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PubMed2003

Reproduction and longevity among the British peerage: the effect of frailty and health selection.

Whether a cost of reproduction exists among humans is still questionable. A major study of aristocratic British families finds a significant positive correlation between parity and late-life mortality, which indicates a trade-off between reproduction and longevity. This result is supported by four other studies, while earlier studies have not found a relationship or came to the opposite conclusion. We show that in natural fertility populations the relationship between fertility and late-life mortality cannot be studied correctly without considering the effects of differences in health and of mortality selection during childbearing ages because these two effects lead to a dampening of the true relationship. If these effects are controlled in Hollingsworth's genealogy of the British peerage a significant trade-off between reproduction and longevity exists for females but not for males.

Aged↗
PubMed2002

Cloning approaches for identifying aging and longevity-related genes in mammals.

Aging is a phenomenon that affects nearly all animal species. Several studies using different systems have identified a number of processes thought to contribute to the aging phenotype. Many differentially expressed genes have been implicated, but the mechanisms governing mammalian aging (and longevity) are not yet fully understood, and the list of concerned genes is still incomplete and fragmented. Different approaches have been used to clone aging and longevity-related genes. In this article we review these cloning techniques and discuss their advantages and limitations. Further research on the function of these genes as well as the network of their protein products will give better insight into the aging process as a whole and its associated pathologies.

Aging↗
PubMed2006

Apolipoprotein E genotype is related to plasma levels of C-reactive protein and lipids and to longevity in nonagenarians.

OBJECTIVE: Apolipoprotein E (APOE) genotype is a regulator of hepatic lipoprotein metabolisms and has been linked with longevity. The relationship between APOE genotype and plasma C-reactive protein (CRP), which is produced by the liver during inflammation, has not been studied in nonagenarians. The aim of the present study was to establish whether APOE genotype is related to plasma concentrations of CRP and lipids, or longevity among nonagenarians. DESIGN AND PATIENTS: This cross-sectional study consisted of 291 Finnish nonagenarians and three previously described and genotyped control populations from the same area (i.e. newborns, 40-year-olds, and 70-year-olds). RESULTS: In all nonagenarians and especially in women (P= 0.038), CRP level decreased linearly in the genotype order of epsilon2/2, epsilon2/3, epsilon3/3, epsilon2/4, epsilon3/4 and epsilon4/4. Total (P= 0.009) and low-density lipoprotein (LDL) cholesterol (P = 0.076) levels, in turn, were increased in the epsilon4 allele carriers. In newborns, the epsilon4 frequency was 0.192, in 40-year-olds 0.181, in 70-year-olds 0.179 and in nonagenarians 0.095 (P < 0.0001). The decrease in the epsilon4 allele frequency in the elderly was more clearly seen in women than in men. CONCLUSIONS: APOEepsilon4 allele seems to be associated with decreased inflammatory response as measured by CRP among nonagenarians. This finding may partly explain why some epsilon4 allele carriers can reach very old age despite increased risk of hypercholesterolaemia.

Aged, 80 and over↗
PubMed2006

MHC class I variation associates with parasite resistance and longevity in tropical pythons.

Using restriction fragment length polymorphism (RFLP) we identified 26 unique major histocompatibility complex (MHC) genotypes in 104 water pythons. We observed a significant independent association between reduced blood parasite load (Hepatozoon sp.) and python body length/age, presence of a specific RFLP fragment (C-fragment) and the overall number of fragments. The parasite has a negative impact on several python life-history traits such as growth, nutritional status and longevity. Thus, the C-fragment could be considered a 'good gene' (a fitness-enhancing genetic element). However, while the number of fragments affected parasite load, the association between level of parasitaemia and fragment number was not linear, and, hence, minimum parasite infection level was achieved at an intermediate number of fragments. Intermediate MHC fragment numbers were also observed among the largest/oldest pythons, suggesting that both a specific fragment and intermediate levels of MHC polymorphism enhanced python longevity. Thus, our results suggest python MHC is subject to both frequency-dependent and balancing selection.

