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PubMed1976

Effect of family size and mother's longevity.

A prospective study of the mother's longevity and of her completed family size has been conducted on the basis of historical demographic records. We show that 1 to 5 pregnancies is associated with the greatest longevity in weakly inbred women and 11 pregnancies is associated with greatest longevity in more inbred women. Taking into account maternal inbreeding, completely sterile women and those who had a large number of pregnancies have an equal mean longevity. It is suggested that repeated pregnancies produce a cumulative hormonal effect, the distribution of which, following family size, should be bell-shaped.

Consanguinity↗
PubMedDate not supplied

Genealogical data and the biodemography of human longevity.

Biodemography of human longevity is an emerging interdisciplinary field of sociobiological research with deep historical roots. Two research questions are examined in this article: (1) What evidence is there for the familial transmission of human longevity?, and (2) what are the effects of parental age at reproduction on offspring longevity, and in particular, are there long-term adverse health consequences associated with the trend toward delayed reproduction? The ability of scientists to conduct biodemographic studies depends not only on merging theoretical and methodological elements from the biological and demographic/actuarial sciences, but unique sources of data and statistical methods must also be developed. In this article we describe how gencalogical data have been used for over a century to explore basic questions about human longevity, and how similar kinds of data now being developed are driving the formation of new testable research hypotheses in the field of biodemography.

Demography↗
PubMed1984

Traits that influence longevity in mice.

Analysis of genetic interactions in the segregating backcross [(C57BL/6 X DBA/2)F1 X DBA/2] mice revealed influences of genetic and environmental factors on life span. Using determinants of coat color (brown locus of chromosome 4 and dilute locus of chromosome 9), serologically determined H-2 antigens (chromosome 17) and sex as genetic markers, we studied the effects of these genes on longevity. The results suggested that genes in the brown locus (b) segment of chromosome 4, genes in a segment of the sex chromosomes and, to a more limited extent, genes in the segment of chromosome 17 which contains the H-2 haplotype all influenced longevity. The coat color (b locus) segment of chromosome 4 was associated with life span predominantly in females, whereas the chromosome 17 (H-2 haplotype) segment was associated with longer life primarily in males. The dilute locus d segment on chromosome 9 did not affect life span. Longevity appears to be influenced by interactions between genes in the chromosomal segment carrying H-2, those in the b segment, gender and the month of birth. Greater heterozygosity at the loci studied was associated with longer life span. Histopathological findings on mice that died at or after 28 months of age were comparable for all genetic combinations except that there was an increased frequency of lymphoma in females and an increased frequency of amyloidosis in males. Our analysis emphasizes the need for comprehensive studies of aging and longevity that would simultaneously determine the effects of several genetic regions and their interactions with the environment with respect to possible causes of death.

Animals↗
PubMed1998

The effect of genetic factors for longevity: a comparison of identical and fraternal twins in the Swedish Twin Registry.

BACKGROUND: The relative importance of genetic influences on longevity was studied on data from the population-based Swedish Twin Registry. METHODS: A sample of 3,656 identical and 6,849 like-sexed fraternal twin pairs was studied regarding mortality rates and within-pair similarity for age at death. Genetic and environmental contributions to variation in longevity, expressed by integrated mortality rates, were estimated from a subsample of 1,734 twin pairs reared together and 130 twin pairs reared apart from the cohorts born 1886 to 1900. RESULTS: The intraclass correlation coefficients suggested that the genetic effect was small, and, for males, perhaps absent. Among pairs in which both twins died relatively young and among pairs in which both twins lived until very old age, the variance in age at death seemed to have no genetic component. Model fitting procedures based on twins reared apart and twins reared together indicated that most of the variance in longevity was explained by environmental factors. CONCLUSIONS: Over the total age range examined, a maximum of around one third of the variance in longevity is attributable to genetic factors, and almost all of the remaining variance is due to nonshared, individual specific environmental factors. The evidence that genetic factors play a minor role depending upon age at death merits further examination.

