Alteration of life span of mice chronically exposed to 2.45 GHz CW microwaves

Female CD 1 mice were exposed from the thirty-fifth day of age for the remainder of their lives to 2.45 GHz, CW-microwave radiation at a power density of 3 or 10 m W/cm² (SAR = 2.0 or 6.8 W/kg). Exposures took place 1 h/day, 5 day/week in an anechoic chamber at an ambient temperature of 22 °C and a relative humidity of 50%. There were 25 animals in each exposure group, and an equal number of controls were concurrently sham exposed. The average life span of animals exposed at 10 mW/cm² was significantly shorter than that of sham-exposed controls (572 days vs. 706 days; P = .049; truncation >20%). In contrast, the average lifespan of the animals exposed at 3 mW/cm² was slightly, but not significantly, longer (738 days) than that of controls (706 days). © 1994 Wiley-Liss, Inc.

1 This article is a US Government work and, as such, is in the public domain in the United States of America.

     

Genetic analysis of extended life span in Drosophila melanogaster I. RAPD screen for genetic divergence between selected and control lines

Using lines selected for long life by Luckinbill and his co-workers, we screened two selected and two control lines for allelic frequency differences at 1200 randomly chosen RAPD marker loci. Twenty-three marker loci showed frequency differences in excess of 80%, and five were greater than 90%. Age-specific effects of the five most differentiated loci were estimated by collecting complete survival data in segregating backcross populations. Alleles at four of the five marker loci were associated with significant extension of life span in males, while two marker loci had significant effects in females. Eighty percent of the total selection response in males can be explained by the identified QTL's, under the assumption of additivity. The N14+ marker allele accounted for a 12-day life span extension in males, but had little effect in females. Both sex-limited and sex-shared effects were observed. Analysis of age-specific mortality rates suggests that life span extension occurs by a combination of genetic factors that moderate both the level of mortality and the rate at which mortality increases with age. This revised version was published online in July 2006 with corrections to the Cover Date.     

Heritability of directional and fluctuating asymmetry for mandibular characters in random-bred mice

In bilateral characters, two kinds of asymmetries are common: fluctuating asymmetry (FA), or nondirectional variation between left and right sides, and directional asymmetry (DA), in which one side is consistently larger than the other. FA has been extensively used as a measure of developmental stability because of its presumed environmental basis whereas DA has not typically been recommended because it has been presumed to have at least some genetic basis. To test these two hypotheses, heritabilities were calculated via parent–offspring regression for both DA and FA in 10 triply measured mandible characters in random-bred mice. Midparent estimates of heritabilities of DA in the 10 characters were quite low (mean = 0.06), but significant for one character as well as the sum of the DA values over all characters (0.21). Midparent estimates of heritability of FA in the 10 characters also were low (mean = 0.03), but not significant for any individual character or the sum of the FA values over all characters. Heritabilities of developmental stability calculated from heritabilities and repeatabilities of FA in the mandible characters were higher in magnitude (mean of midparent estimates = 0.45), but all still were not statistically significant. It was concluded that both hypotheses were supported, but that genetic variation in DA was so small that the potential for DA as an indicator of developmental stability should be explored.     

Heritability of corticosterone response and changes in life history traits during selection in the zebra finch

Vertebrates respond to environmental stressors through the neuro-endocrine stress response, which involves the production of glucocorticoids. We have selected independent, duplicate divergent lines of zebra finches for high, low and control corticosterone responses to a mild stressor. This experiment has shown that over the first four generations, the high lines have demonstrated a significant realized heritability of about 20%. However, the low lines have apparently not changed significantly from controls. This asymmetry in response is potentially because of the fact that all birds appear to be showing increased adaptation to the environment in which they are housed, with significant declines in corticosterone response in control lines as well as low lines. Despite the existence of two- to threefold difference in mean corticosterone titre between high and low lines, there were no observed differences in testosterone titre in adult male birds from the different groups. In addition, there were no consistent, significant differences between the lines in any of the life history variables measured--number of eggs laid per clutch, number of clutches or broods produced per pair, number of fledglings produced per breeding attempt, nor in any of egg, nestling and fledgling mortality. These results highlight the fact that the mechanisms that underlie variation in the avian physiological system can be modified to respond to differences between environments through selection. This adds an additional level of flexibility to the avian physiological system, which will allow it to respond to environmental circumstances.     

