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PubMed2006

Biology of longevity: role of the innate immune system.

Genetic factors play a relevant role in the attainment of longevity because they are involved in cell maintenance systems, including the immune system. In fact, longevity may be correlated with optimal functioning of clonotypic and natural immunity. The aging of the immune system, known as immunosenescence, is the consequence of the continuous attrition caused by chronic antigenic overload. The antigenic load results in the progressive generation of inflammatory responses involved in age-related diseases. Most of the parameters influencing immunosenescence appear to be under genetic control, and immunosenescence fits with the basic assumptions of evolutionary theories of aging, such as antagonistic pleiotropy. In fact, by neutralizing infectious agents the immune system plays a beneficial role until reproduction and parenting. However, by determining chronic inflammation, it can be detrimental later in life, a period largely unforeseen by evolution. In particular, the data coming from the long-lived male population under study show that genetic polymorphisms responsible for a low inflammatory response might result in an increased chance of long lifespan in an environment with a reduced pathogen burden. Such a modern and healthy environment also permits a lower grade of survivable atherogenic inflammatory response.

Aged, 80 and over↗
PubMed1997

Longevity in obese and lean male and female rats of the Zucker strain: prevention of hyperphagia.

Zucker obese (fa/fa) and lean (Fa/Fa) rats were fed a soy protein diet ad libitum under barrier conditions from 4 wk of age until death. Obese rats were also pair fed with lean controls to prevent hyperphagia. Time of death was determined and tissues collected at necropsy for histologic examination. Lean rats had longer 10th percentile survivorship (males 966 compared with 667 d, females 983 compared with 620 d) and maximum life spans (males 1067 compared with 803 d, females 1163 compared with 744 d) than did obese rats. Preventing hyperphagia increased maximum life span in both males (1010 d) and females (975 d). Pathologies in lean rats were similar to those reported for other rodent strains. For obese rats fed ad libitum, end-stage renal disease (ESRD) was the major cause of mortality (males: 91.1%, females: 93.3%). Prevention of hyperphagia decreased deaths attributable to ESRD (males: 64.4%, females: 51.1%). A smaller restriction in energy intake (8-18%) required to prevent hyperphagia compared with the 35-40% in most other studies produced similar increases in longevity, suggesting that obese Zucker rats are particularly sensitive to energy restriction. Amelioration of early onset of renal disease is a likely explanation. Percentage body fat in food-restricted obese rats did not differ from that of animals fed ad libitum; thus, reduced longevity is not the result of obesity per se, but rather is influenced by other metabolic pathologies occurring in this strain of rats homozygous for the fa gene. Because microalbuminuria with progression to ESRD is a complication in human obesity, the Zucker strain offers the opportunity to investigate initiating mechanisms of this pathology.

Aging↗
PubMed1988

Murine chromosomal regions correlated with longevity.

In this longevity analysis of 360 BXD recombinant inbred female mice (20 different strains), 2 strains had very significantly shorter survival and 1 strain had very significantly longer survival than the other 17 strains; 4 other strains had less significant lengthening of survival compared to the other 13 strains in a proportional hazards model of survival. Mean survival on the shortest lived strain was 479 days; on the longest lived strain the mean survival was almost double (904 days). Ranges of survival within strain were very large (averaging 642 days), and strain accounted for only 29% of the variation in survival, showing that there are important environmental and/or special developmental effects on longevity even in this colony housed in a single room. Each strain had been typed for markers of 141 regions on 15 chromosomes; 101 of these markers had distinguishable distributions on the 20 strains. The two shortest lived strains had the same alleles for 63% of the markers. The single region most significantly correlated with survival (marked by P450, Coh, Xmmv-35 on chromosome 7) divided the mice into two groups with survival medians which differed by 153 days (755 days for mice with a B genotype; 602 days for mice with a D genotype). Evaluated individually, 44% of the genetic markers (including some markers on 11 of 15 chromosomes with any markers typed) were found to be significantly correlated with survival (P less than 0.05) although one would only expect 5% of the markers to be significant by chance. While studies of many markers should adjust for the multiple comparisons problem, one interpretation of these crude P values is that any experiment with only one of these "significant" markers typed would be likely to conclude that the marker was a significant predictor of survival. Two types of multiple regression models were used to examine the correlation with survival of groups of genes. When a proportional hazards model for survival was done in terms of genotype regions, a six genetic region model best correlated with survival: that marked by P450, Coh, Xmmv-35 on chromosome 7 (B allele lives longer), Ly-24 on chromosome 2 (B allele lives longer), beta 2M and H-3 on chromosome 2 (D allele lives longer) Lamb-2 on chromosome 1 (D allele lives longer), Ltw-4 on chromosome 1 (B allele lives longer), and the Igh area of chromosome 12 (Igh-Sa4, Igh-Sa2, Igh-Bgl, Igh-Nbp, Igh-Npid, Igh-Gte, Odc-8, and Ox-1; D allele lives longer).(ABSTRACT TRUNCATED AT 400 WORDS)

Alleles↗
PubMed1998

An insulin-like signaling pathway affects both longevity and reproduction in Caenorhabditis elegans.

