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PubMed2000

Common gene variants, mortality and extreme longevity in humans.

Genetic factors influence variation in human life span. The fast technological advancements in genome research and the methodology for statistical analysis of complex traits provided new tools to unravel these genetic influences. Most of the genetic epidemiology and quantitative genetics is focused on the dissection of the genetic component of specific diseases rather than of human life span. Nevertheless, common variants of 22 genes have been tested for their contribution to mortality in the general population and extreme longevity in one or more studies. These studies provide indications as to the nature of biological pathways that might play a role in human ageing. Perhaps even more important at this time is the fact that they give valuable insights in the strengths and weaknesses of current strategies to identify gene variants affecting human life span and point at more powerful approaches.

Apolipoproteins E↗
PubMed2001

Prolonged longevity of hypopituitary dwarf mice.

In two types of mutant dwarf mice, congenital deficiencies in pituitary function are associated with remarkably increased life expectancy. In this review, we will describe the key phenotypic characteristics of these animals, the evidence that they exhibit delayed aging, and the mechanisms that are suspected to account for their prolonged longevity.

Aging↗
PubMed2001

The paradox of great longevity in a short-lived tree species.

Thuja occidentalis is a tree species that was once thought to be relatively short-lived (80 years). Up until 10 years ago maximum ages were considered to be near 400 years, but such trees were thought to be rare. Research along the cliffs of the Niagara Escarpment has altered this view. Exceptionally slow-growing trees of this species have been found with ring counts to 1653 years and estimated ages to 1890 years. Senescence is slow or absent. Injury and death is due to rockfall and sporadic severe drought that kills small sectors of the trees by exposing and killing the roots. Experiments in which colored dyes are infused into roots show that each tree is composed of hydraulically independent units that allow mortality in one part of the 'individual' with little negative effect on the remaining parts of the tree. The trees are small, so environmental loadings of ice, snow, and wind are low. Slow growth of the trees results in a much greater mechanical strength in the wood. Together these properties increase the ability of the cedars to persist on cliffs for long periods of time. The paradox of great longevity in this 'short-lived' tree species is explained by slow growth that minimizes maintenance and repair costs while maximizing durability and strength, combined with an internal architecture that creates functionally independent units within each tree.

Aging↗
PubMed2001

Relationship between increased longevity and stress resistance as assessed through gerontogene mutations in Caenorhabditis elegans.

We review the status of the hypothesis that interventions that increase the resistance to stress offer the potential for effective life prolongation and increased health. The work focuses on research in the nematode worm Caenorhabditis elegans and describes both published and unpublished results consistent with this hypothesis. Correlation between stress resistance and longevity among many gerontogene mutants is provided.

Aging↗
PubMed2001

Low insulin resistance and preserved beta-cell function contribute to human longevity but are not associated with TH-INS genes.

Tyrosine Hydroxylase (TH) and Insulin (INS) genes lie extremely close in the 11p15.5 chromosomal region. An STR marker of the TH gene had revealed this locus associated with longevity. Thus, it seemed of interest to investigate the association between the TH-STR and INS gene variability (FokI-RFLP) with a phenotypic trait, such as the degree of insulin resistance (IR) and beta-cell function in centenarians (C). We analyzed age-related trajectories of IR and beta-cell function in a large sample (n=466) of individuals whose age ranged from 28 to more than 100 years; furthermore, allele average effects on IR and beta-cell function relevant to TH-STR and INS-FokI polymorphisms were estimated in C. Both IR and beta-cell function increased with advancing age and declined in subjects older than 90 years (p for trend <0.001). C had lower IR (1.5+/-0.7 vs. 3.9+/-1.7, p<0.001) and beta-cell function (26.1+/-8.5 vs. 55.4+/-16, p<0.001) than nC. In nC, but not in C, IR and beta-cell function correlated with the main anthropometric and metabolic confounders. Nevertheless, significant allele average effects by TH-STR and INS-FokI polymorphisms on IR and beta-cell function were not observed in C. In conclusion, C has a lower degree of IR and a preserved beta-cell function in comparison to nC, but the cause of such metabolic differences, which are likely does not lie in this genomic region.

Adult↗
PubMed2002

Association of the longevity-associated mitochondrial DNA 5178 A/C polymorphism with serum protein fraction levels in healthy Japanese women.

