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PubMed1992

Selection on stress resistance increases longevity in Drosophila melanogaster.

Tests for the causal involvement of specific physiological mechanisms in the control of aging require evidence that these mechanisms can be used to increase longevity or reproductive lifespan. Selection for later reproduction in Drosophila has been shown to lead to increased longevity, as well as increased resistance to starvation and desiccation stresses. Selection for increased resistance to starvation and desiccation in Drosophila melanogaster is here shown to lead to increased longevity, indicating that alleles that increase stress resistance also may increase longevity. The responses of desiccation and starvation resistance to selection are partly independent of each other, indicating a multiplicity of physiological mechanisms involved in selectively postponed aging, and thus aging in general.

Animals↗

PubMedDate not supplied

Phenotypic enhancement of longevity by environmental urea in Drosophila melanogaster.

The phenotypic enhancement of longevity through a variety of environmental treatments, including dietary manipulations, has been observed in various species of animals, both vertebrate and invertebrate. Elucidating the mechanisms underlying such effects has provided insights into the physiological processes contributing to the determination of lifespan. Here, we report the enhancement of longevity in adult Drosophila melanogaster maintained on food supplemented with urea, a metabolic waste product occurring naturally in Drosophila cultures, especially at high larval densities. The impact of urea on longevity is shown to be through a decrease in the age-independent parameter (A) of the Gompertz equation, rather than the age-dependent parameter (alpha), which reflects the "rate of aging." We also present evidence suggesting that the urea-induced increase in longevity is mediated exclusively through a reduction in some aspect(s) of reproduction in adult flies maintained on urea-supplemented food.

Animals↗

PubMed2005

Does dietary restriction really increase longevity in Drosophila melanogaster?

It is often accepted that dietary restriction (DR) increases longevity in most species so far tested. Showing the same result in the fruit fly Drosophila melanogaster would be of interest, because this species is widely used in aging research. Some studies have shown that dietary restriction decreases longevity in this species while the opposite result has also been reported. However, some recent results appear to be flawed due to the use of not optimal control rearing conditions. It is argued that, for the time being, it cannot be concluded that dietary restriction increases longevity in D. melanogaster. It has also been shown in other fly species that dietary restriction does not increase longevity.

Animal Nutritional Physiological Phenomena↗

PubMed2004

Body weight is not always a good predictor of longevity in mice.

There have been some observations that low body weight and a low level of some hormones (e.g. IGF-1) during the first half of life are predictors of longer life in mice. However, contradictions in the available data on the biomarkers of aging and predictors of longevity have shown that the research in these fields has become a controversial pursuit. In our study we addressed the following questions: (i) Can particular physiological parameters (body weight, food intake, estrus function, body temperature, incidence of chromosome aberrations in bone marrow cells) measured at the age of 3 and 12 months be a predictor of longevity and the rate of tumor development in five strains of mice? (ii) Can a heavy body weight at the age of 3 and 12 months be a predictor of longevity and high tumor risk in five strains of mice? Mice of five strains-CBA, SHR, SAMR, SAMP and transgenic HER-2/neu (FVB/N)-were under observation from the age of 2-3 months until natural death. Body weight and temperature, food consumption, and estrous cycle were longitudinally studied in all animals. Tumors discovered at autopsy were studied morphologically. We calculated the life span's parameters (mean, maximum, mortality rate, mortality rate doubling time) as well as their correlation with other parameters studied. The longest living CBA mice have the lowest body weight at the ages of 3 and 12 months, the lowest food consumption, body temperature, incidence of chromosome aberrations and spontaneous tumor incidence. In comparison with all other mouse strains they also have the latest disturbances in estrus function and highest body weight gain. The shortest living transgenic HER-2/neu mice have the lowest weight at the ages of 12 months, the lowest body weight gain, maximal body temperature, the most rapid disturbances in estrus function and the highest incidence of chromosome aberrations and tumor incidence in comparison to all other mouse strains. Our findings have shown that heavier body weight at the age of 12 months is a predictor of longevity in female CBA and SAMP mice but not in SHR, SAMR and HER-2/neu mice. Excessive body weight at the ages of 3 or 12 months is not a predictor of increased tumor risk in the strains studied. In general, the existence and direction of a significant correlation between body weight and life span depends upon the animals' age and genotype.

