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PubMed2002

Do longevity assurance genes containing Hox domains regulate cell development via ceramide synthesis?

A gene family containing a longevity assurance gene (Lag1p) motif is described. Database searches revealed >40 members of this family of transmembrane proteins, two of which have recently been shown to regulate the synthesis of ceramide, a lipid second messenger involved in a variety of cellular processes. We speculate that other family members, some of which contain a Hox domain, may also be involved in the synthesis of specific ceramide pools, perhaps explaining the role of longevity assurance genes in regulating development.

Animals↗
PubMed1998

Elevated lipoprotein(a) levels and small apo(a) isoforms are compatible with longevity: evidence from a large population of French centenarians.

Epidemiological studies have shown lipoprotein(a) (Lp(a)) to be an independent risk factor for cardiovascular disease. Lp(a) is a cholesterol-rich, low-density lipoprotein (LDL)-like particle to which a large glycoprotein, apolipoprotein(a) (apo(a)) is attached. Plasma Lp(a) levels are highly genetically determined and influenced to a minor degree by environmental factors. In an effort to determine whether Lp(a) might be associated with longevity, we have evaluated Lp(a) levels and apo(a) isoform sizes in a population of French centenarians (n = 109) compared to a control group (n = 227). The mean age of centenarians was 101.5 +/- 2.4 years while the control group was 39.4 +/- 7.2 years. Plasma levels of total cholesterol and triglyceride were within the normal range in both centenarian and control subjects. Lp(a) levels were higher in centenarians (both male and female) than in the normolipidemic control group (mean Lp(a) level = 0.33 +/- 0.42 and 0.22 +/- 0.27 mg/ml, respectively, P < 0.005). The distribution of apo(a) isoforms was significantly shifted towards small isoform size in the centenarian population as compared to the controls (54.4 and 41.4% of isoforms < or = 27 kringles (kr), respectively, P = 0.04). Nonetheless, the apo(a) size distribution in centenarians did not entirely explain the high Lp(a) levels observed in this population. Factors other than apo(a) size, and which may be either genetic or environmental in nature, appear to contribute to the elevated plasma Lp(a) levels of our centenarian population. We conclude therefore that high plasma Lp(a) levels are compatible with longevity.

Adult↗
PubMed1998

In search of a biological pattern for human longevity: impact of apo A-IV genetic polymorphisms on lipoproteins and the hyper-Lp(a) in centenarians.

We studied centenarians to investigate the biological basis of human longevity focusing on the apolipoprotein A-IV and lipoprotein(a), potentially involved in the susceptibility to atherogenic mechanisms. We analyzed two restriction polymorphisms, HinfI347 (alleles +, -) and Fnu4HI360 (alleles 1, 2), and a VNTR (alleles 3, 4) at the 3' region of the apo A-IV gene. The allele frequencies, the lipoprotein concentrations and their association in centenarians and adults have been compared. In centenarians, the HinfI genotype distribution is different (P < 0.05) and the (+13) haplotype is prevalent (0.54 vs. 0.39), with a greater association of (+3), indicating the selection of a favourable allele. The lipoprotein modulation by the apo A-IV polymorphisms is suggested by significant associations in adults ((+/+) homozygotes have lower LDL-cholesterol and apo B than heterozygotes; (1/1) homozygotes have higher TG and apo B than heterozygotes), that in centenarians still exists as a trend. Centenarians show peculiar lipoprotein features: lower LDL-cholesterol (mean 103 vs. 115 mg/dl; P < 0.02), and higher lipoprotein(a) (median 17.5 vs. 4.5; P < 0.002). Large part of them (47%), especially the Hinf(+/+) and the (+13) homozygotes, have a lipoprotein(a) > 20 mg/dl, value considered as the threshold for atherogenic risk, surprisingly compatible with healthy longevity.

Adult↗
PubMed2003

Is height related to longevity?

Over the last 100 years, studies have provided mixed results on the mortality and health of tall and short people. However, during the last 30 years, several researchers have found a negative correlation between greater height and longevity based on relatively homogeneous deceased population samples. Findings based on millions of deaths suggest that shorter, smaller bodies have lower death rates and fewer diet-related chronic diseases, especially past middle age. Shorter people also appear to have longer average lifespans. The authors suggest that the differences in longevity between the sexes is due to their height differences because men average about 8.0% taller than women and have a 7.9% lower life expectancy at birth. Animal experiments also show that smaller animals within the same species generally live longer. The relation between height and health has become more important in recent years because rapid developments in genetic engineering will offer parents the opportunity to increase the heights of their children in the near future. The authors contend that we should not be swept along into a new world of increasingly taller generations without careful consideration of the impact of a worldwide population of taller and heavier people.

Adult↗
PubMed2000

The efficiency of genetic analysis of DNA from aged siblings to detect chromosomal regions implicated in longevity.