Adult↗
PubMed2000

Differential longevity in mouse stocks selected for early life growth trajectory.

Small body size is associated with superior longevity in several intraspecies comparisons, including dogs bred for specific forms of work, mice and rats fed diets low in calories, rats fed diets low in methionine, and mutant mice whose levels of growth hormone and thyroid hormone are atypically low. To further investigate the interactions among body size, genetic endowment, and longevity, we measured the life span of female mice selectively bred from Institute for Cancer Research stock for differences in rate of body weight gain. These mice were selected for differential rates of growth either early (0-10 days) or later (26-56 days) in the first 2 months of life. The data show a good correlation between the average weight of the stock and its mean longevity, with low body size associated, as predicted, with longer life span. Weight at 3, 6, and 12 months, and weight at peak body weight, are all significant predictors of longevity (among stocks) in univariate regressions; weight at 6 months has the strongest association in stepwise multiple regression. There is no significant correlation between the life span for the stock and the proportion of deaths attributable to neoplasia in this group of mice. The data provide support for the hypothesis that genetic factors that influence early life growth trajectories can have a strong influence on life span. These size-selected mice provide useful tools for analysis of the genetic factors that influence life history parameters, including maturation and aging rates.

Adenocarcinoma↗
PubMed2001

Biomarkers of aging: prediction of longevity by using age-sensitive T-cell subset determinations in a middle-aged, genetically heterogeneous mouse population.

Seven T-cell subset values were measured in each of 559 mice at 8 months of age, and then again in the 494 animals that reached 18 months of age. The group included virgin males, virgin females, and mated females, and it was produced by using a four-way cross-breeding system that generates genetic heterogeneity equivalent to a very large sibship. An analysis of covariance showed that four T-cell subsets-CD4, CD4 memory, CD4 naïve, and CD4 cells expressing P:-glycoprotein-were significant predictors (p <.003) of longevity when measured at 18 months of age after adjustment for the possible effects of gender and mating. The subset marked by CD4 and P:-glycoprotein expression showed a significant interaction effect: this subset predicted longevity only in males. Among subsets measured when the mice were 8 months of age, only the levels of CD8 memory cells predicted longevity (p =.016); the prognostic value of this subset was largely limited to mated females. A cluster analysis that separated mice into two groups based upon similarity of T-cell subset patterns measured at 18 months showed that these two groups differed in life expectancy. Specifically, mice characterized by relatively low levels of CD4 and CD8 memory cells, high levels of CD4 naïve cells, and low levels of CD4 cells with P:-glycoprotein (64% of the total) lived significantly longer (50 days = 6%; p <.0007) than mice in the other cluster. The results are consistent with the hypothesis that patterns of T-cell subsets vary among mice in a manner than can predict longevity in middle age, and they suggest that these subsets may prove to be useful for further studies of the genetics of aging and age-sensitive traits.

Aging↗
PubMed2003

Exceptional longevity in pet dogs is accompanied by cancer resistance and delayed onset of major diseases.

To characterize extreme aged pet dogs as a first step in developing an animal model of exceptional longevity, we constructed lifetime medical histories for 345 Rottweiler dogs using information collected from owners and veterinarians. Extreme aged dogs (alive at the 95th percentile age at death for the study population, > or =13.3 years) were compared with a usual longevity group (9-10 years). Exceptional longevity in Rottweiler dogs was accompanied by a significant delay in the onset of major life-threatening diseases; 76% of extreme aged dogs remained free of all major diseases during the first 9 years of life. Only 19% of extreme aged dogs died of cancer versus 82% of dogs with usual longevity (p <.0001). The reduction in cancer mortality in oldest-old pet dogs mimics that seen in human centenarians and provides strong rationale for using this animal model to study comparative mechanisms of cancer resistance in the extreme aged.

Aging↗
PubMed2004

The human life span is not that limited: the effect of multiple longevity phenotypes.