Mitochondrial DNA 5178 adenine/cytosine (mt5178 A/C) polymorphism was reported to be associated with longevity and susceptibility to adult-onset diseases in Japanese. To examine whether mt5178 A/C genotypes are associated with serum protein fraction profiles, we genotyped 461 healthy Japanese individuals, and studied the relationship of mt5178 A/C genotypes to both proportion and levels of serum protein fraction. The mt5178 A/C was genotyped using polymerase chain reaction-restriction fragment length polymorphism method. The alpha-1, alpha-2, and beta globulin proportions in females carrying mt5178A were significantly higher than those in females carrying mt5178C (P=0.002, 0.006, and 0.008, respectively). Moreover, the alpha-1, alpha-2, and beta globulin levels in females carrying mt5178A were significantly higher than those in females carrying mt5178C (P=0.001, 0.002, 0.018, respectively). This difference in globulin fraction level between the two genotypes was more evident in premenopausal females than in postmenopausal females. However, no such difference was found in males. These results provide the first evidence that the mt5178 A/C polymorphism may influence the serum protein fraction levels of the healthy Japanese women.

Adult↗
PubMed2003

Increased circulating Interleukin-18 levels in centenarians with no signs of vascular disease: another paradox of longevity?

Interleukin (IL)-18 is highly expressed in macrophages from human atherosclerotic plaques, suggesting its involvement in ischemic syndromes. We evaluated IL-18 and IL-18 binding protein (BP) in healthy centenarians, as longevity is characterized by a reduced incidence of ischemic events. For comparison, patients with chronic ischemic syndromes (CIS) were evaluated. Serum IL-18 and IL-18BP levels were measured by non-cross-reacting ELISA in 16 healthy centenarians and in two age-control populations, each of 18 healthy individuals aged 55.9+/-1.43 and 74.3+/-1.35, respectively, as well as in 23 CIS patients, and another cohort of 23 healthy subjects that were age- and sex-matched with CIS patients. Centenarians displayed significantly higher total IL-18 serum levels compared to each control group. Elevated IL-18 levels were also present in CIS patients. However, centenarians had a significant higher level of IL-18BP compared to the cohort of 23 controls (P=0.0014), and compared to CIS patients (P=0.043); as a result centenarians exhibited a lower level of free IL-18 than CIS patients. The present results indicate that quenching of IL-18 by IL-18BP may explain the apparent paradox of elevated serum IL-18 with no vascular signs in centenarians.

Aged↗
PubMed2003

Genetics of exceptional longevity.

Centenarians exist at the extreme of life expectancy and are rare. A number of pedigree and molecular genetic studies indicate that a significant component of exceptional longevity is genetically influenced. Furthermore, the recent discovery of a genetic locus on chromosome 4 indicates the powerful potential of studying centenarians for genetic factors that significantly modulate aging and susceptibility to age-related diseases. These studies include siblings and children of centenarians. Siblings have a significantly increased propensity to achieve exceptional old age and have half the mortality risk of their birth cohort from young adulthood through extreme old age. The children of centenarians are emerging as a promising model for the genetic and phenotypic study of aging relatively slowly and the delay and perhaps escape of important age-related diseases.

Aged↗
PubMed2003

Is turtle longevity linked to enhanced mechanisms for surviving brain anoxia and reoxygenation?

We suggest that the processes that protect the turtle brain against anoxia and subsequent reoxygenation might also contribute to turtle longevity since many of them are linked to age related neurodegeneration. In the turtle the mechanisms for conserving ion channel function are particularly robust. The anoxic turtle brain avoids excitatory neurotransmitter toxicity by maintaining a balance between dopamine and glutamate-release and still active uptake mechanisms. In the anoxic turtle brain the inhibitory tone is strengthened through a sustained rise in extracellular GABA, and a corresponding increase in the density of GABA(A) receptors. The turtle has enhanced mechanisms that protect against the formation of ROS and mechanisms to protect from ROS damage. As many of these may be selectively activated during anoxia and recovery, the turtle could serve as a useful model to identify and investigate mechanisms for activating key protection and rescue mechanisms implicated in aging.

Adaptation, Physiological↗
PubMedDate not supplied

Sexual performance and longevity.

