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PubMed2002

The influence of metabolic rate on longevity in the nematode Caenorhabditis elegans.

Much of the recent interest in aging research is due to the discovery of genes in a variety of model organisms that appear to modulate aging. A large amount of research has focused on the use of such long-lived mutants to examine the fundamental causes of aging. While model organisms do offer many advantages for studying aging, it also critical to consider the limitations of these systems. In particular, ectothermic (poikilothermic) organisms can tolerate a much larger metabolic depression than humans. Thus, considering only chronological longevity when assaying for long-lived mutants provides a limited perspective on the mechanisms by which longevity is increased. In order to provide true insight into the aging process additional physiological processes, such as metabolic rate, must also be assayed. This is especially true in the nematode Caenorhabditis elegans, which can naturally enter into a metabolically reduced state in which it survives many times longer than its usual lifetime. Currently it is seen as controversial if long-lived C. elegans mutants retain normal metabolic function. Resolving this issue requires accurately measuring the metabolic rate of C. elegans under conditions that minimize environmental stress. Additionally, the relatively small size of C. elegans requires the use of sensitive methodologies when determining metabolic rates. Several studies indicating that long-lived C. elegans mutants have normal metabolic rates may be flawed due to the use of inappropriate measurement conditions and techniques. Comparisons of metabolic rate between long-lived and wild-type C. elegans under more optimized conditions indicate that the extended longevity of at least some long-lived C. elegans mutants may be due to a reduction in metabolic rate, rather than an alteration of a metabolically independent genetic mechanism specific to aging.

Animals↗
PubMed2002

The genetics of exceptional human longevity.

There is a substantial distinction to be made between the genetics of aging and the genetics of exceptional longevity. Twin studies suggest that the average set of genetic variations facilitates the average human's ability to live well into their octogenarian years. Other studies indicate that taking full advantage of this average set results in spending the majority of those years in good health. However, many people counteract such genetic endowment with poor health habits, resulting in a substantially lower average life expectancy and relatively more time spent in poor health. To live beyond the octogenarian years, life-span experiments in lower organisms and mammals and population and molecular genetic studies of centenarian sibships suggest that genetic factors play an important role in exceptional longevity. These factors are likely to influence basic mechanisms of aging, which in turn broadly influence susceptibility to age-related illnesses. Lacking genetic variations that predispose to disease, and having variations that confer disease resistance (longevity enabling genes), are probably both important to such a remarkable survival advantage. Recent studies indicate the likelihood that such factors will be elucidated in the near future.

Aged↗
PubMed2001

Body mass index: a measure for longevity.

Body mass index has important predictive value for mortality and morbidity both in normal subjects and in those suffering from particular pathologies. However, body mass index was introduced as a measure of body fat, which might not be expected to have such wide implications for various pathological conditions. We argue here that body mass index may actually be a measure for longevity. Our arguments are based on a well-established allometric scaling law for physiological time. The time between heart beats, the time between respirations, and longevity all scale as body weight to the 1/4 power in mammalian species ranging from shrews to blue whales. We find that body mass index also scales with body weight to the 1/4 power in humans from birth to one year of age, and again from approximately 5 to 17 years of age. On the assumption that in these two growth phases humans scale as do species, we postulate that body mass index is a measure of longevity.

Biological Evolution↗
PubMed2004

Multiple-stress analysis for isolation of Drosophila longevity genes.

Long-lived organisms tend to be more resistant to various forms of environmental stress. An example is the Drosophila longevity mutant, methuselah, which has enhanced resistance to heat, oxidants, and starvation. To identify genes regulated by these three stresses, we made a cDNA library for each by subtraction of "unstressed" from "stressed" cDNA and used DNA hybridization to identify genes that are regulated by all three. This screen indeed identified 13 genes, some already known to be involved in longevity, plus candidate genes. Two of these, hsp26 and hsp27, were chosen to test for their effects on lifespan by generating transgenic lines and by using the upstream activating sequence/GAL4 system. Overexpression of either hsp26 or hsp27 extended the mean lifespan by 30%, and the flies also displayed increased stress resistance. The results demonstrate that multiple-stress screening can be used to identify new longevity genes.

Animals↗
PubMed2001

A genome-wide scan for linkage to human exceptional longevity identifies a locus on chromosome 4.

Substantial evidence supports the familial aggregation of exceptional longevity. The existence of rare families demonstrating clustering for this phenotype suggests that a genetic etiology may be an important component. Previous attempts at localizing loci predisposing for exceptional longevity have been limited to association studies of candidate gene polymorphisms. In this study, a genome-wide scan for such predisposing loci was conducted by using 308 individuals belonging to 137 sibships demonstrating exceptional longevity. By using nonparametric analysis, significant evidence for linkage was noted for chromosome 4 at D4S1564 with a MLS of 3.65 (P = 0.044). The analysis was corroborated by a parametric analysis (P = 0.052). These linkage results indicate the likelihood that there exists a gene, or genes, that exerts a substantial influence on the ability to achieve exceptional old age. Identification of the genes in humans that allow certain individuals to live to extreme old age should lead to insights on cellular pathways that are important to the aging process.