Animals↗

PubMed2004

Is early life body weight a predictor of longevity and tumor risk in rats?

Heavy body weight (BW) is thought to be associated with reduced longevity and age-associated diseases, including cancer, both in laboratory rodents and humans. To further investigate the interactions between BW, longevity and spontaneous tumor development, we measured the correlations between BW in early life, BW in middle life, and parameters of life span and tumorigenesis in male and female outbred rats. The data show that BW at the ages of both 3 and 12 months are significant predictors of longevity in rats. Heavier female rats tend to live longer than the lighter female rats, while in male those who were light at 3 months but heavy at 12 month had the best longevity. BW at the age 3 months was not predictive of tumor growth but being heavier at the age of 1 year did confer an increased risk of tumor development for both male and female rats.

Age Factors↗

PubMed2005

The effect of diet, sex and mating status on longevity in Mediterranean fruit flies (Ceratitis capitata), Diptera: Tephritidae.

Dietary Restriction (DR) extends lifespan in a range of model organisms such as yeast, flies and worms suggesting it is a 'public' mechanism for longevity extension. Lifespan extension has also been reported in the Mediterranean fruit fly (medfly), Ceratitis capitata in response to various types of dietary manipulation, however, the responses can be complex. There are also reported differences in the responses of medfly and Drosophila melanogaster longevity to DR, but it is not clear to what extent these are due to differences in feeding protocols or to what extent they reflect real biological differences. In order to investigate this, we applied a DR feeding protocol similar to that used in many D. melanogaster studies and tested for effects on male and female virgin and mated medfly longevity. Our results show a clear effect of DR and a cost of reproduction for both sexes. Female flies lived significantly longer than male flies at all food levels, indicating minimal interactions between diet and sex in determining longevity.

Aging↗

PubMed2006

Decrease in the lgl tumor suppressor dose in Drosophila increases survival and longevity in stress conditions.

Recent studies suggest that downregulation of tumor suppressor genes might not only favor cancer development but also postpone organisms' aging and increase longevity. However, there is lack of population-based studies directly supporting this idea. We studied the lgl lethal alleles which are widespread in natural Drosophila populations. We demonstrate, for the first time, that animals heterozygous on the loss-of-function lgl tumor suppressor gene display a clear pre-adult viability advantage under stressful conditions (high 29 degrees C and low 16 degrees C temperatures). We found also the survival and longevity advantage effect of the lgl loss-of-function in the temperature stress conditions. The main features of this longevity influence are following. First, the lgl-dependent life span increase is sex-dependent; in all experimental combinations males are more sensitive than females of relevant genotypes. Second, the effect is stronger under the life-shortening temperature stress, 29 degrees C, where the hormesis was demonstrated. Third, the favoring effect of reduced dosage of tumor suppressor displays clearly in old but not young animals, delaying aging. Forth, the maternal or epigenetic inheritance of thermotolerance from mother to offspring appears to strengthen the observed longevity effects. One possible explanation of this stress-adaptive effect of reduced tumor suppressor dose might be a better resistance of Drosophila post-mitotic cells to a stress-associated apoptosis at old ages.

Alleles↗

PubMed2006

Methuselah life history in a variety of conditions, implications for the use of mutants in longevity research.