Sex differences in aging,life span and spontaneous tumorigenesis in 129/Sv mice neonatally exposed to metformin

The perinatal (prenatal and early neonatal) period is a critical stage for hypothalamic programming of sexual differentiation as well as for the development of energy and metabolic homeostasis. We hypothesized that neonatal treatment with antidiabetic drug biguanide metformin would positively modify regulation of growth hormone – IGF-1 – insulin signaling pathway slowing down aging and improving cancer preventive patterns in rodents. To test this hypothesis male and female 129/Sv mice were s.c. injected with metformin (100 mg/kg) at the 3rd, 5th and 7th days after birth. Metformin-treated males consumed less food and water and their body weight was decreased as compared with control mice practically over their entire lifespan. There were no significant differences in age-related dynamics of food and water consumption in females and they were heavier than controls. The fraction of mice with regular estrous cycles decreased with age and demonstrated a tendency to decrease in the females neonatally treated with metformin. Neonatal exposure to metformin practically failed to change the extent of hormonal and metabolic parameters in blood serum of male and female mice. In males, neonatal metformin treatment significantly increased the mean life span (+20%, P < 0.05) and slightly increased the maximum life span (+3.5%). In females, the mean life span and median in metformin-treated groups were slightly decreased (?9.1% and ?13.8% respectively, P > 0.05) in comparison to controls, whereas mean life span of last 10% survivors and maximum life span were the same as in controls. Almost half (45%) of control male mice and 71.8% male mice neonatally exposed to metformin survived up to 800 d of age, the same age was achieved by 54.3% of mice in control female group and 30% of metformin-treated females (P < 0.03). Thus, neonatal metformin exposure slows down aging and prolongs lifespan in male but not in female mice.     

Sex differences in aging,life span and spontaneous tumorigenesis in 129/Sv mice neonatally exposed to metformin

The perinatal (prenatal and early neonatal) period is a critical stage for hypothalamic programming of sexual differentiation as well as for the development of energy and metabolic homeostasis. We hypothesized that neonatal treatment with antidiabetic drug biguanide metformin would positively modify regulation of growth hormone – IGF-1 – insulin signaling pathway slowing down aging and improving cancer preventive patterns in rodents. To test this hypothesis male and female 129/Sv mice were s.c. injected with metformin (100 mg/kg) at the 3rd, 5th and 7th days after birth. Metformin-treated males consumed less food and water and their body weight was decreased as compared with control mice practically over their entire lifespan. There were no significant differences in age-related dynamics of food and water consumption in females and they were heavier than controls. The fraction of mice with regular estrous cycles decreased with age and demonstrated a tendency to decrease in the females neonatally treated with metformin. Neonatal exposure to metformin practically failed to change the extent of hormonal and metabolic parameters in blood serum of male and female mice. In males, neonatal metformin treatment significantly increased the mean life span (+20%, P < 0.05) and slightly increased the maximum life span (+3.5%). In females, the mean life span and median in metformin-treated groups were slightly decreased (−9.1% and −13.8% respectively, P > 0.05) in comparison to controls, whereas mean life span of last 10% survivors and maximum life span were the same as in controls. Almost half (45%) of control male mice and 71.8% male mice neonatally exposed to metformin survived up to 800 d of age, the same age was achieved by 54.3% of mice in control female group and 30% of metformin-treated females (P < 0.03). Thus, neonatal metformin exposure slows down aging and prolongs lifespan in male but not in female mice.     

Aging in inbred strains of mice: study design and interim report on median lifespans and circulating IGF1 levels

To better characterize aging in mice, the Jackson Aging Center carried out a lifespan study of 31 genetically-diverse inbred mouse strains housed in a specific pathogen-free facility. Clinical assessments were carried out every 6 months, measuring multiple age-related phenotypes including neuromuscular, kidney and heart function, body composition, bone density, hematology, hormonal levels, and immune system parameters. In a concurrent cross-sectional study of the same 31 strains at 6, 12, and 20 months, more invasive measurements were carried out followed by necropsy to assess apoptosis, DNA repair, chromosome fragility, and histopathology. In this report, which is the initial paper of a series, the study design, median lifespans, and circulating insulin-like growth factor 1 (IGF1) levels at 6, 12, and 18 months are described for the first cohort of 32 females and 32 males of each strain. Survival curves varied dramatically among strains with the median lifespans ranging from 251 to 964 days. Plasma IGF1 levels, which also varied considerably at each time point, showed an inverse correlation with a median lifespan at 6 months ( R  = −0.33, P  = 0.01). This correlation became stronger if the short-lived strains with a median lifespan < 600 days were removed from the analysis ( R  = −0.53, P  < 0.01). These results support the hypothesis that the IGF1 pathway plays a key role in regulating longevity in mice and indicates that common genetic mechanisms may exist for regulating IGF1 levels and lifespan.     

Heritability estimates of life history traits in small white butterflyPieris rapae crucivora

Heritabilities and genetic correlations of life history characters (pupal weight, age-specific fecundities, and egg weight) of small white butterfly Pieris rapae crucivora are estimated by a quantitative genetic method (sib analysis). The results indicate moderate or high heritabilities and a largely negative genetic correaltion in age-specific fecundities.     