Aged↗
PubMed2004

Shared transcriptional signature in Caenorhabditis elegans Dauer larvae and long-lived daf-2 mutants implicates detoxification system in longevity assurance.

In the nematode Caenorhabditis elegans, formation of the long-lived dauer larva and adult aging are both controlled by insulin/insulin-like growth factor-1 signaling. Potentially, increased adult life span in daf-2 insulin/insulin-like growth factor-1 receptor mutants results from mis-expression in the adult of a dauer larva longevity program. By using oligonucleotide microarray analysis, we identified a dauer transcriptional signature in daf-2 mutant adults. By means of a nonbiased statistical approach, we identified gene classes whose expression is altered similarly in dauers and daf-2 mutants, which represent potential determinants of life span. These include known determinants of longevity; the small heat shock protein/alpha-crystallins are up-regulated in both milieus. The cytochrome P450, short-chain dehydrogenase/reductase, UDP-glucuronosyltransferase, and glutathione S-transferase (in daf-2 mutants) gene classes were also up-regulated. These four gene classes act together in metabolism and excretion of toxic endobiotic and xenobiotic metabolites. This suggests that diverse toxic lipophilic and electrophilic metabolites, disposed of by phase 1 and phase 2 drug metabolism, may be the major determinants of the molecular damage that causes aging. In addition, we observed down-regulation of genes linked to nutrient uptake, including nhx-2 and pep-2. These work together in the uptake of dipeptides in the intestine, implying dietary restriction in daf-2 mutants. Some gene groups up-regulated in dauers and/or daf-2 were enriched for certain promoter elements as follows: the daf-16-binding element, the heat shock-response element, the heat shock-associated sequence, or the hif-1-response element. By contrast, the daf-16-associated element was enriched in genes down-regulated in dauers and daf-2 mutants. Thus, particular promoter elements appear longevity-associated or aging associated.

Aging↗
PubMed2005

Estrogen, insulin, and dietary signals cooperatively regulate longevity signals to enhance resistance to oxidative stress in mice.

To investigate the biological significance of a longevity mutation found in daf-2 of Caenorhabditis elegans, we generated a homologous murine model by replacing Pro-1195 of insulin receptors with Leu using a targeted knock-in strategy. Homozygous mice died in the neonatal stage from diabetic ketoacidosis, whereas heterozygous mice showed the suppressed kinase activity of the insulin receptor but grew normally without spontaneously developing diabetes during adulthood. We examined heterozygous insulin receptor mutant mice for longevity phenotypes. Under 80% oxygen, mutant female mice survived 33.3% longer than wild-type female mice, whereas mutant male mice survived 18.2% longer than wild-type male mice. These results suggested that mutant mice acquired more resistance to oxidative stress, but the benefit of the longevity mutation was more pronounced in females than males. Manganese superoxide dismutase activity in mutant mice was significantly upregulated, suggesting that the suppressed insulin signaling leads to an enhanced antioxidant defense. To analyze the molecular basis of the gender difference, we administered estrogen to mutant mice. It was found that the survival of mice under 80% oxygen was extended when they were administered estradiol. In contrast, mutant and wild-type female mice showed shortened survivals when their ovaries were removed. The influence of estrogen is remarkable in mutant mice compared with wild-type mice, suggesting that estrogen modulates insulin signaling in mutant mice. Furthermore, we showed additional extension of survival under oxidative conditions when their diet was restricted. Collectively, we show that three distinct signals; insulin, estrogen, and dietary signals work in independent and cooperative ways to enhance the resistance to oxidative stress in mice.

Animals↗
PubMed2004

Influence of temperature on the development, reproduction and longevity of Ceratothripoides claratris (Thysanoptera: Thripidae) on tomatoes.

