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PubMed2002

A systematic RNAi screen identifies a critical role for mitochondria in C. elegans longevity.

We report a systematic RNA interference (RNAi) screen of 5,690 Caenorhabditis elegans genes for gene inactivations that increase lifespan. We found that genes important for mitochondrial function stand out as a principal group of genes affecting C. elegans lifespan. A classical genetic screen identified a mutation in the mitochondrial leucyl-tRNA synthetase gene (lrs-2) that impaired mitochondrial function and was associated with longer-lifespan. The long-lived worms with impaired mitochondria had lower ATP content and oxygen consumption, but differential responses to free-radical and other stresses. These data suggest that the longer lifespan of C. elegans with compromised mitochrondria cannot simply be assigned to lower free radical production and suggest a more complex coupling of metabolism and longevity.

Adenosine Triphosphate↗
PubMed2005

A stress-sensitive reporter predicts longevity in isogenic populations of Caenorhabditis elegans.

When both genotype and environment are held constant, 'chance' variation in the lifespan of individuals in a population is still quite large. Using isogenic populations of the nematode Caenorhabditis elegans, we show that, on the first day of adult life, chance variation in the level of induction of a green fluorescent protein (GFP) reporter coupled to a promoter from the gene hsp-16.2 predicts as much as a fourfold variation in subsequent survival. The same reporter is also a predictor of ability to withstand a subsequent lethal thermal stress. The level of induction of GFP is not heritable, and GFP expression levels in other reporter constructs are not associated with differences in longevity. HSP-16.2 itself is probably not responsible for the observed differences in survival but instead probably reflects a hidden, heterogeneous, but now quantifiable, physiological state that dictates the ability of an organism to deal with the rigors of living.

Animals↗
PubMed2005

Identification of direct DAF-16 targets controlling longevity, metabolism and diapause by chromatin immunoprecipitation.

DAF-16, a forkhead transcription factor, is a key regulator of longevity, metabolism and dauer diapause in Caenorhabditis elegans. The precise mechanism by which DAF-16 regulates multiple functions, however, is poorly understood. Here, we used chromatin immunoprecipitation (ChIP) to identify direct targets of DAF-16. We cloned 103 target sequences containing consensus DAF-16 binding sites and selected 33 targets for further analysis. Expression of most of these genes is regulated in a DAF-16-dependent manner, and inactivation of more than half of these genes significantly altered DAF-16-dependent functions, including life span, fat storage and dauer formation. Our results show that the ChIP-based cloning strategy leads to greater enrichment for DAF-16 target genes than previous screening strategies. We also demonstrate that DAF-16 is recruited to multiple promoters to coordinate regulation of its downstream targets. The large number of target genes discovered provides insight into how DAF-16 controls diverse biological functions.

Alleles↗
PubMed2006

The quest for genetic determinants of human longevity: challenges and insights.

Twin studies show that genetic differences account for about a quarter of the variance in adult human lifespan. Common polymorphisms that have a modest effect on lifespan have been identified in one gene, APOE, providing hope that other genetic determinants can be uncovered. However, although variants with substantial beneficial effects have been proposed to exist and several candidates have been put forward, their effects have yet to be confirmed. Human studies of longevity face numerous theoretical and logistical challenges, as the determinants of lifespan are extraordinarily complex. However, large-scale linkage studies of long-lived families, longitudinal candidate-gene association studies and the development of analytical methods provide the potential for future progress.

Alleles↗
PubMed2005

Calorie restriction, SIRT1 and metabolism: understanding longevity.

Calorie restriction (CR) is the only experimental manipulation that is known to extend the lifespan of a number of organisms including yeast, worms, flies, rodents and perhaps non-human primates. In addition, CR has been shown to reduce the incidence of age-related disorders (for example, diabetes, cancer and cardiovascular disorders) in mammals. The mechanisms through which this occurs have been unclear. CR induces metabolic changes, improves insulin sensitivity and alters neuroendocrine function in animals. In this review, we summarize recent findings that are beginning to clarify the mechanisms by which CR results in longevity and robust health, which might open new avenues of therapy for diseases of ageing.

Animals↗
PubMed2002

Genetic polymorphisms of Fas (CD95) and FasL (CD178) in human longevity: studies on centenarians.

Apoptosis plays a crucial role in immunosenescence, as also evidenced by the increased expression of Fas in lymphocytes from aged people. However, little is known about the genetic regulation of Fas and its ligand, FasL. We have studied their polymorphisms in 50 centenarians and 86 young donors living in Northern Italy. The first Fas polymorphism, at position -670, has in Caucasian a heterozigosity of 51%; the second, at -1377 position, has the wild type allele (G) with a very high frequency (83%) respect to the mutant allele. Genotype and allele distribution for both polymorphisms were similar in controls and centenarians. Similar results were found as far as two FasL polymorphisms (IVS2nt-124 and IVS3nt169) are concerned. On the whole, our data suggest that Fas and FasL polymorphisms, as well as their haplotypes, are unlikely to be associated with successful human longevity.