Animals↗
PubMed2006

Genetic and environmental correlations between longevity and litter size in rabbits.

An estimation of the genetic and environmental correlations between prolificacy (kits born alive and number of kits at weaning) and functional longevity in a population selected for litter size at weaning since 1992 was carried out. The method is only an approximation, but suggests that genetically longevity and litter size are not antagonistic objectives in breeding programmes, because the estimated genetic correlations are not significantly different from zero.

Animals↗
PubMed2006

Impact of dominance effects on sow longevity.

The purpose of the current study was to estimate variance components, especially dominance genetic variation, for overall leg action, length of productive life and sow stayability until third and fifth parity in the Finnish pig populations. The variance components were estimated in two purebred [Landrace (LR), n = 23 602 and Large White (LW), n =22 984] and crossbred (LR x LW, n = 17 440) data sets. Five different analyses were carried out for all the traits to compare the effect of sows' inbreeding, common litter environment and parental dominance in the statistical model when determining the genetic correlations of the traits for the two purebred and crossbred populations. Estimated heritabilities for the traits ranged from 0.04 to 0.06. The estimates for the proportion of dominance variance of phenotypic variance (d(2)) varied between 0.01 and 0.17, and was highest in the crossbred dataset. The genetic correlations of the same traits in purebred and crossbred were all high (>0.75). Based on current results, the effect of dominance should be accounted for in the breeding value estimation of sow longevity, especially when data from crossbred animals are included in the analyses. Because dominance genetic variation for sow longevity exists that variation should be utilized through planned matings in producing sows for commercial production.

Animals↗
PubMed2004

Longevity-associated mitochondrial DNA 5178 A/C polymorphism is associated with intraocular pressure in Japanese men.

BACKGROUND: Mitochondrial DNA 5178 adenine/cytosine (mt5178 A/C) polymorphism has been reported to be associated with longevity in Japanese individuals, with experimental findings concluding that mt5178 A is an anti-atherogenic genotype. The aim of this study was to determine whether mt5178 A/C polymorphism influences intraocular pressure (IOP), and its relationship with the development of arteriosclerosis. METHODS: Four hundred and forty-nine male volunteers who had visited a general hospital for medical check-up between August 1999 and August 2000 were enrolled. Of these, 386 Japanese men who had not undergone any medical treatment for hypertension, ocular hypertension or glaucoma were selected as subjects of this study. After these subjects were genotyped, a cross-sectional study regarding the relationship between genotype and IOP was conducted. RESULTS: Mean IOP was significantly higher in men with mt5178 C (13.3 mmHg) than in those with mt5178 A (12.7 mmHg) (P = 0.037). This significant difference in mean IOP between the two genotypes remained evident after adjusting for age, body mass index, blood pressure, habitual smoking and habitual drinking. Interactions between mt5178 A/C polymorphism and habitual smoking or daily alcohol consumption with regard to IOP were observed. According to multiple regression analysis, habitual smoking was significantly associated with IOP in men with mt5178 A (P for trend = 0.020), while daily alcohol consumption was significantly associated with IOP in those with mt5178 C (P for trend = 0.021). CONCLUSION: Longevity-associated mitochondrial DNA 5178 A/C polymorphism may be associated with IOP in Japanese men.

Blood Pressure↗
PubMed2005

17beta-oestradiol up-regulates longevity-related, antioxidant enzyme expression via the ERK1 and ERK2[MAPK]/NFkappaB cascade.