Studies of the frequencies of different alleles in young adults and aged individuals have implicated several genes, such as ApoE and ACE, in longevity. However such association studies can easily give rise to spurious results through unsuspected population subdivision, and an approach making use of genetic relationships among relatives is desirable. We have studied the effectiveness of non-parametric genetic analysis to detect different types of loci affecting longevity. The non-parametric method has high statistical power to detect infrequent recessive alleles that are required for, or significantly increase the probability of, survival to advanced age. Statistical power is reduced if a proportion of carriers of the alternative allele is allowed to survive. The method is least effective in detecting alleles that occur at low frequency in young individuals and that subsequently experience high mortality, as is the case for carriers of the epsilon4 allele of ApoE. Genotyping errors will also reduce the value of the NPL statistic in a linear fashion with the error rate and the number of loci genotyped. We have also used the method to analyse genotypes of seven highly polymorphic markers near the ApoE gene in a sample of 188 sibships of nonagenarians and centenarians (n=434) and their children (n=124), however no excess sharing of alleles was detected.

Adult↗
PubMed2002

Searching for genetic determinants of human aging and longevity: opportunities and challenges.

One way of testing possible causal relationships between various functional pathways and aging and longevity processes is to comparatively analyze groups of elderly individuals with select phenotypes for sequence variation in all genes participating in these pathways. Such direct association analysis to identify 'candidate pathways' in aging and longevity is theoretically feasible, with the complete sequence of the human genome known and massive gene annotation projects underway. To find all possible sequence variation of a large number of genes in aging populations, efficient genotyping methods are needed. Here, we describe the use of one such method, two-dimensional gene scanning (TDGS), for screening populations of centenarians and controls for polymorphic variation in the large BRCA1 breast cancer susceptibility gene.

Aged↗
PubMed2002

The influences on human longevity by HUMTHO1.STR polymorphism (Tyrosine Hydroxylase gene). A relative risk approach.

A new method based on the recently developed relative risk approach is introduced, and applied to data from Italian centenarian study (965 subjects aged from 13 to 109 years old) for investigating influences on longevity by Tyrosine Hydroxylase (TH) gene variability. The strategic parameterization enables the model to disentangle the various ways by which HUMTHO1.STR alleles (alleles 6, 7, 8, 9, 10*, 10, as defined according to the number of repeats) may contribute in reducing or increasing the hazard of death with different patterns of influences. Among all the alleles, we have found that allele 10* (10 imperfect repeats) shows a remarkable dominant and beneficial effect that reduces the log hazard of death in an additive manner. The results confirm that HUMTHO1.STR polymorphism is involved in the modulation of human longevity.

Adolescent↗
PubMed2003

Longevity-associated mitochondrial DNA 5178 A/C polymorphism influences effects of cigarette smoking on serum protein fraction levels in Japanese men.

Mitochondrial DNA 5178 adenine/cytosine (mt5178 A/C) polymorphism is reportedly associated with longevity and susceptibility to age-related diseases in Japanese individuals. We previously reported an association between mt5178 A/C polymorphism and serum protein fraction levels in healthy Japanese women. An association between habitual smoking and serum protein fraction levels has also been reported previously. The aim of this study was to examine whether mt5178 A/C polymorphism influenced the effects of habitual smoking on serum protein fraction levels in 321 healthy Japanese men. In mt5178C genotype men, alpha-1 and alpha-2 globulin levels were higher in smokers than in nonsmokers (P<0.001, and P=0.002, respectively). The influence of smoking on these globulin levels depended on cigarette consumption. However, in mt5178A genotype men, no significant difference was observed in alpha-1 or alpha-2 globulin levels between smokers and nonsmokers. These results suggest that longevity-associated mt5178 A/C polymorphism may influence the effects of cigarette smoking on serum protein fraction levels in healthy Japanese men.

Aging↗
PubMed1997

Molecular genetic approaches to the genes of longevity, aging and neurodegeneration in mammals.

Accumulative evidence suggests that species life-span is determined, at least in part, genetically. Recent cloning works using yeast (Saccharomyces cerevisiae) and worms (Caenorhabditis elegans) revealed several potential candidate genes, e.g. SIR4, a transcriptional silencing factor, and age-1, a putative signal transduction molecule, respectively, that may be involved in determining and/or regulating species life-span in lower organisms. It is, however, not clear yet whether mammalian homologs of these genes are also relevant to controlling longevity in higher organisms. In mice and humans several silencing factors are essential for cell-type specific gene expression. A variety of signal transducing molecules are also known to play important roles in mammals. I will briefly summarize recent progress in molecular genetic studies on such longevity-related genes, and discuss these results with our recent findings on a neural-selective silencing factor and a neural-specific signaling molecule that are important for functioning of the nervous system.