Adult↗
PubMed2004

Longevity-associated mitochondrial DNA 5178 A/C polymorphism and blood pressure in the Japanese population.

It has been reported that the mitochondrial DNA 5178 adenine/cytosine (mt5178 A/C) polymorphism, also called NADH dehydrogenase subunit 2-237 methionine/leucine (ND2-237 Met/Leu) polymorphism, may be associated with longevity in Japanese individuals, and that the mt5178A genotype may have an antiatherogenic influence. To determine whether mt5178 A/C polymorphism influences blood pressure, we genotyped 412 healthy Japanese individuals and performed a cross-sectional study investigating the relationship between genotype and blood pressure. In women with mt5178A, the mean diastolic blood pressure was higher than in those with mt5178C by 3.2 mmHg (P=0.040). In men, no statistically significant difference in systolic or diastolic blood pressure was observed between mt5178 A/C genotypes. However, a significant correlation between mt5178 A/C genotypes and the effects of habitual drinking on blood pressure was found. After adjustment for several factors, in men carrying mt5178C, both systolic and diastolic blood pressure were significantly higher in daily drinkers than in occasional (P=0.002 and 0.002, respectively) as well as nondrinkers (P<0.001 and 0.001, respectively), whereas in men carrying mt5178A, no significant differences in blood pressure were detected, irrespective of alcohol consumption. These results suggest that mt5178 A/C (=ND2-237 Met/Leu) polymorphism may influence both diastolic blood pressure in Japanese women and the blood-pressure-increasing effect of drinking in Japanese men.

Alcohol Drinking↗
PubMed2006

Role of 2-5A-dependent RNase-L in senescence and longevity.

Senescence is a permanent growth arrest that restricts the lifespan of primary cells in culture, and represents an in vitro model for aging. Senescence functions as a tumor suppressor mechanism that can be induced independent of replicative crisis by diverse stress stimuli. RNase-L mediates antiproliferative activities and functions as a tumor suppressor in prostate cancer, therefore, we examined a role for RNase-L in cellular senescence and aging. Ectopic expression of RNase-L induced a senescent morphology, a decrease in DNA synthesis, an increase in senescence-associated beta-galactosidase activity, and accelerated replicative senescence. In contrast, senescence was retarded in RNase-L-null fibroblasts compared with wild-type fibroblasts. Activation of endogenous RNase-L by 2-5A transfection induced distinct senescent and apoptotic responses in parental and Simian virus 40-transformed WI38 fibroblasts, respectively, demonstrating cell type specific differences in the antiproliferative response to RNase-L activation. Replicative senescence is a model for in vivo aging; therefore, genetic disruption of senescence effectors may impact lifespan. RNase-L-/- mice survived 31.7% (P<0.0001) longer than strain-matched RNase-L+/+ mice providing evidence for a physiological role for RNase-L in aging. These findings identify a novel role for RNase-L in senescence that may contribute to its tumor suppressive function and to the enhanced longevity of RNase-L-/- mice.

Aging↗
PubMed1999

Bad genes, good people, association, linkage, longevity and the prevention of cardiovascular disease.

1. Cardiovascular disease, the most common cause of death, is the product of risk factors such as hypertension, lipid disturbances, diabetes mellitus, left ventricular hypertrophy and nicotine smoking, all of which are influenced by genetic variance. Thus, genes that influence these factors have a considerable bearing on longevity. 2. Although mortality rates increase exponentially with increasing age, an interesting tendency towards a plateau occurs, suggesting that old individuals are somewhat protected from the propensity to die. This phenomenon is difficult to explain. 3. One possibility is a model of repair, in which certain alleles exert a beneficial influence at an advanced age. 4. An alternative explanation might be a mutation that exerts both negative and positive effects. 5. The insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme (ACE) gene exerts was observed to have an effect on heart size. The D allele was linked to a greater heart size, compared with the I allele in a modified sibpair model. This potentially deleterious effect was counter-balanced by linkage of the D allele to increased heart rate variability, which is potentially a beneficial attribute. Furthermore, in a cohort of the German population over age 80 years, it was observed that the D allele occurred at a frequency higher than would be expected. 6. The present study discusses the hypothesis that the ACE gene I/D polymorphism may be a genetic variant with both negative and positive effects.

Adult↗
PubMed2002

Sleep health and lifestyle of elderly people in Ogimi, a village of longevity.