Females live longer than males. Oestrogens protect females against aging by up-regulating the expression of antioxidant, longevity-related genes such as glutathione peroxidase (GPx) and Mn-superoxide dismutase (Mn-SOD). The mechanism through which oestrogens up-regulate those enzymes remains unidentified, but may have implications for gender differences in lifespan. We show that physiological concentrations of oestradiol act through oestrogen receptors to reduce peroxide levels in MCF-7 cells (a mammary gland tumour cell line). Oestradiol increases MAP kinase (MAPK) activation as indicated by ERK1 and ERK2 phosphorylation in MCF-7 cells, which in turn activates the nuclear factor kappa B (NFkappaB) signalling pathways as indicated by an increase in the p50 subunit of NFkappaB in nuclear extracts. Blockade of MAPK and NFkappaB signalling reduces the antioxidant effect of oestradiol. Finally, we show that activation of MAPK and NFkappaB by oestrogens drives the expression of the antioxidant enzymes Mn-SOD and GPx. We conclude that oestradiol sequentially activates MAPK and NFkappaB following receptor activation to up-regulate the expression of antioxidant enzymes, providing a cogent explanation for the antioxidant properties of oestrogen and its effects on longevity-related genes.

Analysis of Variance↗
PubMed2006

Trade-offs between longevity and pathogen resistance in Drosophila melanogaster are mediated by NFkappaB signaling.

The innate immune response protects numerous organisms, including humans, from the universe of pathogenic molecules, viruses and micro-organisms. Despite its role in promoting pathogen resistance, inappropriate activation and expression of NFkappaB and other immunity-related effector molecules can lead to cancer, inflammation, and other diseases of aging. Understanding the mechanisms leading to immune system activation as well as the short- and long-term consequences of such activation on health and lifespan is therefore critical for the development of beneficial immuno-modulating and longevity-promoting interventions. Mechanisms of innate immunity are highly conserved across species, and we take advantage of genetic tools in the model organism, Drosophila melanogaster, to study the effects of acute and chronic activation of immunity pathways on pathogen resistance and general fitness of adult flies. Our findings indicate that fat body specific overexpression of a putative pathogen recognition molecule, peptidoglycan recognition protein (PGRP-LE), is sufficient for constitutive up-regulation of the immune response and for enhanced pathogen resistance. Primary components of fitness are unaffected by acute activation, but chronic activation leads to an inflammatory state and reduced lifespan. These phenotypes are dependent on the NFkappaB-related transcriptional factor, Relish, and they establish a mechanistic basis for a link between immunity, inflammation, and longevity.

Animals↗
PubMed2005

Reduced insulin/IGF-1 signalling and human longevity.

Evidence is accumulating that aging is hormonally regulated by an evolutionarily conserved insulin/IGF-1 signalling (IIS) pathway. Mutations in IIS components affect lifespan in Caenorhabditis elegans, Drosophila melanogaster and mice. Most long-lived IIS mutants also show increased resistance to oxidative stress. In D. melanogaster and mice, the long-lived phenotype of several IIS mutants is restricted to females. Here, we analysed the relationship between IIS signalling, body height and longevity in humans in a prospective follow-up study. Based on the expected effects (increased or decreased signalling) of the selected variants in IIS pathway components (GHRHR, GH1, IGF1, INS, IRS1), we calculated composite IIS scores to estimate IIS pathway activity. In addition, we analysed the relative impact on lifespan and body size of the separate variants in multivariate models. In women, lower IIS scores are significantly associated with lower body height and improved old age survival. Multivariate analyses showed that these results were most pronounced for the GH1 SNP, IGF1 CA repeat and IRS1 SNP. In females, for variant allele carriers of the GH1 SNP, body height was 2 cm lower (P = 0.007) and mortality 0.80-fold reduced (P = 0.019) when compared with wild-type allele carriers. Thus, in females, genetic variation causing reduced IIS activation is beneficial for old age survival. This effect was stronger for the GH1 SNP than for variation in the conserved IIS genes that were found to affect longevity in model organisms.

Aged↗
PubMed1975

The longevity of gerontologists.