Sexually inactive ("low-performing," LP) and highly active ("high-performing," HP) rats were selected from a sexually inexperienced population. Saline control LP rats (n = 44) lived 134.58 +/- 2.29 weeks, their HP peers (n = 49) lived 151.24 +/- 1.36 weeks. Life-long treatment with 0.25 mg/kg (-)deprenyl, a selective inhibitor of MAO-B that also stimulates action potential-transmitter release coupling in the catecholaminergic neurons in the brain (catecholaminergic activity enhancer, CAE, effect), enhanced the sexual and learning performance of both LP and HP rats and prolonged their life. LP rats (n = 48) treated with (-)deprenyl lived 152.54 +/- 1.36 weeks and HP rats on (-)deprenyl (n = 50) lived 185.30 +/- 1.96 weeks. As an indicator of the basic activity of catecholaminergic neurons, the resting release of dopamine from the striatum, substantia nigra, and tuberculum olfactorium, and of norepinephrine from the locus coeruleus, was measured in 2-, 4-, 8-, 16-, and 32-week-old male and female rats. The release of transmitters between weaning and the second month of age, i.e., during the crucial developmental phase of life, was significantly higher than either before or after that period, indicating that a CAE mechanism starts working with high intensity after weaning, lasts until the completion of full scale sexual development, and shows an unparalleled decay thereafter. It was concluded that the CAE regulation in the brain, stimulated by (-)deprenyl, controls general activity and consequently the longevity of rats.

Animals↗
PubMedDate not supplied

Genetics of longevity.

Recent studies on the genetics of aging in the yeast Saccharomyces cerevisiae, the roundworm Caenorhabditis elegans, and the fruit fly Drosophila melanogaster have converged revealing the central role of metabolic capacity and resistance to stress in determining life span. Signal transduction has emerged from these studies as an important molecular mechanism underlying longevity. In their broad features, the results obtained in these genetic models are applicable to the dietary restriction paradigm in mammals, suggesting a general significance. It will be of interest to determine whether many of the molecular details will also pertain. The examination of centenarian populations for the frequency of certain alleles of pertinent genes may provide insights into the relevance of the conclusions of studies in invertebrates to human aging. These population genetic studies can be augmented by mechanistic studies in transgenic mice.

Animals↗
PubMed1999

A review of the effects of microgravity and of hypergravity on aging and longevity.

This article reviews the literature dealing with the effects of acute or chronic exposure to microgravity (spacecrafts) or hypergravity (centrifuge) on longevity and the aging process. Even if space flights are now common, the effects of these two kinds of environment on aging are still poorly documented, particularly in mammals. However, there is a growing interest for the use of the fruit fly Drosophila melanogaster, and this species may be now considered as a model organism in gravitational biology studies dealing with aging.

Aging↗
PubMed1999

Investigation of the endocrine system in extended longevity lines of Drosophila melanogaster.

There is a complete absence of information about the endocrinology of Drosophila melanogaster in relation to genetic-based differential longevity in this model species. In the present study, aspects of the endocrine system of D. melanogaster were investigated in selected and control lines characterized by relative differences in life span. By using extracts from whole bodies, steroid hormone (ecdysteroid) titers were determined by radioimmunoassay in all replicate selected and control lines on the first and fourth day of adult life. The results suggest that ecdysteroid titers were relatively reduced on the first day post-eclosion in females from the long-lived lines, but this difference was not present on the fourth day posteclosion. The reduction in early-age ecdysteroid titers in long-lived females might be related to the decrease in early-age fecundity in the selected lines. There was no difference between line types in male ecdysteroid titers on either day post-eclosion. Two classes of enzymes that act on juvenile hormone were also investigated in the present study. Esterase and epoxide hydrolase activity on juvenile hormone was assessed in females in all replicate selected and control lines at approximately 12 h or 4 days post-eclosion. There was no difference between selected and control lines in the specific activity of either class of enzymes that metabolize juvenile hormone.

Animals↗
PubMed2005

[Is caloric restriction a means of delaying ageing and increasing longevity?].

Calorie restriction increases longevity in rodents, delays the onset of certain diseases and has positive effects on ageing. Studies are ongoing in non-human primates. Eight persons following such a diet for 2 years reacted as anticipated (loss of body weight and fat, decrease in glycaemia and body temperature, etc.). Calorie restriction perhaps teaches us more on the means of resisting malnutrition than on ageing in normal dietary conditions. Calorie restriction is a tool for research, but it should not be recommended by practitioners, notably in elderly patients.

Aged↗
PubMed2001

A study of French centenarians: are ACE and APOE associated with longevity?

Association study is the method of choice to identify genes involved in complex processes that result from the interaction of environmental and genetic factors. However, because of biases that increase the risk of false positive reports, preliminary positive conclusions have to be reproduced on other populations to be validated as firm conclusions. In 1994, certain alleles of two genes, APOE (Apolipoprotein E) and ACE (angiotensin converting enzyme), were reported to be more frequent in French centenarians, suggesting an association with such a complex polyfactorial process as longevity. Enlargement of the French centenarian cohort allows a new assessment of this hypothesis on 563 centenarians. In contrast to APOE, the ACE association was not confirmed. Retrospective analysis of the initial study revealed discrepancies that may in part explain this observation. Risk of reporting false positive associations is discussed and recommendations to set up a rigorous experimental design are proposed.