Changes in genetic architecture during relaxation in Drosophila melanogaster selected on divergent virgin life span

Artificial selection experiments often confer important information on the genetic correlations constraining the evolution of life history. After artificial selection has ceased however, selection pressures in the culture environment can change the correlation matrix again. Here, we reinvestigate direct and correlated responses in a set of lines of Drosophila melanogaster that were selected on virgin life span and for which selection has been relaxed for 10 years. The decrease in progeny production in long-lived lines, a strong indication of antagonistic pleiotropy, had disappeared during relaxation. This was associated with a higher cost of reproduction to long-lived flies in mated, but not in virgin life span. These data strongly suggest that genetic mechanisms of mated and virgin life span determination are partly independent. Furthermore, data on body weight, developmental time and viability indicated deleterious effects of longevity selection in either direction, giving rise to a nonlinear relationship with life span for these characters. In order to reclaim original patterns, we founded a new set of derived lines by resuming selection in mixed replicate lines of the original set. Although selection was successful, most patterns in correlated characters remained, showing that these new patterns are resistant to new episodes of selection.     

长寿和衰老基因及相关基因研究进展

简要介绍了长寿和衰老基因及相关基因在酵母、线虫、果蝇和哺乳动物中的最新遗传学研究进展；概述了“生物钟”、端粒和端粒酶在人类长寿和衰老进程中的重要作用。相信随着人类遗传学和分子生物学研究的深入，将有更多的长寿和衰老基因及相关基因被发现，为揭示衰老机制和延年益寿提供依据。     

Heritability of resistance to oxidative stress in early life

Oxidative stress has recently been suggested to play an important role in life‐history evolution, but little is known about natural variation and heritability of this physiological trait. Here, we explore phenotypic variation in resistance to oxidative stress of cross‐fostered yellow‐legged gull (Larus cachinnans) chicks. Resistance to oxidative stress was not related to plasma antioxidants at hatching, which are mostly derived from maternal investment into eggs. Common environmental effects on phenotypic variation in resistance to oxidative stress were not significant. Heritability was relatively low and nonsignificant in hatchlings, but interestingly, the chicks of age 8 days showed high and significant heritability (h² = 0.59). Our results suggest that resistance to oxidative stress is determined mainly by the genotype as chicks grow. Further work is required to explore the genetic role of oxidative stress in life‐history evolution.     

Low Mitochondrial Free Radical Production Per Unit O2 Consumption Can Explain the Simultaneous Presence of High Longevity and High Aerobic Metabolic Rate in Birds

Birds are unique since they can combine a high rate of oxygen consumption at rest with a high maximum life span (MLSP). The reasons for this capacity are unknown. A similar situation is present in primates including humans which show MLSPs higher than predicted from their rates of O₂ consumption. In this work rates of oxygen radical production and O₂ consumption by mitochondria were compared between adult male rats (MLSP = 4 years) and adult pigeons (MLSP = 35 years), animals of similar body size. Both the O₂ consumption of the whole animal at rest and the O₂ consumption of brain, lung and liver mitochondria were higher in the pigeon than in the rat. Nevertheless, mitochondrial free radical production was 2-4 times lower in pigeon than in rat tissues. This is possible because pigeon mitochondria show a rate of free radical production per unit O₂ consumed one order of magnitude lower than rat mitochondria: bird mitochondria show a lower free radical leak at the respiratory chain. This result, described here for the first time, can possibly explain the capacity of birds to simultaneously increase maximum longevity and basal metabolic rate. It also suggests that the main factor relating oxidative stress to aging and longevity is not the rate of oxygen consumption but the rate of oxygen radical production. Previous inconsistencies of the rate of living theory of aging can be explained by a free radical theory of aging which focuses on the rate of oxygen radical production and on local damage to targets relevant for aging situated near the places where free radicals are continuously generated.     

Clonal growth and culture life span of bovine adrenocortical cells in a serum-free medium

Summary The life span and growth from clonal density of bovine adrenocortical cell cultures were studied in serum-supplemented medium and a serum-free defined medium, which supported sustained cell proliferation and steroid production. The total culture life span was 79 population doublings in serum-supplemented medium with fibroblast growth factor (FGF) and 36 population doublings in the defined medium without serum. Older passage cell cultures grown in the defined medium progressively lost the ability to produce 11β- and 21-hydroxylated steroids, which was observed previously for cultures in serum-supplemented medium, and also had a decline of 17α-hydroxylated steroid production. The cloning efficiency in the defined medium was 12.2% as compared to 24% in serum-supplemented medium with FGF. Five isolated clonal cell lines grown in the defined medium were characterized for steroid function in response to steroidogenic agents. All five clonal cell lines had stimulated steroid production with 8-bromo-cAMP, but only four of the clonal lines were stimulated also by adrenocorticotropin. None of the clonal cell lines produced 11β-, 21- or 17α-hydroxylated steroids in response to treatment with either steroidogenic agent, results that were similar to data obtained from older mass cultures. The apparent deficiency of the defined medium as compared to serum-supplemented medium for maximum support of the culture life span and cloning efficiency may be useful in studies of cellular aging and its relation to differentiated function for this cell culture system. This study was supported by the Iowa Diabetes and Endocrinology Research Center (grant AM25295 from the National Institutes of Health, Bethesda, MD). D.A.F. was supported by a National Research Service Award from the National Institutes of Health (grant HL07485).     