The forces of mortality are the prime determinants of longevity. Longevity is a basic consideration of gerontology and includes the life expectancy of the species, the average expectancy of survival at birth, and the average of lifespan. In the history of the study of old age, for which the modern period began about 1930, there are no reports of the average lifespan for the students of aging. A survey revealed that the average lifespan of 28 special groups (15,000 individuals) was 68 years; this included an average of 68.01 years for 394 gerontologists during the same eras. These figures are comparable because the attainment of a particular status in a profession or vocation is evidence of survival to maturity. Comparison could not be made with data for the general population whose vital statistics begin at birth. The average duration of life for men whose work in part or in whole prior to the 20th century was in gerontology falls midway between the high level of 77 years for classical Greek authors and the low level of 51 years for revolutionary statesmen, and exactly between the levels of life duration for eunuchs and physical and medical scientists.

Aged↗
PubMed1994

Is the phenotypic combination A1B8Cw7DR3 a marker for male longevity?

OBJECTIVE: To study whether individual Human Leucocyte Antigens (HLA) at the HLA 1 or 11 loci or the phenotypic combination A1B8Cw7DR3 were associated with longevity. DESIGN: Direct comparison of the > 90-year-old subjects with a control group. SETTING: Northern Ireland population with little migratory mobility. SUBJECTS: The > 90-year-old group (79 females, 38 males) was compared with a control group consisting of 150 unrelated blood donors (81 females, 69 males). MEASUREMENTS: Human Leucocyte Antigen (HLA) Class 1 typing was carried out on 117 nonagenarians (mean age 93.7 years) and 150 younger controls (mean age 33.7 years) using conventional serological methods; HLA DR typing was carried out on 102 of the 117 > 90-year-old subjects, together with the 150 control subjects, and performed using restriction fragment length polymorphisms. The frequency of the phenotypic combination A1B8Cw7DR3 was measured in both groups. RESULTS: There were no significant differences in the HLA antigen frequencies between the very elderly groups and the younger subjects at the A, B, C, and DR loci. The phenotypic combination A1B8Cw7DR3 was significantly increased (X3) in nonagenarian men compared with young men but not between elderly women and young women. There was a trend for increased representation of this phenotype in elderly men compared with women of the same age. CONCLUSIONS: The frequency of the supratype A1B8Cw7DR3 was significantly increased in very elderly men but not in elderly women. Since this phenotypic combination has been associated with immune surveillance and/or hyperactivity in Caucasians, there is the suggestion that it could influence longevity through immune mechanisms but that sex differences may exist in its influence and expression.

Aged↗
PubMed2006

Quantitation of sleep and spinal curvature in an unusually longevous owl monkey (Aotus azarae).

BACKGROUND: A table summarizing the primary literature on 19 species of longevous non-human primates, other than owl monkey, is presented. METHODS: We prospectively quantitated the sleep of a longevous female owl monkey (Aotus azarae), aged >30 years, longitudinally for 2 years and also evaluated the senility-induced change in spinal curvature. RESULTS: The mean daily total sleep time (TST) of this monkey ranged between 790 and 1106 minutes, and was markedly higher in comparison with its female progeny (aged 16 years and used as a control) whose daily TST during the same experimental period ranged between 612 and 822 minutes. CONCLUSIONS: The calculated kyphotic index (KI) of 2.27 for this monkey, compared with the KIs 4.83 and 5.42, for its progeny and female grandprogeny (aged 1 year) respectively, confirmed the prominent spinal curvature.

Aging↗
PubMed1991

Longevity and heredity in humans. Association with the human leucocyte antigen phenotype.

