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PubMed2005

A complex dietary supplement extends longevity of mice.

Key factors implicated in aging include reactive oxygen species, inflammatory processes, insulin resistance, and mitochondrial dysfunction. All are exaggerated in transgenic growth hormone mice (TGM), which display a syndrome resembling accelerated aging. We formulated a complex dietary supplement containing 31 ingredients known to ameliorate all of the above features. We previously showed that this supplement completely abolished the severe age-related cognitive decline expressed by untreated TGM. Here we report that longevity of both TGM and normal mice is extended by this supplement. Treated TGM showed a 28% increase (p < .00008) in mean longevity. An 11% increase in mean longevity was also significant (p < .002093) for treated normal mice, compared to untreated normal mice. These data support the hypothesis that TGM are a model of accelerated aging, and demonstrate that complex dietary supplements may be effective in ameliorating aging or age-related pathologies where simpler formulations have generally failed.

Aging↗
PubMed1986

The aging AXC/SSh rat: assessment of longevity and prevalence of neoplastic and nonneoplastic diseases in necropsied rats.

Median life span, 906 days, was identical for conventionally reared, ad libitum fed AXC/SSh male and female rats and exceeded that of most other conventionally or barrier maintained rats. AXC/SSh rat longevity partially reflects the 25% incidence of moderate to severe nephropathy occurring at 30 to 41 months. Because male survival was related to sibship, p less than .02, and female survival was not, p greater than .05, a genetic component may affect male longevity. Maximum body weight was achieved during the initial 20% of life span and maintained through the final 10% when mean loss was 14 and 15%, respectively, for males and females. Pituitary adenomas occurred in 65% of females and 10% of males. Mammary adenocarcinoma occurred in 26% of females. Interstitial cell tumors were not detected in males younger than 24 months. Prostate adenocarcinomas occurred in 23% of males older than 29 months. The longevity of AXC/SSh rats and their low incidence of nephropathy suggests they are an attractive model for studies in aging.

Aging↗
PubMed1996

The oldest man ever? A case study of exceptional longevity.

This article summarizes recent findings in a case study of exceptional longevity. CM, a resident of San Rafael, California, was 114 years old in August 1996. He is the first properly verified case of a 114-year-old man in human history (although a few women have been known to live longer). Our investigation of CM continues as we attempt to gather additional information about his life, family history, and current condition. Here, we consider only two aspects of this case: its authenticity and its significance in the history of human longevity. We believe that we have proven that CM's stated age is accurate. Based on the available information, it also seems a reasonable conjecture that he may be the oldest man alive today and perhaps the oldest man who has ever lived. This study documents an extreme example of human longevity and records characteristics of the man's life that may provide clues about the causes of his exceptional survivorship.

Aged↗
PubMed1997

Centenarians: human longevity outliers.

This article is about the few humans who reach very old ages--here called "longevity outliers." They are a distinct group, with lower mortality rates than most of the population. Centenarians are human longevity outliers. They are more resistant to causes of death such as heart disease and cancer than those who die at younger ages. Inheritance of life span, the present condition of centenarians, and their causes of death are considered. The maximum human life span in the future will be affected, at least marginally, as more longevity outliers survive to challenge today's maximum of 121 years.

Aged↗
PubMed2003

Family history, longevity, and risk of coronary heart disease: the PRIME Study.