There is an ongoing debate as to whether or not human longevity is approaching its limits. The debate and its outcome are important since they might affect public policy. We review the evidence presented by both schools. We add our empirical observation that there exist multiple longevity phenotypes, each of which arises from the alteration of fundamental aging processes. The current debate only considers two of the three known mammalian longevity phenotypes. The overlooked phenotype is the delayed onset of senescence phenotype, which can be induced by various interventions, including pharmaceuticals. The existence of multiple phenotypes means that an overview of potential life expectancy outcomes for a species should be based on the analysis of all longevity phenotypes likely to occur in that species.

Animals↗
PubMed2005

Peroxisome proliferator-activated receptor gamma coactivator 1 in caloric restriction and other models of longevity.

Dietary restriction of calories (caloric restriction [CR]) increases longevity in phylogenetically diverse species. CR retards or prevents age-dependent deterioration of tissues and an array of spontaneous and chemically induced diseases associated with obesity including cardiovascular disease, diabetes, and cancer. An understanding of the molecular mechanisms that underlie the beneficial effects of CR will help identify novel dietary, pharmacological, and lifestyle strategies for slowing the rate of aging and preventing these diseases as well as identify factors which modulate chemical toxicity. Here, we review the involvement of transcriptional coactivator proteins, peroxisome proliferator-activated receptor (PPAR) gamma coactivator 1 (PGC-1) alpha and beta, and regulated nuclear receptors (NR) in mediating the phenotypic changes found in models of longevity which include rodent CR models and mouse mutants in which insulin and/or insulin-like growth factor-I signaling is attenuated. PGC-1alpha is transcriptionally or posttranslationally regulated in mammals by: 1) forkhead box "other" (FoxO) transcription factors through an insulin/insulin-like growth factor-I -dependent pathway, 2) glucagon-stimulated cellular AMP (cAMP) response element binding protein, 3) stress-activated kinase signaling through p38 mitogen-activated protein kinase, and 4) the deacetylase and longevity factor sirtuin 1 (SIRT1). PGC-1alpha and PGC-1beta regulate the ligand-dependent and -independent activation of a large number of NR including PPARalpha and constitutive activated receptor (CAR). These NR regulate genes involved in nutrient and xenobiotic transport and metabolism as well as resistance to stress. CR reverses age-dependent decreases in PGC-1alpha, PPARalpha, and regulated genes. Strategies that target one or multiple PGC-1-regulated NR could be used to mimic the beneficial health effects found in models of longevity.

Animals↗
PubMed1975

Life-span and the inheritance of longevity of inbred mice.

Measures of life-span were obtained for male and female A/J, BALB/cJ, C57BL/6J, and DBA/2J inbred mouse strains and the six possible hybrid combinations (N equals 500, 10 groups, 25 male and 25 female per group). C57BL/6J mice were long lived, while A/J, BALB/cJ and DBA/2J mice were short lived, with the exception of female BALB/cJ mice, which lived as long as C57BL/6J mice. Female BALB/cJ and two female hybrid mouse groups with a BALB/cJ parent lived longer than males, but significant sex differences were not obtained for other groups. In general, the mode of inheritance of longevity was overdominant. For a second study (N equals 400) of the longevity of A/J and C57BL/6J strains and F1 and F2 hybrids it was estimated that one genetic factor was associated with longevity and the coefficient of genetic determination for longevity was estimated as between .48 and .79.

Analysis of Variance↗
PubMed1993

Exercise increases average longevity of female rats despite increased food intake and no growth retardation.