Aging↗
PubMed1998

Apolipoprotein E and longevity among Han Chinese population.

The apolipoprotein E gene (APOE), which locates on chromosome 19, has three common APOE alleles encoding APOE*2, APOE*3, APOE*4. It has been considered to be closely associated with human longevity among Western population. However, the allele frequency varies among racial and ethnic groups. We studied the relationship between APOE and longevity among 1562 Han Chinese (246 female and 1316 male) whose ages ranged from 20-108 years old in Shanghai metropolitan area and Lian Yungang, Jiangsu province. APOE was amplified by one-stage PCR using the forward primer: 5'-GGC ACG GCT GTC CAA GGA GCT-3' and reverse primer: 5'-GAT GGC GCT GAG GCC GCG CT-3'. The PCR product was digested directly with 5 U of CfoI and separated by a 20% polyacrylamide (acrylamide:bisacrylamide = 29:1) nondenaturing gel. The allele frequency of APOE*4 in thevery old age group (> or = 85 years) was significantly different from that in the youth (20-39 years), middle (40-59 years) and old (60-84 years) age group (2.5% vs 8.4, 7.9 or 7.6%; P < 0.05), respectively.

Adult↗
PubMed1999

Human longevity: an evolutionary approach.

Humans are unique in having a considerably longer life span post female reproductive age as compared to other primates. It is proposed that transmission of knowledge from grandparents to progeny served as a driving force for extending human longevity. It is suggested that grandparents and grandchildren have evolved adaptive complementary behaviors that fit the educator/pupil roles. Older individuals specifically retain the ability to preserve their knowledge base that allows them to focus on transmitting to children knowledge accumulated over generations. A repair management model of aging is proposed, according to which inhibition of repair in older individuals at times of stress allows to focus resources on the task at hand. Such an adaptation will inevitably accelerate the rate of aging in animals and in humans and will appear as 'programmed aging'. It is further suggested that in humans, older individuals in early societies who are no longer useful could increase their reproductive success by activating this programmed aging mechanism, which would result in channeling resources to progeny. Decreased emotional support and mastery are mortality risk factors in the elderly, supporting this hypothesis of programmed death in humans, and providing a rationale for increasing longevity.

Aged↗
PubMedDate not supplied

P13-kinase inhibition induces dauer formation, thermotolerance and longevity in C. elegans.

The effects of 2-(4-Morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002), an inhibitor of mammalian phosphatidylinositol 3-OH kinase, was tested on an insulin signaling-like pathway in the nematode Caenorhabditis elegans. Populations of C. elegans were treated with LY294002 at different stages of the life cycle, and its effects on development, thermotolerance and longevity were assessed. At concentrations of 160 microM and above, LY294002 significantly induced both dauer formation and thermotolerance. Treatment of adult worms also resulted in a small, but significant, increase in life span. The results presented are consistent with the view that a neuroendocrine signaling pathway functions in adult worms to determine stress resistance and longevity.

Animals↗
PubMed2003

Longevity after early surgical menopause-the long-term effect of a permanent cessation of reproductive function and female sex hormone loss.

OBJECTIVE: To investigate longevity in women after bilateral salpingo-oophorectomy (BSOE), not given hormonal replacement therapy (HRT) post-operatively, as compared to the national mean. STUDY DESIGN: Long-term follow-up study of a historical cohort of young women undergoing BSOE in the early 20th century at the General Hospital, Malmö, Sweden. Comparison was made with mean life expectancy in corresponding birth cohorts. RESULTS: No difference in life expectancy was recorded in 152 women with an early menopause caused by BSOE and not substituted with HRT, as compared to national statistics of contemporary women. Half of the operated women died of cardiovascular disease and a minority of cancer, none of which was a breast cancer. CONCLUSION: Permanent loss of female sex hormones and reproductive function in early life does not seem to influence longevity but may change patterns of morbidity and mortality.

Adult↗
PubMed2002

An allele of HRAS1 3'variable number of tandem repeats is a frailty allele: implication for an evolutionarily-conserved pathway involved in longevity.

The human HRAS1 belongs to an evolutionarily-conserved family of genes which enrolls among its members the yeast RAS2, a gene which regulates stress response and longevity in the Saccharomyces cerevisiae. In this paper we report that the frequency of the a3 allele of HRAS1 3'variable number tandem repeat (HRAS1 3'VNTR) decreases in centenarians in respect to young people, and we estimate that during aging a3 carriers have a relative mortality risk of 1.126 (95% CI=1.044-1.213). We propose that the germ-line variability at the HRAS1 locus impacts on the individual's capacity to reach the extreme limits of human life-span. Furthermore, we provide suggestive evidence that a3 HRAS1 3'VNTR allele and inherited variants of the mitochondrial genome (mtDNA haplogroups) do not affect independently human longevity, thus recalling the nucleus-mitochondrion interaction which regulates stress response and life-span in the yeast.

