this article provide a powerful tool for analyzing the influence of candidate genes on longevity and survival. We also show how factors such as changes in the initial frequencies of candidate genes in subsequent cohorts, or secular trends in cohort mortality, may influence the results of an analysis. (+info)
Overexpression of glutathione reductase extends survival in transgenic Drosophila melanogaster under hyperoxia but not normoxia.
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The purpose of this study was to test the hypothesis that overexpression of glutathione reductase in transgenic Drosophila melanogaster increases resistance to oxidative stress and retards the aging process. Transgenic flies were generated by microinjection and subsequent mobilization of a P element construct containing the genomic glutathione reductase gene of Drosophila, with 4 kb upstream and 1.5 kb downstream of the coding region. Transgenic animals stably overexpressed glutathione reductase by up to 100% throughout adult life and under continuous exposure to 100% oxygen or air. Under hyperoxic conditions, overexpressors had increased longevity, decreased accrual of protein carbonyls, and dramatically increased survival rates after recovery from a semi-lethal dose of 100% oxygen. Under normoxic conditions, overexpression of glutathione reductase had no effect on longevity, protein carbonyl content, reduced glutathione, or glutathione disulfide content, although the total consumption of oxygen was slightly decreased. Glutathione reductase activity does not appear to be a rate-limiting factor in anti-aging defenses under normoxic conditions, but it may become a limiting factor when the level of oxidative stress is elevated. (+info)
The evolution of age-specific mortality rates in Drosophila melanogaster: genetic divergence among unselected lines.
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Age-specific effects of spontaneous mutations on mortality rates in Drosophila are inferred from three large demographic experiments. Data were collected from inbred lines that were allowed to accumulate spontaneous mutations for 10, 19, and 47 generations. Estimates of age-specific mutational variance for mortality were based on data from all three experiments, totalling approximately 225,000 flies, using a model developed for genetic analysis of age-dependent traits (the character process model). Both within- and among-generation analyses suggest that the input of genetic variance is greater for early life mortality rates than for mortality at older ages. In females, age-specific mutational variances ranged over an order of magnitude from 5.96 x 10(-3) at 2 wk posteclosion to 0.02 x 10(-3) at 7 wk. The male data show a similar pattern. Age-specific genetic variances were substantially less at generation 47 than at generation 19-an unexplained observation that is likely due to block effects. Mutational correlations among mortality rates at different ages tend to increase with the accumulation of new mutations. Comparison of the mutation-accumulation lines at generations 19 and 47 with their respective control lines suggests little age-specific mutational bias. (+info)
Mated Drosophila melanogaster females require a seminal fluid protein, Acp36DE, to store sperm efficiently.
(28/3329)
Mated females of many animal species store sperm. Sperm storage profoundly influences the number, timing, and paternity of the female's progeny. To investigate mechanisms for sperm storage in Drosophila melanogaster, we generated and analyzed mutations in Acp36DE. Acp36DE is a male seminal fluid protein whose localization in mated females suggested a role in sperm storage. We report that male-derived Acp36DE is essential for efficient sperm storage by females. Acp36DE(1) (null) mutant males produced and transferred normal amounts of sperm and seminal fluid proteins. However, mates of Acp36DE(1) males stored only 15% as many sperm and produced 10% as many adult progeny as control-mated females. Moreover, without Acp36DE, mated females failed to maintain an elevated egg-laying rate and decreased receptivity, behaviors whose persistence (but not initiation) normally depends on the presence of stored sperm. Previous studies suggested that a barrier in the oviduct confines sperm and Acp36DE to a limited area near the storage organs. We show that Acp36DE is not required for barrier formation, but both Acp36DE and the barrier are required for maximal sperm storage. Acp36DE associates tightly with sperm. Our results indicate that Acp36DE is essential for the initial storage of sperm, and that it may also influence the arrangement and retention of stored sperm. (+info)
Longevity, lifetime pig production and productivity, and age at first conception in a cohort of gilts observed over six years on commercial farms.
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An observational cohort study was conducted using a producer group of 33 farms selected based on their completeness of reproduction data, including dates of birth, entry to a herd, and removal. Average lifetime pig production and parity at removal in a cohort of 2,265 females born in 1990 were 67.2 pigs born alive and 5.6 parities, respectively. Approximately 90% of farrowings occurred from the second through the fourth year from birth. Farrowing rates between parities of 2 and 4 were higher than other parities, and pigs born alive from parities 3 to 5 were the greatest among parities. The 10th and 90th percentiles of age at first conception were 227 and 322 days. Increasing the age at first mating was associated with low farrowing rate (P<0.01) in parity 0. Older age at first conception was associated with lower parity at removal, shorter reproductive herd life, and fewer lifetime pigs born alive (P< 0.01). Of the 2,265 breeding females, 253 (11.2%) were re-mated at parity 0 and farrowed. These sows with a record re-mating at parity 0 had lower parity at removal, less lifetime pig production and lower lifetime productivity than those with no re-mating at parity 0 (P<0.01). It is recommended that unbred gilts 230 days of age or older should be mated soon. (+info)
HSF1 is required for extra-embryonic development, postnatal growth and protection during inflammatory responses in mice.