In previous studies, male rats given access to voluntary running wheels showed improved survival. Because the male runners did not increase food intake, it was not clear whether their improvement in average longevity was due to decreased availability of energy for cell proliferation and growth or to another effect of exercise. In this study, female rats, which increase their food intake in response to wheel running, were used to determine whether exercise can increase longevity when availability of energy for cell proliferation and growth is not decreased. At age 5 mo, the female voluntary wheel runners were running 9173 +/- 3640 m/day (mean +/- SD); running distance declined to 965 +/- 483 m/d by age 34 mo. From 5 mo to 10 mo of age, the runners ate approximately 37% more than the sedentary rats. Thereafter, the runners ate approximately 20% more. The runners and sedentary rats attained similar peak body weights. However, the runners gained weight more rapidly, attaining steady state by 11 mo; the sedentary rats' weights did not plateau until approximately 15 mo. The runners had a significant prolongation of average longevity without an increase in maximal life span. The sedentary rats' average age at death was 924 +/- 155 days (mean +/- SD; range, 619-1263 d) compared to 1009 +/- 132 days (range, 693-1259 d) for the runners, p < .001. These results show that exercise improves average longevity of rats independent of decreased availability of energy for cell proliferation and growth. They also provide evidence that an increase in food intake is not harmful when balanced by an increase in energy expenditure.

Animals↗
PubMed1993

A correlation between DNA repair capacity and longevity in adult Drosophila melanogaster.

Mutagen-sensitive (mus) mutants in Drosophila melanogaster have been biochemically characterized as defective in DNA repair. Life spans of three temperature-sensitive mus strains have been measured to determine if loss of DNA repair capacity has a substantial influence on the longevity of adult Drosophila. The mus(ts) strains have been tested for an effect on longevity, with and without exposure to low doses of the alkylating agent methyl methanesulfonate. All three strains tested show substantially reduced life spans in the absence of the mutagen. The effect is seen at the restrictive temperature but not at the permissive temperature. In addition, the reduction in life span is enhanced by exposure to very low, sublethal doses of MMS during development. This effect is also temperature-sensitive. Temperature-shift studies indicate that it is mutagen-sensitivity during development that is leading to reduced longevity in adults. These results suggest that the integrity of DNA repair systems may play a role in the longevity of adult Drosophila melanogaster.

Animals↗
PubMed1987

Crucial dietary factors in maximizing life span and longevity in autoimmune-prone mice.

When the energy intake of (NZB X NZW)F1 female mice was reduced to 60% of the intake of simultaneously ad libitum-fed mice, the early death associated with autoimmune-based renal disease in this strain was greatly delayed. The length of prolongation of disease-free life depended not only on the decreased energy intake but also on the energy source. In the group of mice with 60% intake of a carbohydrate-free (i.e., high fat) diet, mean longevity was doubled as compared to that of ad libitum-fed mice. However, when the nonprotein energy was supplied by carbohydrate (sucrose and glycerol) the mean longevity was three times that of the ad libitum-fed groups, although survival times varied widely. With ad libitum feeding the nonprotein energy source did not significantly affect longevity. Clearly, although energy intake restriction provides significant influence on longevity, very high fat diets do not give the same protection as do high carbohydrate diets. The basis for this difference is not entirely clear and several explanations are possible.

Animals↗
PubMed2000

Evidence of sex-linked effects on the inheritance of human longevity: a population-based study in the Valserine valley (French Jura), 18-20th centuries.

A long-standing puzzle in gerontology is the sex dependence of human longevity and its inheritance. We have analysed the sex-linked pattern of inheritance of longevity from 643 nuclear families on the historical population register of a French valley. We have focused on mean conditional life expectancy at a minimum age of 50 years, thus, in the present study, longevity refers to late or post-reproductive survival. A comparison of parents' and offspring's longevity has shown the existence of a heritable component of late survival in this population. We have found that the heritable component was substantially larger for daughters compared to sons. Moreover, this result appeared to be specific to late survival, that is, when only post-reproductive mortality for parental and offspring generations is taken into account. The stronger resemblance of parents to their daughters was no longer observed when considering younger ages at death for the offspring. This observation explains the hitherto unaccountable diversity of data in previous studies.

Female↗
PubMed2006

The unusual genetics of human longevity.

In no species other than humans do cultural, social, and biological factors interact with each other in modulating complex phenotypes. Thus, the identification of genetic factors that affect human longevity is a true challenge. The model of centenarians provides us a unique opportunity to tackle this challenge. In this Perspective, we discuss some recent findings (the impact of geography and demography on the longevity phenotype, the relationship between longevity and homozygosity, the role of the nuclear-mitochondrial genome cross-talk) by which new ideas are suggested, such as the concept of a complex allele timing as a pivotal process in modulating the probability of achieving longevity.