Mild mitochondrial uncoupling in mice affects energy metabolism, redox balance and longevity

Caloric restriction is the most effective non-genetic intervention to enhance lifespan known to date. A major research interest has been the development of therapeutic strategies capable of promoting the beneficial results of this dietary regimen. In this sense, we propose that compounds that decrease the efficiency of energy conversion, such as mitochondrial uncouplers, can be caloric restriction mimetics. Treatment of mice with low doses of the protonophore 2,4-dinitrophenol promotes enhanced tissue respiratory rates, improved serological glucose, triglyceride and insulin levels, decrease of reactive oxygen species levels and tissue DNA and protein oxidation, as well as reduced body weight. Importantly, 2,4-dinitrophenol-treated animals also presented enhanced longevity. Our results demonstrate that mild mitochondrial uncoupling is a highly effective in vivo antioxidant strategy, and describe the first therapeutic intervention capable of effectively reproducing the physiological, metabolic and lifespan effects of caloric restriction in healthy mammals.     

The human apoE7 and apoE4 transgenic mice models

To scrutinize the disorders caused by human mutant apoE7/apoE4, human apoE4 and E7 transgenic mice were established with microinjection technique to examine molecular genetic phenomenain vivo. The integration and expression of h-apoE mutant genes in transgenic mice were determined with Southern blot, Northern blot and ELISA. The current studies indicated that the transgenes and the phenotypes regarding expression of transgenes could be transmitted stably in transgenic lines. The levels of serum lipid in transgenic mice showed the characteristics of hyperlipidemia. Besides, behavior tests demonstrated the degeneration of learning and memory in transgenic mice. Short life span was observed in 2 transgenic lines. After fed with high lipid food high serum lipid was found both in normal and transgenic mice, but their mechanism regulating lipid metabolism was different. It was also verified that the human apoE mutants located at either N-terminal or C-terminal had the same pathogenesis regarding disorders of lipid metabolism in murine.     

Effects of UV‐A exposures on longevity and reproduction in Helicoverpa armigera,and on the development of its F1 generation

Abstract Helicoverpa armigera adults display a conspicuous positive phototactic behavior to light stimuli, and are especially sensitive to ultraviolet (UV) light. The effects of UV‐A (longwave) exposures on adult longevity and reproduction in H. armigera were investigated, as well as the development of the F₁ generation. Paired adults were exposed to UV‐A for various time periods (0, 1, 5 and 9 h/day), until the end of adult life. The results showed that adult longevity decreased with increasing exposure time for both sexes, and a significant decrease was observed after exposure for 5 and 9 h/day. Fecundity increased when adults were exposed for 1 and 5 h/day, and a significant difference was observed in the 5 h/day group. Oviposition rates of females in all treatments were significantly higher than in the control. Exposure to UV‐A for longer periods (5 and 9 h/day) caused a decline in cumulative survival of F₁ immature stages, but no significant differences were found in egg hatch, pupation and eclosion. The developmental periods of F₁ larvae were significantly prolonged after exposure to UV‐A for 5 and 9 h/day. UV‐A radiation had no significant effects on F₁ pupal period.     

Developmental and age-specific effects of selection on divergent virgin life span on fat content and starvation resistance in Drosophila melanogaster

Investigations into the genetic basis of longevity variation have shown life span to be positively correlated with starvation resistance and negatively with female fecundity, both of which rely on lipid content. To assess the firmness of this relation, we assayed correlated responses in age-specific relative fat content (RFC) and starvation resistance in lines successfully selected for divergent virgin life span. We have previously demonstrated that genetic differentiation in female fecundity between our selection lines had disappeared during relaxation of selection. Therefore, we also expected genetic differences in lipid content and starvation resistance to have disappeared. However, RFC and starvation resistance were still significantly lower in short-lived flies than in control flies. Surprisingly, also in long-lived flies RFC and starvation resistance were mostly, but not invariably, found to be significantly lower than in control flies. These results indicate that the genetic correlation of RFC and starvation resistance with reproduction has broken down. Furthermore, the relationship between life span and starvation resistance appears to be more complex than previously anticipated. Also, we could demonstrate that differences in RFC were not brought about by differences in lipid accumulation during adult life, but were already present at eclosion. These findings suggest that pre-adult developmental pathways already impact on the rate of ageing of the adult fly.