BACKGROUND: To assess the contribution of family history of coronary heart disease (CHD) and longevity in parents to 5-year incidence of coronary events in middle-aged men. METHODS: A prospective study in men from Northern Ireland and the French cities and environs of Lille, Strasbourg, and Toulouse. A total of 10 600 men aged 50-59 years were examined between 1991 and 1994 and followed annually by questionnaire for incident cases of coronary disease. A detailed family history was taken and a quantitative family risk score for CHD was calculated for each subject. Five-year follow-up is complete; all coronary events (coronary deaths, myocardial infarction, and angina) documented by clinical records were reviewed by an independent medical committee. RESULTS: At screening, 9758 subjects were free of clinical and historical evidence of CHD; in this group there were 317 coronary events by 5 years of follow-up. Subjects whose parents had both survived until >/=80 years showed a relative odds of 0.49 (95% CI: 0.31-0.77) for risk of a coronary event compared with subjects whose parents had not survived until >/=80 years old with adjustment for age and nine other risk factors including family history. The pattern of results was similar in France and Northern Ireland, although parental survival was longer in France. Likewise, subjects with a strong family history showed a relative odds of 1.93 (95% CI: 1.25-3.00) compared with subjects without such a history, after adjustment for age and the nine risk factors including parental longevity. The pattern of results was similar in France and Northern Ireland. CONCLUSIONS: These results indicate that a family history of coronary disease and parental longevity, although related, act independently of one another and of other major cardiovascular risk factors in predicting 5-year risk of subsequent coronary events.

Aged↗
PubMed2004

Methodological problems in genetic association studies of longevity--the apolipoprotein E gene as an example.

BACKGROUND: Cross-sectional genetic association studies are now widely employed to look for genes which confer longevity. Such studies are based on two assumptions; (a) initial relative allele frequencies in the different age cohorts are similar, and (b) the risk of mortality conferred by genotypes does not depend on year of birth. METHODS: We explored the validity of these assumptions and reviewed 15 cross-sectional studies of common apolipoprotein E (APOE) polymorphisms and longevity. RESULTS: Higher relative epsilon2 frequencies, and lower relative epsilon4 allele frequencies were observed in elderly versus younger populations. If assumptions (a) and (b) were correct the estimates for epsilon2 and epsilon4 alleles respectively versus epsilon3 alleles would be 1.34 (95% CI: 1.19, 1.35) and 0.54 (95% CI: 0.46, 0.63) in elderly versus younger individuals. However, there was an association between relative epsilon4 allele frequency in controls and APOE epsilon4 effect (beta = -0.45, 95% CI: -0.89, 0.00). In relation to assumption (a) there is substantial variation in relative APOE allele frequencies (4-21%), with considerable heterogeneity evident within geographically proximate populations, population admixture is likely to have resulted in changes in allele frequency over time, and assumption (b) APOE related causes of death are context specific and have changed considerably over the last 30 years. CONCLUSION: The validity of case-control type studies of the genetic basis of longevity based on the above assumptions is questionable, especially when considerable differences exist in allele frequency by population and when the genes in question interact with environmental factors, which vary by time and place.

Aging↗
PubMed1991

Hormonal manipulation of the prenatal environment alters reproductive morphology and increases longevity in autoimmune NZB/W mice.

Steroid hormones, which affect development of reproductive traits, alter immune responses in rodents and appear to control severity of disease in F1 hybrid NZB/W mice, an animal model of systemic lupus erythematosus. We tested the hypothesis that exposure of NZB/W fetuses to altered hormonal environments would influence subsequent expression of autoimmune renal disease and affect longevity. NZB females, pregnant with NZB/W fetuses, were treated from Days 13-18 of gestation with testosterone or the antiandrogen, flutamide. Similar treatments were carried out in C57BL/6 dams mated to DBA/2 males to permit comparison with nonautoimmune hybrid mice. Serum concentrations of testosterone were greater in testosterone-implanted dams of both strains, but concentrations of estradiol were greater only in C57BL/6 dams treated with flutamide. Alpha fetoprotein (AFP), which binds estrogen and modulates immune responsiveness, was greater in serum from both groups of testosterone-treated dams, while flutamide treatment increased serum AFP only in NZB dams. We conclude that factors governing circulating estradiol and AFP differed in pregnant NZB and C57BL/6 females. Morphological analyses confirmed effects of hormonal manipulation on the developing fetuses. Testosterone implants resulted in female offspring with greater anogenital spaces, and treatment of dams with flutamide eliminated the expected difference between anogenital spaces in females and males. Effects of altered prenatal hormonal environments on immune-mediated disease in NZB/W offspring were examined in a longevity study. Early deaths were delayed in NZB/W females produced by flutamide-treated dams. An unexpected result was observed in NZB/W males. Male offspring from both testosterone- and flutamide-treated mothers lived longer than males from control dams. This paradox suggested that a characteristic shared by both groups of treated NZB dams had similar effects on the developing fetuses. It is proposed that elevated concentrations of AFP modulated the course of autoimmune disease and contributed to increased longevity in NZB/W offspring of treated dams.