Ceratothripoides claratris (Shumsher) is a serious pest attacking tomatoes in Thailand. Temperature-dependent development of C. claratris was studied at seven constant temperatures, i.e. 22, 25, 27, 30, 34, 35 and 40 degrees C. Pre-adult survivorship was greatest (95%) at 25 and 30 degrees C and shortest at 22 degrees C. Egg-to-adult time decreased within the range of 20 to 30 degrees C and at 34 degrees C it started to increase. The lower thermal threshold for egg-to-adult development was estimated at 16 and 18 degrees C by linear regression and the modified Logan model, respectively. The optimum temperature for egg-to-adult development was estimated at 32-33 degrees C by the modified Logan model. The influence of temperature on reproduction and longevity of C. claratris was determined at 25, 30 and 35 and 40 degrees C. Both inseminated and virgin females failed to reproduce at 40 degrees C. Virgin females produced only male offspring, confirming arrhenotoky. The sex ratio of the offspring of fertilized females was strongly female-biased, except at 25 degrees C. Mean total fecundity per female and mean daily total fecundity per female were highest for both virgin and inseminated females at 30 degrees C. Female longevity was longest at 25 degrees C and shortest at 40 degrees C. Male longevity was longest at 30 degrees C and shortest at 40 degrees C. The net reproductive rate (R0) and intrinsic rate of natural increase (rm) was greatest at 30 degrees C while, mean generation time (G) and the doubling time (t) were highest at 25 degrees C. The finite rate of increase (lambda) was fairly constant (1.1-1.5 days) over the three temperatures tested. The pest potential of C. claratris for tropical Asia is discussed.

Animals↗
PubMed2006

Role of mitochondrial oxidative stress to explain the different longevity between genders: protective effect of estrogens.

Females live longer than males. Work from our laboratory has shown that this may be due to the up-regulation of longevity-associated genes by estrogens. Estrogens bind to the estrogen receptors and subsequently activate the mitogen activated protein kinase and nuclear factor kappa B signalling pathways, resulting in an up-regulation of antioxidant enzymes. Estrogen administration, however, has serious undesirable effects and of course, cannot be administered to males because of its powerful feminizing effects. Thus, we tested the effect of genistein, a phytoestrogen of high nutritional importance whose structure is similar to estradiol, on the regulation of the expression of antioxidant, longevity-related genes and consequently on oxidant levels in mammary gland tumour cells in culture. Phytoestrogens mimic the protective effect of oestradiol using the same signalling pathway. The critical importance of up-regulating antioxidant genes, by hormonal and dietary manipulations, to increase longevity is discussed.

Animals↗
PubMed1999

Genes, demography, and life span: the contribution of demographic data in genetic studies on aging and longevity.

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.

Aging↗
PubMed1987

Sexual hyperactivity and reduced longevity of dunce females of Drosophila melanogaster.

The dunce gene of Drosophila melanogaster codes for a cyclic adenosine-3',5'-monophosphate-specific phosphodiesterase. Mutations of dunce alter or abolish the activity of this enzyme, produce elevated cAMP levels, cause recessive female sterility, and produce learning deficiencies in both sexes. Aberrant male sexual behavior has also been associated with the memory defects of dunce mutants. Here we show that the longevity of dunce mutant females, homozygous for null-enzyme alleles, is reduced by 50% in the presence of males compared to control dunce females kept without males. Mutant dunce females, mate every 22-24 hr. We propose a cause-effect relationship between mating and reduced longevity. Pheromones or peptides transferred during mating may activate adenylate cyclase and create an increase in cAMP levels that cannot be damped in dunce females. This increase may affect basic physiological functions and lead to reduced longevity.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1996

Longevity in the united states: age and sex-specific evidence on life span limits from mortality patterns 1960-1990.

Determining the biological limits to human longevity is more difficult than for most other species because humans are long-lived. Consequently, mortality data, such as from the U.S. vital statistics system, which have been available for a long time (relative to most epidemiological studies) and have large numbers of cases, including deaths reported to advanced ages, are important in studying human longevity-though care must be exercised in dealing with error in age reporting. Furthermore, it is unlikely that free-living humans can realize as much of their biological endowment for longevity as animals living in a highly controlled experimental environment. We examined changes, 1960 to 1990, in U.S. White male and female extinct cohort life tables and age at death distributions to (a) examine evidence for the effects of a biological life span limit in current U.S. mortality patterns and (b) produce lower bound estimates of that limit.

Aged↗
PubMed1998

Aged-rodent models of long-term growth hormone therapy: lack of deleterious effect on longevity.

Studies were carried out to examine the effects of long-term recombinant human growth hormone (GH) therapy on longevity in rodents. In the first study, 150 18-month-old female F344 rats were divided into three groups of 50 rats per group: Group 1, solvent vehicle; Group 2, 10 microg GH/kg body weight three times per week; Group 3, 50 microg GH/kg body weight three times per week. GH and solvent vehicle therapies were started at 18 months of age and continued until all the animals died spontaneously. Serum insulin-like growth factor (IGF)-I was measured at 18 and 29 months of age and on 3-month-old rats. Serum IGF-I level decreased between 3 and 29 months of age. GH therapy reversed the decrease in a dose-dependent manner, with the 50 microg GH dose returning the serum IGF-I level to that of 3-month-old animals. However, statistical analysis revealed no significant effect of GH therapy on median life span, 10th percentile life span, or maximum life span. Similar observations on longevity were made on aged F344 male rats and on aged Balb/c mice, even when the dose of GH was increased to 1.0 mg/kg body weight two times per week. The main pathologic lesions in control animals were nephropathy, cardiomyopathy, leukemia, and testicular interstitial cell tumor; the prevalence of these lesions was not significantly altered by GH therapy. We conclude that long-term low-dose GH therapy that includes doses in the range that is given to humans in clinical trials in GH deficiency and to revert age-related physiologic declines has no overt deleterious effects on longevity and pathology in aged rodents.