The laboratory has yielded many long-lived mutants of several model-organisms in the past few years. Many of the resulting claims for extended longevity have been nuanced or shown to be restricted to specific conditions, including environments and genetic backgrounds. Here, we test whether the long-lived mutant fruit fly methuselah (mth(1)) displays its apparent superiority in longevity and stress resistance in different environments, at different ages and in correlated traits. The results demonstrate that stress resistance at different times in life is not consistently higher in the mutant relative to its progenitor strain (w(1118)). Furthermore, the mth(1) genotype only leads to an increase in longevity in an environment where reproduction is not stimulated. Also, virgin and mated life span were compared and showed that mating negatively affects life span, especially in the mth(1) individuals. This reduced the life span enhancing effect of the mutation to zero. This apparent environment and mating dependent trade-off between longevity and reproduction supports the disposable soma theory of ageing. We conclude that these data can only provide limited information on natural variation. The data show the need to uncover the full complexity of variation in such traits in natural environments.

Animal Experimentation↗

PubMed2004

Vascular genetic factors and human longevity.

Complex inter-relationships between age-associated illnesses, such as vascular disease and Alzheimer's disease (AD), suggest that biological and genetic pathways may be worthy of examination in centenarian populations to provide insights into human longevity. This is also borne out by the involvement of lipoprotein metabolism and a number of vascular genetic risk factors. Repeated findings of a higher frequency of the apolipoprotein E (APOE) epsilon4 allele in middle-aged subjects compared with centenarians were reported. Furthermore, we have also shown how in different populations there is a significant trend in reduction of serum APOE levels from APOE epsilon2- to epsilon4-carrier as well as significant differences in serum APOE levels respect to age in epsilon4-carriers but only after adjustment for HDL cholesterol. In contrast, findings of increased prevalence of the angiotensin I converting enzyme 1 (ACE1) D allele in French centenarians have not been replicated, suggesting the possibility that regional differences may occur in ACE1(*)D frequency within Europe in centenarians, as has been recently reported for APOE epsilon2 and epsilon4 alleles. A number of studies have examined the potential role in longevity of other genes involved in vascular risk, haemostasis, and blood pressure regulation [methyltetrahydrofolatereductase (MTHFR), apolipoprotein A1 (APOA-I), apolipoprotein C3 (APOC-III), apolipoprotein A4 (APOA-IV), paraoxonase 1 (PON1), plasminogen activator inhibitor type I (PAI-1)], with contrasting results. While further studies are needed to confirm the possible role of APOE concentration as putative longevity factor, this paper provides an overview of genetic vascular factors potentially involved in human longevity.

Aging↗

PubMed2004

Quantitative trait loci affecting natural variation in Drosophila longevity.

Limited life span and senescence are universal phenomena, controlled by genetic and environmental factors whose interactions both limit life span and generate variation in life span between individuals, populations and species. To understand the genetic architecture of longevity it is necessary to know what loci affect variation in life span, what are the allelic effects at these loci and what molecular polymorphisms define quantitative trait locus (QTL) alleles. Here, we used quantitative complementation tests to determine whether genes that regulate longevity also contribute to naturally occurring variation in Drosophila life span. Inbred strains derived from a natural population were crossed to stocks containing null mutations (m) or deficiencies (Df) uncovering the candidate genes, maintained over a Balancer (Bal) chromosome. We measured the life span of the resulting F(1) genotypes, +(i)/m (Df) and +(i)/Bal, where +(i) denotes one of the i natural alleles. Failure of the QTL alleles to complement the candidate gene mutation is indicated by a significant cross (mutant versus wild-type allele of the candidate gene) by inbred line interaction term from analysis of variance of life span. Failure to complement indicates a genetic interaction between the candidate gene allele and the naturally occurring life span QTL, and implicates the candidate gene as potential cause of variation in longevity. Of the 16 candidate regions and genes tested, Df(2L)c17, Df(3L)Ly, Df(3L)AC1 and Df(3R)e-BS2 showed significant failure to complement wild-type alleles in both sexes, and an Alcohol dehydrogenase mutant failed to complement in females. Several genes that regulate life span (e.g., Superoxide dismutase, Catalase, and rosy) complemented the life span effects of wild-derived alleles, suggesting little natural variation affecting longevity at these loci, at least in this sample of alleles. Quantitative complementation tests are therefore useful for identifying QTL contributing to segregating genetic variation in life span in nature.