Animals↗
PubMed2001

Does longevity in beagles injected with bone-seeking radionuclides depend upon radiation dose in the absence of known radiation effects?

Regression analyses of longevity as a function of skeletal radiation dose among groups of beagles injected with 226Ra, 228Ra, 228Th, 241Am, 90Sr or monomeric 239Pu suggested that at low doses and dose-rates (those at which induced effects are low), age at death seems to be independent of dose when animals dying with specific radiation effects were excluded, although longevity does appear to be a function of dose when animals dying with established radiation effects and at all doses were included. We conclude tentatively that, for mammals receiving skeletal dose from bone-seeking radionuclides at low doses and low dose-rates, longevity may not be dependent upon skeletal radiation dose in the absence of radiation-induced malignancies or other radiation effects.

Americium↗
PubMed2000

Fitness, reproduction and longevity among European aristocratic and rural Finnish families in the 1700s and 1800s.

The life histories of two socio-economically different groups of humans comprising birth cohorts from the 1700s and 1800s were investigated. It was discovered that fertility selection was greater among European aristocrats and mortality selection greater among rural Finns. The life history of the rural Finns involved shorter female life spans, a considerably longer period of reproduction, higher juvenile mortality, a greater total production of offspring and slightly higher individual fitness. In a comparison of parental cohorts, it was discovered that longevity and progeny survival improved significantly from the 1700s to the 1800s. Out of the three factors investigated, longevity was found to influence reproduction and fitness more than socio-economic group or birth cohort. The reproductive efficacy and fitness of women increased along with their life span. However, reproductive success and fitness were lower among women with the longest life span (over 80 years). Among men, reproductive success improved consistently along with the increase in longevity. When birth intervals were examined, it was discovered that the sex of previous offspring did not influence the interval between births.

Adult↗
PubMed2001

Juvenile hormone regulation of longevity in the migratory monarch butterfly.

Monarch butterflies (Danaus plexippus) of eastern North America are well known for their long-range migration to overwintering roosts in south-central Mexico. An essential feature of this migration involves the exceptional longevity of the migrant adults; individuals persist from August/September to March while their summer counterparts are likely to live less than two months as adults. Migrant adults persist during a state of reproductive diapause in which both male and female reproductive development is arrested as a consequence of suppressed synthesis of juvenile hormone. Here, we describe survival in monarch butterflies as a function of the migrant syndrome. We show that migrant adults are longer lived than summer adults when each are maintained under standard laboratory conditions, that the longevity of migrant adults is curtailed by treatment with juvenile hormone and that the longevity of summer adults is increased by 100% when juvenile hormone synthesis is prevented by surgical removal of its source, the corpora allatum. Thus, monarch butterfly persistence through a long winter season is ensured in part by reduced ageing that is under endocrine regulation, as well as by the unique environmental properties of their winter roost sites. Phenotypic plasticity for ageing is an integral component of the monarch butterflies' migration-diapause syndrome.

Animal Migration↗
PubMed2004

Life-history trade-offs and ecological dynamics in the evolution of longevity.

Longevity is a life-history trait that is shaped by natural selection. An unexplored consequence is how selection on this trait affects diversity and diversification in species assemblages. Motivated by the diverse rockfish (Sebastes) assemblage in the North Pacific, the effects of trade-offs in longevity against competitive ability are explored. A competition model is developed and used to explore the potential for species diversification and coexistence. Invasion analyses highlight that life-history trait trade-offs in longevity can mitigate the effects of competitive ability and favour the coexistence of a finite number of species. Our results have implications for niche differentiation, limiting similarity and assembly dynamics in multispecies interactions.

Animals↗
PubMed2005

Are reproductive and somatic senescence coupled in humans? Late, but not early, reproduction correlated with longevity in historical Sami women.