Adult↗
PubMed2000

Identical longevity phenotypes are characterized by different patterns of gene expression and oxidative damage.

Some years ago we applied simultaneously an identical regime of selection for late-life reproduction to several normal-lived sister lines (Ra and Rb) so as to produce several selected long-lived sister lines (La and Lb). The long-lived La and Lb sister lines had statistically identical longevity phenotypes and paraquat resistance phenotypes; however, we noticed some statistically different responses of the two strains at the biochemical level. Extensive work with the La strain showed that transcriptional alterations in antioxidant gene expression are robustly associated with its extended longevity. We decided to critically test the assumption of phenotypic equivalence by subjecting the Lb strain to the same series of molecular assays as was the La strain. The two sister strains are characterized by significantly different mechanisms and patterns of antioxidant gene expression, antioxidant enzyme activity, and oxidative damage. We find that the Lb strain appears to depend on the transcriptional activation of different genes than does the La strain, and on a post-translational up-regulation of at least one other antioxidant defense gene. The phenotypic equivalence observed at the organism level need not hold at the molecular genetic level. This finding suggests that there is more than one molecular mechanism by which antioxidant defense genes can bring about an increased resistance to oxidative stress. The theoretical and empirical implications of these findings are discussed.

Animals↗
PubMed2001

Age and longevity in fish, with consideration of the ferox trout.

In the first part of this paper, we review the evolutionary aspects of age and longevity in fish and then summarize the theory of maturity due to Ray Beverton. This theory allows one to predict age at maturity (and thus a putative point for the onset of senescence) from information on growth rate and mortality rate. We illustrate the application of this theory with data on tilapia species and then discuss the limitations of the theory. In the second part of the paper, we develop an individual based model for the ferox trout. This is a morph of brown trout Salmo salar that is an exception to the common notion that caloric restriction extends lifespan, in the sense that ferox trout achieve long life by eating more, not less. The model allows one to identify the role that ecological and biochemical adaptations play in the longevity of the ferox trout.

Age Factors↗
PubMedDate not supplied

The Sam and Ann Barshop Center for Longevity and Aging Studies: the University of Texas Health Science Center at San Antonio.

The Sam and Ann Barshop Center for Longevity and Aging Studies is a focal point for advanced research designed exclusively to study the genes involved in aging and the diseases of aging. The research performed at the Barshop Center is based on a solid foundation of nearly twenty-five years of aging research at The University of Texas Health Science Center at San Antonio. Internationally recognized scientists in aging are now leading innovative research programs using state-of-the-art technologies in molecular and cellular biology to explore aging processes at the gene level in the four major programs that comprise the research at the Barshop Center: the Cellular Aging Program, the Invertebrate Aging Program, the Rodent Models of Aging Program, and the Human Genetics of Aging Program. The researchers involved in these programs share a common purpose in an atmosphere of collaboration to gain the scientific insights necessary to understand the molecular basis of aging. Their long-term goal is to gain the knowledge that will give rise to the development of interventions that retard or arrest the debilitating conditions associated with aging. February or March 2003 marks the groundbreaking for the first building of Barshop Center's new stand-alone facility. This is the initial step toward a $70 million, world-class research complex dedicated to the study of aging and healthy longevity.

Academic Medical Centers↗
PubMed2003

Longevity-associated mitochondrial DNA 5178 A/C polymorphism modulates effects of daily drinking and cigarette consumption on serum triglyceride levels in middle-aged Japanese men.

Mitochondrial DNA 5178 adenine/cytosine (mt5178 A/C) polymorphism is one of the longevity-associated mitochondrial DNA polymorphisms. The frequency of the mt5178A genotype is significantly higher in Japanese centenarians than in the general population. We previously reported that serum high-density lipoprotein cholesterol levels were significantly higher in men with mt5178A than in those with mt5178C. However, this significant difference disappeared after adjusting for drinking frequency. To investigate the interaction between mt5178 A/C polymorphism and habitual drinking on serum lipid levels, we performed an association study in 321 healthy middle-aged Japanese men. Interaction between mt5178 A/C polymorphism and daily drinking on serum triglyceride (TG) levels was observed (P=0.019). Moreover, interaction between mt5178 A/C polymorphism and cigarette consumption on serum TG levels was also observed (P=0.022). Multiple regression analysis showed that, in men with mt5178A, daily drinking decreased TG levels (P=0.025), and cigarette consumption increased TG levels (P<0.001), while in men with mt5178C, the effects of daily drinking and cigarette consumption on TG levels were unclear. No interaction was observed on other lipid levels. Longevity-associated mitochondrial DNA 5178 A/C polymorphism thus influences the effects of daily drinking and cigarette consumption on TG levels in middle-aged Japanese men.

Alcohol Drinking↗