Demography↗
PubMed2003

Longevity regulation in Saccharomyces cerevisiae: linking metabolism, genome stability, and heterochromatin.

When it was first proposed that the budding yeast Saccharomyces cerevisiae might serve as a model for human aging in 1959, the suggestion was met with considerable skepticism. Although yeast had proved a valuable model for understanding basic cellular processes in humans, it was difficult to accept that such a simple unicellular organism could provide information about human aging, one of the most complex of biological phenomena. While it is true that causes of aging are likely to be multifarious, there is a growing realization that all eukaryotes possess surprisingly conserved longevity pathways that govern the pace of aging. This realization has come, in part, from studies of S. cerevisiae, which has emerged as a highly informative and respected model for the study of life span regulation. Genomic instability has been identified as a major cause of aging, and over a dozen longevity genes have now been identified that suppress it. Here we present the key discoveries in the yeast-aging field, regarding both the replicative and chronological measures of life span in this organism. We discuss the implications of these findings not only for mammalian longevity but also for other key aspects of cell biology, including cell survival, the relationship between chromatin structure and genome stability, and the effect of internal and external environments on cellular defense pathways. We focus on the regulation of replicative life span, since recent findings have shed considerable light on the mechanisms controlling this process. We also present the specific methods used to study aging and longevity regulation in S. cerevisiae.

Gene Expression Regulation, Fungal↗
PubMed2004

No evidence for a genetic relationship between Alzheimer's disease and longevity.

OBJECTIVE: Late onset Alzheimer's disease (AD) is frequent in subjects who have reached an age above the average life expectancy. AD and life expectancy are both influenced by genetic factors. Consequently, a possible genetic relationship between AD and longevity was investigated using family study data. METHODS: First-degree relatives of patients with AD (n = 645) and of non-demented controls (n = 1,106) were examined by direct interview or by family history in the case of already deceased or unavailable subjects. Survival of subjects with an assumed familial load for AD (i.e. first-degree relatives of AD patients) and of controls was compared using the Kaplan-Meier analysis and log-rank statistics. RESULTS: Relatives with AD reached higher ages than other family members. However, there was no significant co-aggregation of AD and longevity in first-degree relatives of AD patients in comparison with those of controls. This applied to all diseased as well as non-demented relatives. CONCLUSIONS: Longevity is an independent prerequisite for the development of the disease, but is not genetically related to AD. The apparent longevity in relatives with AD is likely to result from the selection of subjects fulfilling this prerequisite.

Age Factors↗
PubMedDate not supplied

Aging, longevity, and diet: historical remarks on calorie intake reduction.

BACKGROUND: The link between longevity and diet is of great interest to biological and gerontological research. The fact that relevant knowledge has generally been available for many centuries is often not remarked upon. OBJECTIVE: This article examines three aspects of early modern Western medicine which thematize the following links between the elderly, longevity and caloric intake: (1) the question of a diet specifically tailored to old age as background to certain theories of aging; (2) the transfer of these dietetic concepts to younger patients in order to improve health and extend life, and (3) the promotion of dieting in order to avoid the consequences of plethora and to retard the aging process. METHODS: A number of Latin texts from premodern medical and health literature will be examined and their contents will be analyzed for material relating to diet for the elderly and longevity in their historic contexts. RESULTS: We will clearly indicate fundamental parallels as well as differences between historic and modern scientific thought. We will thereby show that although a modern understanding of hormones and molecular genetics was obviously lacking, basic knowledge of the influence of nutrition on old age was prevalent. In contrast, the early modern lay concept of longevity through calorie reduction was based on coincidental observation. CONCLUSION: These premodern, but nonetheless rational ideas must be integrated into the socio-cultural setting and the question must be raised as to the link between contemporary research aims and social reality.

Aging↗