Evolutionary theory of senescence emphasizes the importance of intense selection on early reproduction owing to the declining force of natural selection with age that constrains lifespan. In humans, recent studies have, however, suggested that late-life mortality might be more closely related to late rather than early reproduction, although the role of late reproduction on fitness remains unclear. We examined the association between early and late reproduction with longevity in historical post-reproductive Sami women. We also estimated the strength of natural selection on early and late reproduction using path analysis, and the effect of reproductive timing on offspring survival to adulthood and maternal risk of dying at childbirth. We found that natural selection favoured both earlier start and later cessation of reproduction, and higher total fecundity. Maternal age at childbirth was not related to offspring or maternal survival. Interestingly, females who produced their last offspring at advanced age also lived longest, while age at first reproduction and total fecundity were unrelated to female longevity. Our results thus suggest that reproductive and somatic senescence may have been coupled in these human populations, and that selection could have favoured late reproduction. We discuss alternative hypotheses for the mechanisms which might have promoted the association between late reproduction and longevity.

Aging↗
PubMed2005

A systematic RNAi screen for longevity genes in C. elegans.

We report here the first genome-wide functional genomic screen for longevity genes. We systematically surveyed Caenorhabditis elegans genes using large-scale RNA interference (RNAi), and found that RNAi inactivation of 89 genes extend C. elegans lifespan. Components of the daf-2/insulin-like signaling pathway are recovered, as well as genes that regulate metabolism, signal transduction, protein turnover, and gene expression. Many of these candidate longevity genes are conserved across animal phylogeny. Genetic interaction analyses with the new longevity genes indicate that some act upstream of the daf-16/FOXO transcription factor or the sir2.1 protein deacetylase, and others function independently of daf-16/FOXO and sir2.1, and might define new pathways to regulate lifespan.

Animals↗
PubMed1993

Developmental and age-related processes that influence the longevity and senescence of photosynthetic tissues in arabidopsis.

Factors that influence the longevity and senescence of photosynthetic tissues of Arabidopsis were investigated. To determine the influence of reproductive development on the timing of somatic tissue senescence, the longevity of rosette leaves of the Landsberg erecta strain and of isogenic mutant lines in which flowering is delayed (co-2) or sterile flowers are produced (ms1-1) were compared. No difference in the timing of senescence of individual leaves was observed between these lines, indicating that somatic tissue longevity is not governed by reproductive development in this species. To examine the role of differential gene expression in the process of leaf senescence, cDNA clones representing genes that are differentially expressed in senescing tissues were isolated. Sequence analysis of one such clone indicated homology to previously cloned cysteine proteinases, which is consistent with a role for the product of this gene in nitrogen salvage. RNA gel blot analysis revealed that increased expression of senescence-associated genes is preceded by declines in photosynthesis and in the expression of photosynthesis-associated genes. A model is presented in which it is postulated that leaf senescence is triggered by age-related declines in photosynthetic processes.

Amino Acid Sequence↗
PubMed1997

Molecular genetic studies on DNA polymorphism of the HLA class II genes associated with human longevity.

Okinawan Japanese are well known for their longevity; the population rate of centenarians in Okinawa is about 3.8 times higher than that of the whole Japan, where the average life expectancies both among men and among women are the highest in the world. In this study, we analyzed HLA class II alleles of Okinawan centenarians by the polymerase chain reaction-restriction fragment-length polymorphism (PCR-RFLP) method for the purpose of clarifying the presence of primary genetic factors in the major histocompatibility complex (MHC) region associated with human longevity. DRB1*1401, DQB1*0503, DQA1*0101=0104 and DQA1*05 were significantly increased in the centenarians. The significant increase of HLA-DQB1*0503 and/or DQA1*0101=0104 in the centenarians can be explained by a linkage disequilibrium with DRB1*1401, or vice versa. Further, the tendency was observed toward increase with respect to DRB1*0101 and DRB1*1201. These data suggest that several alleles of the HLA-DRB1 and/or HLA-DQ genes are involved in human longevity.