The study was conducted in the Prefecture of Longevity, Okinawa, on the elderly living in the village of Ogimi. It was revealed that those in the good sleep health group took short naps, a significantly fewer number fell into dozes, and a significantly greater number exercised regularly or walked. A significantly greater number of this group maintained regular eating habits over a 10-year span, and consumed more seaweed and fish. Participation in senior citizens' clubs was higher, reflecting high emotional adaptability. The study's results indicates a relationship between lifestyle and sleep health among the elderly, and suggest that deterioration of sleep health is related to physical and mental health.

Aged↗
PubMed2003

Evolution of male longevity bias in nematodes.

Many animal species exhibit sex differences in aging. In the nematode Caenorhabditis elegans, under conditions that minimize mortality, males are the longer-lived sex. In a survey of 12 independent C. elegans isolates, we find that this is a species-typical character. To test the hypothesis that the C. elegans male longevity bias evolved as a consequence of androdioecy (having males and hermaphrodites), we compared sex-specific survival in four androdioecious and four dioecious (males and females) nematode species. Contrary to expectation, in all but C. briggsae (androdioecious), males were the longer-lived sex, and this difference was greatest among dioecious species. Moreover, male lifespan was reduced in androdioecious species relative to dioecious species. The evolutionary theory of aging predicts the evolution of a shorter lifespan in the sex with the greater rate of extrinsic mortality. We demonstrate that in each of eight species early adult mortality is elevated in females/hermaphrodites in the absence of food as the consequence of internal hatching of larvae (matricide). This age-independent mortality risk can favour the evolution of rapid aging in females and hermaphrodites relative to males.

Animals↗
PubMed2003

Androgens shorten the longevity of women: sopranos last longer.

Earlier we found that longevity of castrati was identical to that of intact singers. These findings were in disagreement with the prevailing concept that testosterone might shorten life and might be responsible for the shorter life expectancy of men compared to women. We have now continued our research into the life expectancy of singers, considering them as a paradigm of nature to investigate life-long effects of sex hormones, and resulting in the finding that sopranos, being more oestrogenised, live significantly longer than altos who are more androgenised, while basses, more androgenised, show a tendency towards a longer life than tenors, who are less androgenised. These findings, supported by results of epidemiological investigations indicate that women are protected from cardiovascular diseases, diabetes and osteoporosis by higher oestrogen levels, while the same effect maybe exerted in men by testosterone.

Aged↗
PubMed1995

Longevity and Medicare expenditures.

BACKGROUND: In the United States, the elderly account for over one third of health care spending. The total population over the age of 65 is projected to increase, as is life expectancy beyond the age of 65. We studied current patterns of Medicare expenses according to age at death and the possible effect of future demographic changes on Medicare spending. METHODS: We used data from the Medicare program to estimate lifetime Medicare expenses for a sample of 129,166 beneficiaries, 65 or older, who died in 1989 and 1990, according to age at death. Spending for nursing home care not covered by Medicare was excluded. (Nursing home costs represent about 20 percent of total health care spending for the elderly and increase with age.) Through simulation, we assessed the lifetime payments by Medicare for enrollees who turned 65 in 1990 and those who will do so in 2020. RESULTS: Estimated lifetime Medicare payments (in 1990 dollars) ranged from $13,044 for persons who died at 65 years of age, to $56,094 for those who died at 80, to $65,633 for those who died at 101 or older. The payments associated with an additional year of life and the average annual payments over an enrolle's lifetime both decreased as the age at death increased. The estimated 7.9 percent increase in life expectancy beyond 65 years that will have taken place between 1990 and 2020 (19.1 years past the age of 65 in 2020, as compared with 17.7 years in 1990) was associated with an estimated increase of 2.0 percent in lifetime Medicare payments. Of the estimated $98 billion increase in total lifetime payments (in 1990 dollars) from the 1990 group to the 2020 group, 74.3 percent was due to the larger size of the original birth cohort who will reach the age of 65 in 2020, 22.5 percent to an increase in the proportion of that birth cohort projected to survive to 65 years of age, and 3.2 percent to improved life expectancy beyond 65. CONCLUSIONS: The effect on Medicare spending of increased longevity beyond the age of 65 may not be great. Total Medicare payments will be more substantially affected by the expected increase in the absolute number of elderly people.

Aged↗
PubMed2005

Infection, inflammation, height, and longevity.

Using historical data from cohorts born before the 20th century in four northern European countries, we show that increasing longevity and declining mortality in the elderly occurred among the same birth cohorts that experienced a reduction in mortality at younger ages. Concurrently, these cohorts also experienced increasing adult height. We hypothesize that both the decline in old-age mortality and the increase in height were promoted by the reduced burden of infections and inflammation. Thus, early growth and cardiovascular diseases of old age may share infectious and inflammatory causes rooted in the external environment.

Adolescent↗
PubMed2002

The emergence of humans: the coevolution of intelligence and longevity with intergenerational transfers.