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HSF1 is the major heat shock transcriptional factor that binds heat shock element (HSE) in the promoter of heat shock proteins (Hsps) and controls rapid Hsp induction in cells subjected to various environmental stresses. Although at least four members of the vertebrate HSF family have been described, details of their individual physiological roles remain relatively obscure. To assess whether HSF1 exhibited redundant or unique in vivo functions, we created Hsf1(-/-) deficient mice. We demonstrate that homozygous Hsf1(-/-) mice can survive to adulthood but exhibit multiple phenotypes including: defects of the chorioallantoic placenta and prenatal lethality; growth retardation; female infertility; elimination of the 'classical' heat shock response; and exaggerated tumor necrosis factor alpha production resulting in increased mortality after endotoxin challenge. Because basal Hsp expression is not altered appreciably by the HSF1 null mutation, our findings suggest that this factor, like Drosophila Hsf protein, might be involved in regulating other important genes or signaling pathways. Our results establish direct causal effects for the HSF1 transactivator in regulating critical physiological events during extra-embryonic development and under pathological conditions such as sepsis to modulate pro-inflammatory responses, indicating that these pathways have clinical importance as therapeutic targets in humans. (+info)
Baseline heart rate variability in healthy centenarians: differences compared with aged subjects (>75 years old).
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Healthy centenarians have better anthropometric, endocrine, metabolic and immunological parameters than aged subjects (>75 years old). Heart rate variability (HRV) has been demonstrated to be a good index of the cardiac autonomic nervous system. It is not known whether there are any differences in cardiac autonomic nervous system activity between aged subjects and healthy centenarians. It is possible that differences in cardiac autonomic nervous system activity could represent one of a cluster of factors explaining the extreme survival of centenarians. Thus we aimed to answer the following question: is there any difference in baseline HRV parameters between aged subjects and healthy centenarians? Therefore power spectral analysis of HRV at baseline was investigated in 25 aged subjects (age > or = 75 years) and 30 healthy centenarians (age > or = 0 years). Anthropometric measurements were made in all subjects, fasting blood samples were drawn for metabolite determinations, and HRV was determined. Independent of age, gender, body mass index and fasting plasma noradrenaline and free 3,3',5-tri-iodothyronine concentrations, healthy centenarians had lower basal values for total power (1318+/-546 compared with 1918+/-818 ms(2); P<0.01) and the low-frequency component (33+/-21 compared with 50+/-11 normalized units; P<0.03) and a higher value for the high-frequency component (77+/-15 compared with 61+/-18 normalized units; P<0.05) than aged subjects. Consequently, the low-frequency/high-frequency ratio (0.43+/-0.07 compared with 0.91+/-0.05; P<0.02) was also lower in the healthy centenarians than in the aged subjects. Our study demonstrates that the basal low-frequency/high-frequency ratio, an indirect index of cardiac sympathovagal balance, is lower in healthy centenarians than in aged subjects. (+info)
Mutation rates in humans. I. Overall and sex-specific rates obtained from a population study of hemophilia B.
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A population-based study of hemophilia B mutations was conducted in the United Kingdom in order to construct a national confidential database of mutations and pedigrees to be used for the provision of carrier and prenatal diagnoses based on mutation detection. This allowed the direct estimate of overall (micro), male (v), and female (u) mutation rates for hemophilia B. The values obtained per gamete per generation and the 95% confidence intervals are micro;=7.73 (6. 29-9.12&parr0;x10-6; v=18.8 (14.5-22.9&parr0;x10-6; and u=2.18 (1. 44-3.16&parr0;x10-6. The ratio of male-to-female mutation rates is 8. 64, with a 95% confidence interval of 5.46-14.5. The higher male rate was not caused by a much higher rate of transition at CpG sites in the male. Attempts to detect evidence of gonadal mosaicism for hemophilia B mutation in suitable families did not detect any instances of ovarian mosaicism in any of 47 available opportunities. This suggests that the risk of a noncarrier mother manifesting as a gonadal mosaic by transmitting the mutation to a second child should be <0.062. (+info)