Several arguments support the idea of a link between longevity and heredity, both in experimental animals and in the human species. In mice, genes in the major histocompatibility complex (MHC) are associated with a significant effect on life span. Results of analogous studies in man are confusing and contradictory. We have therefore investigated the question of an association of the human leucocyte antigen (HLA) and longevity in a large and ethnically homogeneous population. Our study population consisted of all 964 available inhabitants aged 85 years and over in the Dutch community of Leiden (pop. 104,000). Our control group comprised 2444 young inhabitants, aged 20-35 years, with an identical ethnic and demographic background. In addition, control groups of different age-brackets from the same region were used. Two antigens differed in frequency: HLA-B40 was lower and HLA-DR5 was higher in the group of 85 years and over, as compared to the control group, aged 20-35 years. Both differences were more evident in females. No major disease associations with HLA-B40 or HLA-DR5 have been reported. It is unlikely that these results are a chance observation: the overall similarity of the HLA pattern of the old and young age groups is a confirmation of their identical ethnic and demographic background and the changes as observed in the different age-groups were gradual. The biological meaning of these results is still unclear.

Adult↗
PubMed2000

Genetics of human aging. The search for genes contributing to human longevity and diseases of the old.

An aging population of humans reflects early-onset morbidity and mortality as well as late-onset disease in the phase when the mortality rate doubles and, finally, longevity of extremely long-lived subjects. Genetic influences have been reported to be relevant for each of these three phases. A growing field in genetic research is aimed at the identification of genes involved in multifactorial diseases of the old and in longevity. Important issues in these studies include the definition of phenotype, which maximally highlights the genetic contribution, whether earlier and later onset phenotypes have loci in common, and how to rank or reject the many candidate disease loci found in different studies. These issues will be illustrated from research on cardiovascular disease and osteoarthritis.

Age of Onset↗
PubMed2000

Aging and longevity. A paradigm of complementation between homeostatic mechanisms and genetic control?

Aging is a universal and inevitable phenomenon that affects nearly all animal species. It can be considered the product of an interaction between genetic, environmental, and lifestyle factors, which in turn influence longevity that varies between and within species. It has been proposed not only that the aging process is under genetic control, but that it can also be considered a result of the failure of homeostasis due to the accumulation of damage. This review article discusses these issues, focusing on the function of genes that associate with aging and longevity, as well as on the molecular mechanisms that control cell survival and maintenance during aging.

Aging↗
PubMed2001

Gene expression and regulation in the extended longevity phenotypes of Drosophila.

We used both selection and single-gene mutagenesis studies to identify the mechanisms underlying the genetic control of longevity in Drosophila. The expression of the extended longevity phenotype (ELP) in our forward-selected strains depends on an early and specific upregulation of the antioxidant defense system (ADS) genes and enzymes, which results in decreased oxidative damage levels and a delayed onset of senescence. This mechanism does not alter metabolic rate and is itself reversed by a reverse selection regime. Single-gene mutational analysis of the regulatory genes controlling ADS gene expression show they are under the positive and negative control of several such genes, each of which can bring about the expression/repression of the ELP. Sister strains with identical ELPs have different patterns of ADS gene expression, showing that phenotypic equivalence does not require molecular equivalence. The organism may have multiple genetic strategies to cope with similar levels of oxidative stress.

Animals↗
PubMed2002

Genetic and environmental influences on exceptional longevity and the AGE nomogram.

To live beyond the octogenarian years, population and molecular genetic studies of centenarian sibships indicate that genetic factors play an increasingly important role as the limit of life span is approached. These factors are likely to influence basic mechanisms of aging that in turn broadly influence susceptibility to age-related illnesses. Lacking genetic variations that predispose to disease as well as having variations that confer disease resistance (longevity enabling genes) are probably both important to achieving exceptional old age. The AGE (aging, genetics, environment) nomogram is introduced as an illustrative construct for understanding the influence of environmental and genetic factors on survival to various ages, depending on variations in the hypothesized relative importance of genes and environment to longevity. The rapid rise in the incidence of centenarians could indicate that many more people than we originally thought have the optimal set of genetic factors necessary to get to 100 and beyond. Recent studies indicate the likelihood that such factors will be elucidated in the near future.

Aged↗