Aged↗
PubMed2000

Plasma antioxidants and longevity: a study on healthy centenarians.

A large body of experimental research indicates that oxidative stress contributes to the processes related to aging and to the pathogenesis of several age-related diseases. Vitamins and antioxidant enzymes have a fundamental role in defending the organism from oxidative stress. To better understand the role of antioxidants in human aging, we measured plasma levels of vitamin C (ascorbic acid), uric acid, vitamin E (alpha-tocopherol), vitamin A (retinol), carotenoids, total thiol groups, and the activity of plasma superoxide dismutase (SOD) and glutathione peroxidase (GPX) as well as the activity of red blood cell (RBC) SOD in 32 healthy centenarians-17 elderly subjects aged 80-99 years, 34 elderly subjects aged 60-79 years, and 24 adults aged less than 60 years. Considering the "noncentenarians" only, we observed a consistent behavior in the antioxidant pattern, with a decrease of the nonenzymatic antioxidants and an increase of the enzymatic antioxidant activities relative to age. Remarkably, centenarians were characterized as having the highest levels of vitamins A and E, whereas the activities of both plasma and RBC SOD, which increase with age, decreased in centenarians. From these results, it is evident that healthy centenarians show a particular profile in which high levels of vitamin A and vitamin E seem to be important in guaranteeing their extreme longevity.

Aged↗
PubMed2003

Ectopic expression of catalase in Drosophila mitochondria increases stress resistance but not longevity.

The goal of this study was to test the hypothesis that the rate of mitochondrial oxidant production governs the aging process of the fruit fly, Drosophila melanogaster. Catalase, an antioxidative enzyme expressed in the cytosol and peroxisomes of Drosophila, was targetted ectopically to the mitochondrial matrix by fusion of a leader peptide derived from ornithine aminotransferase with its N-terminus. The presence of the transgene encoding this fusion protein was associated with moderate (35 +/- 13%) increases in total catalase activity in most lines, and measurable levels of catalase activity in the mitochondria (30-140 U/mg protein). There was no impact on the life span of the flies at 25 degrees C, even in an exceptional line with a 149% increase in total catalase activity, and there was a small decrease in longevity at 29 degrees C. There were no compensatory changes in the rate of metabolism or physical activity, or in the levels of other major antioxidants, suggesting that the aging process was largely unaffected. Resistance to exogenous hydrogen peroxide, paraquat, and cold stress was enhanced, but there was no appreciable effect on resistance to hyperoxia. The results demonstrate the importance of mitochondrial antioxidant levels in the resistance to oxidative stress at the organismal level, and illustrate that different effects on aging and stress resistance may ensue from a single treatment. The main inferences drawn are that: (i) levels of stress resistance may neither be a cause nor a reliable indicator of the rate of aging, and (ii) bolstering antioxidant levels in Drosophila may not delay or slow down the aging process.

Animals↗
PubMed2000

Effects of chronic kombucha ingestion on open-field behaviors, longevity, appetitive behaviors, and organs in c57-bl/6 mice: a pilot study.

Kombucha is a lightly fermented tea beverage popularly consumed as a self-prescribed folk-remedy for numerous ailments. Kombucha is claimed to enhance cognition, aid weight loss, and prolong life. This pilot study reports longevity, general health, and open-field exploratory behavioral outcomes from a 3-y longitudinal study of 64 C57-BL/6 mice (males and females), half of which chronically drank kombucha, and all of which experienced natural mortality. Compared by MANOVA to controls, mice that drank kombucha showed greater vertical exploration (P = 0.001) and a sex-interactive effect in novel object manipulation (P = 0.049). MANOVA of kombucha-drinking mice compared to controls detected differences in appetitive behaviors (food consumption, P < 0.001; beverage consumption, P = 0. 008), and gross body weight (P < 0.001). Appetitive behaviors changed with the addition of voluntary exercise on a running wheel, with differing patterns of change noted for males and females. Both male and female mice who drank kombucha lived longer than controls (P < 0.001), with the greatest variability among the male mice (sex interactive effect, P < 0.001). Comparable effects and mechanisms in humans remain uncertain, as do health safety issues, because serious health problems and fatalities have been reported and attributed to drinking kombucha.

Animals↗