Aging↗
PubMed2000

Extended longevity in Drosophila is consistently associated with a decrease in developmental viability.

It has proven relatively easy to select normal-lived strains of Drosophila for extended longevity in the laboratory. Long-lived strains have not been observed in the wild as yet. Of the various life-history traits that have been investigated for their role in modulating the evolution of extended longevity, none have yet shown a consistent or convincing relationship. Other than developmental time, the traits usually investigated in this regard are those associated with the adult phase of the life cycle. We assayed developmental timing and viability in six pairs of normal- and long-lived strains, four pairs of which are from previously described strains and two pairs of which are new strains that have been independently and recently selected. We find that the life-history trait most obviously associated with all our long-lived strains is a significantly reduced developmental viability, with the long-lived strains' having as much as twice the developmental lethality as do any of the normal-lived strains. The long-lived strains also pupate closer to the food, a behavior known to decrease fitness. Thus the reduced fitness of the long-lived strains appears to be due to both physiological and behavioral factors and may well explain why long lived strains are not usually found in the wild. The extension of longevity involves costs as well as benefits that, in this case, are borne by different individuals.

Animals↗
PubMed2000

Oxidative stress resistance: a robust correlated response to selection in extended longevity lines of Drosophila melanogaster?

Stress resistance is associated with longevity in Drosophila melanogaster and other model organisms used for genetic research. The present study tests for oxidative stress resistance in one set of lines selected for late-life reproduction and extended longevity. Both females and males from the selected lines were appreciably more resistant to oxidative stress than were flies from the control lines. A relative increase in oxidative stress resistance is a correlated response to selection in this laboratory selection experiment. Increased oxidative stress resistance appears to be a relatively robust correlated response to laboratory selection for late-life reproduction and extended longevity.

Analysis of Variance↗
PubMed2001

Direct selection for paraquat resistance in Drosophila results in a different extended longevity phenotype.

When normal-lived Ra strain Drosophila were indirectly selected for longevity, they gave rise to long-lived La strain animals with lower oxidized protein and lipid levels that were temporally coincident with higher antioxidant activities. We wanted to determine whether it was possible to create long-lived animals by a direct selection for increased antioxidant activities. Using the same Ra strain, we selected them over 24 generations for increased resistance to paraquat. Selection was successful: the paraquat-resistant flies had a fourfold increase in their LT(50) (mean lethal time) values. Their extended longevity pattern differs from that of the La strain. The paraquat-resistant animals also have a lower level of antioxidant activity, an increased total P450 enzyme activity level, an altered pattern of energy metabolism, and a significantly lower developmental viability. We interpret these findings as suggesting that similar stress response phenotypes may be generated by different molecular mechanisms, some of which may generate very different types of extended longevity phenotypes.

Animals↗
PubMed2002

A case-only approach for assessing gene by sex interaction in human longevity.

As one aspect of the complex feature of longevity, gene by sex interaction plays an important role in influencing human life span. With advances in molecular genetics, more studies aimed at assessing gene by sex interaction are expected. New and valid statistical methods are needed. In this article, we introduce a nontraditional approach, the case-only design, which was originally proposed for assessing gene and disease associations, to detect gene by sex interaction in human longevity. Applications of this method to data collected from centenarian studies show that it can produce consistent results as compared with results obtained from case-control and other approaches. The method cannot be used as a substitute for traditional case-control studies since it is limited to the detection of interactions only. However, the easily applicable case-only approach can be an important tool for screening many potential genes that contribute to human longevity.

Aged↗
PubMed2002

Physical performance and longevity in aged rats.

In humans, physical performance declines with increasing age, and in nondisabled older persons, scores on standardized performance measures, such as walking speed, repeated chair stands, and a balance test, predict the incidence of disability and reduced longevity. Here we show in aged rats (24-month-old Brown Norway x Fischer 344 male rats; n = 48) that conceptually similar performance measures, such as swimming speed and an inclined plane procedure, can be assessed longitudinally, and that over 6 months of follow-up from the age of 24 to 30 months, performance declines progressively with increasing age. High baseline performance scores predict long-term longevity, a relationship that is also found in humans. The application of standardized physical performance measures to a variety of animal models of aging may help to define similarities between species in the underlying mechanisms of the age-related decline in performance, disability, and longevity.

Aging↗