Aging↗

PubMed2005

Longevity genes: from primitive organisms to humans.

Recent results indicate that the longevity of both invertebrates and vertebrates can be altered through genetic manipulation and pharmacological intervention. Most of these interventions involve alterations of one or more of the following: insulin/IGF-I signaling pathway, caloric intake, stress resistance and nuclear structure. How longevity regulation relates to aging per se is less clear, but longevity increases are usually accompanied by extended periods of good health. How these results will translate to primate aging and longevity remains to be shown.

Aging↗

PubMed2005

Genes involved in immune response/inflammation, IGF1/insulin pathway and response to oxidative stress play a major role in the genetics of human longevity: the lesson of centenarians.

In this paper, we review data of recent literature on the distribution in centenarians of candidate germ-line polymorphisms that likely affect the individual chance to reach the extreme limit of human life. On the basis of previous observations on the immunology, endocrinology and cellular biology of centenarians we focused on genes that regulate immune responses and inflammation (IL-6, IL-1 cluster, IL-10), genes involved in the insulin/IGF-I signalling pathway and genes that counteract oxidative stress (PON1). On the whole, data indicate that polymorphisms of these genes likely contribute to human longevity, in accord with observations emerging from a variety of animal models, and suggest that a common core of master genes and metabolic pathways are responsible for aging and longevity across animal species. Moreover, in the concern of our plan to discover new genetic factors related to longevity, we explored the possibility to by-pass the need of an a-priori choice of candidate genes, extending the search to genes and genomic regions of still unknown function. Alu sequences may be considered as good markers of highly variable and potentially unstable loci in functionally important genomic regions. We extensively screened Alu-rich genomic sites and found a new genomic region associated with longevity.

Adult↗

PubMed2005

Broad spectrum detoxification: the major longevity assurance process regulated by insulin/IGF-1 signaling?

Our recent survey of genes regulated by insulin/IGF-1 signaling (IIS) in Caenorhabditis elegans suggests a role for a number of gene classes in longevity assurance. Based on these findings, we propose a model for the biochemistry of longevity assurance and ageing, which is as follows. Ageing results from molecular damage from highly diverse endobiotic toxins. These are stochastic by-products of diverse metabolic processes, of which reactive oxygen species (ROS) are likely to be only one component. Our microarray analysis suggests a major role in longevity assurance of the phase 1, phase 2 detoxification system involving cytochrome P450 (CYP), short-chain dehydrogenase/reductase (SDR) and UDP-glucuronosyltransferase (UGT) enzymes. Unlike superoxide and hydrogen peroxide detoxification, this system is energetically costly, and requires the excretion from the cell of its products. Given such costs, its activity may be selected against, as predicted by the disposable soma theory. CYP and UGT enzymes target lipophilic molecular species; insufficient activity of this system is consistent with age-pigment (lipofuscin) accumulation during ageing. We suggest that IIS-regulated longevity assurance involves: (a) energetically costly detoxification and excretion of molecular rubbish, and (b) conservation of existing proteins via molecular chaperones. Given the emphasis in this theory on investment in cellular waste disposal, and on protein conservation, we have dubbed it the green theory.

Animals↗

PubMed2005

A genetic and genomic approach to identify longevity genes in mice.

Natural variation in rate of aging or longevity in mice and humans shows a very complex inheritance pattern. Few targeted genetic screens have identified longevity genes in mammals, partly as a result from the fact that the genetics of longevity can only be studied reliably in cohorts of mice. In this paper we propose that a combined genetic and genomic analysis of large families of fully genotyped recombinant inbred mice may provide a crucial tool to the aging research community. As a proof of principle we describe preliminary studies in which variation in gene expression patterns in hematopoietic stem cells and brain were genetically linked to longevity.

Animals↗

PubMed2004

The Sun determines human longevity: teratogenic effects of chaotic solar radiation.