Two striking differences between humans and our closest living relatives, chimpanzees and gorillas, are the size of our brains (larger by a factor of three or four) and our life span (longer by a factor of about two). Our thesis is that these two distinctive features of humans are products of coevolutionary selection. The large human brain is an investment with initial costs and later rewards, which coevolved with increased energy allocations to survival. Not only does this theory help explain life history variation among primates and its extreme evolution in humans; it also provides new insight into the evolution of longevity in other biological systems. We introduce and apply a general formal demographic model for constrained growth and evolutionary tradeoffs in the presence of life-cycle transfers between age groups in a population.

Animals↗
PubMed1985

Peroxide-producing potential of tissues: inverse correlation with longevity of mammalian species.

Peroxidation reactions may cause many of the dysfunctions associated with aging. Accordingly, the 30-fold differences in aging rate among the mammalian species could be determined in part by peroxidation defense processes. This possibility was tested by measuring the spontaneous autoxidation of aerobically incubated brain and kidney tissue homogenates of 24 different mammalian species as a function of their maximum lifespan potential. Results show a statistically significant inverse correlation between both the rate of autoxidation and the amount of peroxidizable substrate with maximum lifespan potential. Kinetic analysis of the data indicates that the amount of peroxidizable substrate was the major factor determining the rate of autoxidation. For human tissues, antioxidants also appear to contribute to their unusually low sensitivity to peroxidation. These results support the hypothesis that aging may be caused in part by oxygen radicals initiating peroxidation reactions and that peroxidation defense processes are involved in governing the longevity of mammalian species.

Animals↗
PubMed1994

Protein synthesis elongation factor EF-1 alpha expression and longevity in Drosophila melanogaster.

It has been proposed that the decline in protein synthesis observed in aging organisms may result from a decrease in elongation factor EF-1 alpha. Transgenic Drosophila melanogaster flies carrying an additional copy of the EF-1 alpha gene under control of a heat-inducible promoter have an extended lifespan, further indicating that the EF-1 alpha gene may play an important role in determining longevity. To test this hypothesis, we have quantitated EF-1 alpha mRNA, EF-1 alpha protein, and the EF-1 alpha complex-formation activity in these transgenic flies. Furthermore, we have tested whether the transgene construct is functional--i.e., whether transgenic mRNA is induced when flies are grown at higher temperature. The results show that although there is a clear difference in mean lifespan between the EF-1 alpha transgenic (E) flies and the control transgenic (C) flies, E flies do not express more EF-1 alpha protein or mRNA than C flies kept at the same experimental conditions. Although the transgene can be induced when E flies are heat-shocked at 37 degrees C, transgenic mRNA is not detectable in E flies aged at 29 degrees C. In both lines, the loss in catalytic activity with age is the same. We conclude that the E flies examined here do not live longer because of overexpressing the EF-1 alpha gene.

Animals↗
PubMed1997

Mitochondrial ubiquinone homologues, superoxide radical generation, and longevity in different mammalian species.

Rates of mitochondrial superoxide anion radical (O-2) generation are known to be inversely correlated with the maximum life span potential of different mammalian species. The objective of this study was to understand the possible mechanism(s) underlying such variations in the rate of O-2 generation. The hypothesis that the relative amounts of the ubiquinones or coenzyme Q (CoQ) homologues, CoQ9 and CoQ10, are related with the rate of O-2 generation was tested. A comparison of nine different mammalian species, namely mouse, rat, guinea pig, rabbit, pig, goat, sheep, cow, and horse, which vary from 3.5 to 46 years in their maximum longevity, indicated that the rate of O-2 generation in cardiac submitochondrial particles (SMPs) was directly related to the relative amount of CoQ9 and inversely related to the amount of CoQ10, extractable from their cardiac mitochondria. To directly test the relationship between CoQ homologues and the rate of O-2 generation, rat heart SMPs, naturally containing mainly CoQ9 and cow heart SMPs, with high natural CoQ10 content, were chosen for depletion/reconstitution experiments. Repeated extractions of rat heart SMPs with pentane exponentially depleted both CoQ homologues while the corresponding rates of O-2 generation and oxygen consumption were lowered linearly. Reconstitution of both rat and cow heart SMPs with different amounts of CoQ9 or CoQ10 caused an initial increase in the rates of O-2 generation, followed by a plateau at high concentrations. Within the physiological range of CoQ concentrations, there were no differences in the rates of O-2 generation between SMPs reconstituted with CoQ9 or CoQ10. Only at concentrations that were considerably higher than the physiological level, the SMPs reconstituted with CoQ9 exhibited higher rates of O-2 generation than those obtained with CoQ10. These in vitro findings do not support the hypothesis that differences in the distribution of CoQ homologues are responsible for the variations in the rates of mitochondrial O-2 generation in different mammalian species.

Animals↗