Adult↗
PubMed2005

Correlated responses to selection for stress resistance and longevity in a laboratory population of Drosophila melanogaster.

Laboratory studies on Drosophila have revealed that resistance to one environmental stress often correlates with resistance to other stresses. There is also evidence on genetic correlations between stress resistance, longevity and other fitness-related traits. The present work investigates these associations using artificial selection in Drosophila melanogaster. Adult flies were selected for increased survival after severe cold, heat, desiccation and starvation stresses as well as increased heat-knockdown time and lifespan (CS, HS, DS, SS, KS and LS line sets, respectively). The number of selection generations was 11 for LS, 27 for SS and 21 for other lines, with selection intensity being around 0.80. For each set of lines, the five stress-resistance parameters mentioned above as well as longevity (in a nonstressful environment) were estimated. In addition, preadult developmental time, early age productivity and thorax length were examined in all lines reared under nonstressful conditions. Comparing the selection lines with unselected control revealed clear-cut direct selection responses for the stress-resistance traits. Starvation resistance increased as correlated response in all sets of selection lines, with the exception of HS. Positive correlated responses were also found for survival after cold shock (HS and DS) and heat shock (KS and DS). With regard to values of resistance across different stress assays, the HS and KS lines were most similar. The resistance values of the SS lines were close to those of the LS lines and tended to be the lowest among all selection lines. Developmental time was extended in the SS and KS lines, whereas the LS lines showed a reduction in thorax length. The results indicate a possibility of different multiple-stress-resistance mechanisms for the examined traits and fitness costs associated with stress resistance and longevity.

Adaptation, Physiological↗
PubMed2005

Drosophila longevity is not affected by heterochromatin-mediated gene silencing.

Two highly conserved histone deacetylases, Sir2 and Rpd3, have been linked to caloric restriction and the extension of longevity. Because the Drosophila forms of each protein can silence genes in either euchromatin or heterochromatin, we determined whether longevity extension is mediated by silencing in the latter domain. When silencing was increased and decreased using mutations that affect heterochromatin protein 1 (HP1), but have no direct effect upon Sir2 or Rpd3, lifespan was unaffected. Heterochromatin-mediated gene silencing was then modulated without directly influencing HP1 as well as the deacetylases, again yielding no effect on lifespan. Mortality rates were unchanged by all manipulations, indicating that euchromatic targets are likely to be the effectors of deacetylase-mediated longevity extension in Drosophila [corrected]

Animals↗
PubMed2004

The G/C915 polymorphism of transforming growth factor beta1 is associated with human longevity: a study in Italian centenarians.

Sequence variations in a variety of pro- or anti-inflammatory cytokine genes have been found to influence successful aging and longevity. Because of the role played by the transforming growth factor beta1 (TGF-beta1) cytokine in inflammation and regulation of immune responses, the variability of the TGF-beta1 gene may affect longevity by playing a role in inflamm-aging. Two polymorphisms, G/A -800 and C/T -509, located in the 5' region, and two missense polymorphisms, T/C 869 and G/C 915 which change (Leu > Pro)10 and (Arg > Pro)25, respectively, located in the signal peptide, were analysed in 419 subjects from Northern and Central Italy, including 172 centenarians and 247 younger controls. In addition, the effects of the TGF-beta1 genetic variability on plasma levels of the biologically active form (naturally processed) of this cytokine were studied in 143 randomly selected subjects, including 73 centenarians. Significant differences were found at the +915 site as far as the C allele and GC genotype were concerned, both of them being lower in centenarians than in young controls (P=0.034 and 0.028, respectively), but none of the other tested genetic variants was significantly different between centenarians and controls. Moreover, a particular haplotype combination (G -800/C -509/C 869/C 915) was notably lower in centenarians than in younger individuals (P=0.007). Finally, active TGF-beta1 plasma levels were significantly increased in the elderly group, but no relationship with TGF-beta1 genotypes was observed. These results suggest that, at least in this population, the variability of the TGF-beta1 gene influences longevity and that the age-related increase in plasma levels of active TGF-beta1 seems not to be genetically regulated.

Adolescent↗