An association between fertility and longevity has been known for many years, and considerable research has been focused on the mechanisms of ageing that ultimately determine longevity, which has remained essentially unchanged despite a near doubling of human life expectancy in the past 200 years. In this paper, the authors present evidence that the Sun determines the limits of longevity for the longest-living complex organisms. The Sun is a dynamical system and although solar cycles occur every 8-14 years (averaging approximately 11.1 years), the authors show that 28% of these cycles exhibit chaotic features and irregularly release up to 300% more ultraviolet radiation than usual. These chaotic solar cycles create an environment mutagenic to DNA that must be largely avoided in order to pass uncorrupted genes to the next generation. This requirement determines the limits of fertility, e.g., menarche and menopause in humans, and sets longevity to approximately 100 years.

Abnormalities, Radiation-Induced↗

PubMed2003

Duration of senescent cell survival in vitro as a characteristic of organism longevity, an additional to the proliferative potential of fibroblasts.

More than 40 years have passed since the original publication by Hayflick and Moorhead led to the concept of the 'Hayflick limit' of the maximum number of divisions which somatic cells undergo in vitro. This concept is still regarded as a fundamental characteristic of species longevity. Here we want to emphasize another characteristic of somatic cells, namely, the duration of their survival in vitro in the non-dividing state after cessation of proliferation. This is suggested on the basis of results of recent experiments with so-called Japanese accelerated senescent mice. Results of these experiments reveal a good correlation between the longevity of the mice, the number of duplications of their fibroblasts in vitro, and the survival time of these cells in the non-dividing state. In routine culture conditions, cell survival time may be very long, as much as a few years. However, when the cells are grown under conditions of oxidative stress, cellular longevity is markedly shortened. This new test may serve as an additional marker of organismic longevity. The comparative value of both tests, the classical 'Hayflick limit' and the new test, is discussed.

Animals↗

PubMed2000

DNA damage susceptibility and repair in correlation to calendric age and longevity.

In two mouse strains, SAM P (senescence acceleration prone) and SAM R (senescence acceleration resistant), of different longevities, with a ratio of P/R=1:2), the DNA status in the course of aging has been investigated using the DNA Alkaline Filter Elution (AFE) technique. Six different organs (brain, liver, heart, lung, intestine, and muscle) have been used in each of the four animals of a given age. Earlier it had been shown, that DNA is damaged the more the higher the age of the animal. DNA damage susceptibility, measured after exposure of organ pieces to nitroquinoline-N-oxide (NQO), is also significantly increased at higher ages, while repair, measured of NQO damaged tissue after 3 h incubation in full medium is significantly reduced. In the strain with shorter longevity the damage increments and the repair deficiencies are drastically deviating from those with higher longevity. These findings of strong coupling of the DNA status to aging as well as longevity suggest causative relations.

4-Nitroquinoline-1-oxide↗

PubMed1998

Disease incidence and longevity are unaltered by dietary antioxidant supplementation initiated during middle age in C57BL/6 mice.

The ability of augmented antioxidant consumption to alter disease incidence, lesion burden and/or longevity was studied in adult male C57BL/6 mice. Mice were fed modified AIN76 diet or modified AIN76 supplemented with vitamin E, glutathione (GSH), vitamin E and GSH, melatonin or strawberry extract starting at 18 months of age. All the mice in this study were heavier than reference populations of male C57BL/6 mice fed NIH-07 or NIH-31, which were maintained without a mid-life change in diet. Fatty liver, focal kidney atrophy and proteinacious casts in the renal tubules were observed more frequently in this study population than in the reference populations. Lesion burden and incidence of specific lesions observed amongst the various groups in this study did not differ. There were no differences observed for longevity of any of the study groups. The longevity observed in this study was similar to that previously reported for male C57BL/6 mice. Thus, diet supplementation with antioxidants initiated during middle age did not appear to affect age-associated lesions patterns, lesion burden or longevity for ad libitum fed male C57BL/6 mice.

Aging↗