Mutations in daf-2 and age-1 cause a dramatic increase in longevity as well as developmental arrest at the dauer diapause stage in Caenorhabditis elegans. daf-2 and age-1 encode components of an insulin-like signaling pathway. Both daf-2 and age-1 act at a similar point in the genetic epistasis pathway for dauer arrest and longevity and regulate the activity of the daf-16 gene. Mutations in daf-16 cause a dauer-defective phenotype and are epistatic to the diapause arrest and life span extension phenotypes of daf-2 and age-1 mutants. Here we show that mutations in this pathway also affect fertility and embryonic development. Weak daf-2 alleles, and maternally rescued age-1 alleles that cause life span extension but do not arrest at the dauer stage, also reduce fertility and viability. We find that age-1(hx546) has reduced both maternal and zygotic age-1 activity. daf-16 mutations suppress all of the daf-2 and age-1 phenotypes, including dauer arrest, life span extension, reduced fertility, and viability defects. These data show that insulin signaling, mediated by DAF-2 through the AGE-1 phosphatidylinositol-3-OH kinase, regulates reproduction and embryonic development, as well as dauer diapause and life span, and that DAF-16 transduces these signals. The regulation of fertility, life span, and metabolism by an insulin-like signaling pathway is similar to the endocrine regulation of metabolism and fertility by mammalian insulin signaling.

Animals↗
PubMed1996

Failure to confirm increased longevity in Drosophila melanogaster submitted to a food restriction procedure.

Several studies have shown that, contrary to what occurs in rodents and in some invertebrate species, food restriction has no positive effect on longevity in Drosophila melanogaster. However, Chippindale et al. (1993) reported that flies subjected to food restriction, by modulating the yeast level, could live longer. In the present study we used the same yeast levels as Chippindale et al. in an attempt to confirm these results. No positive effect of food restriction on longevity could be observed in either sex in mated and virgin flies.

Agar↗
PubMed1997

Transgenic mice overexpressing urokinase-type plasminogen activator in the brain exhibit reduced food consumption, body weight and size, and increased longevity.

Transgenic mice designated alpha MUPA overproduce in many brain sites the urokinase-type plasminogen activator (uPA), a protease implicated in fibrinolysis and extracellular proteolysis. Here we report that, compared to their parental wild-type control, alpha MUPA mice spontaneously consumed less food (approximately 20%), exhibited reduced body weight (approximately 20%) and length (approximately 6%), and also prolonged life span (approximately 20%). The alpha MUPA phenotype is thus reminiscent of experimental animals in which dietary restriction enhances longevity. Reduced eating and body weight were observed in alpha MUPA mice shortly after weaning, and these levels were maintained virtually throughout their lifetime. alpha MUPA mice also exhibited lower levels of blood sugar (approximately 9%), smaller litter size (approximately 14%), and lower birth frequency (approximately 10%). In the adult alpha MUPA brain, uPA mRNA has been localized through in situ hybridization also in neuronal cells of the hypothalamic paraventricular nucleus, a region implicated in feeding behavior. No signals of uPA mRNA could be detected in the paraventricular nucleus of control mice. It is suggested that in alpha MUPA mice, overproduction of uPA in brain sites controlling feeding leads to reduced food consumption that, in turn, results in retardation of growth and body weight and also in increased longevity. The alpha MUPA experimental model may have implications for normal mice.

Animals↗
PubMed1997

Comparative longevity of pet dogs and humans: implications for gerontology research.

The effect of breed and body weight on longevity in the pet dog was analyzed, and a method was developed to standardize the chronological age of dogs in terms of physiological time, using human year equivalents. Mortality data from 23,535 pet dogs were obtained from a computerized data base of North American veterinary teaching hospitals, and the median age at death was determined for pure and mixed breed dogs of different body weight. Body size in the dog was inversely related to longevity. Within each body weight category, the median age at death was lower for pure breed dogs compared with mixed breed dogs. The difference between the standardized physiological ages of mixed breed dogs of the same chronological age in the smallest and largest body weight categories varied from 8 to > 15 years, and between large and small pure breed dogs, the disparity was even greater. Laboratory research to explore the biological basis for these breed and body weight specific differences in life span among dogs may provide additional clues to genetic factors influencing senescence.

Aging↗
PubMed1998

Selection for longevity confers resistance to low-temperature stress in Drosophila melanogaster.

One theory of the evolution of longevity says that improvement in life span is dependent on an increased ability to resist environmental stresses of all kind. Selective breeding of Drosophila melanogaster populations for longevity has demonstrably increased life span and also altered a number of other traits, such as resistance to starvation, desiccation, and ethanol fumes, and the ability to sustain longer flight. While the exact physiologic basis of some of these traits is not yet fully understood, at least some are known to derive from the properties of metabolic substrates of glycolysis. Improvement in those characters can depend partially, therefore, on altered stores of metabolites created from glycogen. Based on the known general relationship of some traits and the suspected basis in metabolism of others, we examine the possibility here that increased life span is accompanied by other traits that also confer physiologic resistance to stress. Specifically, we test the prediction that long-lived populations of fruit flies should be more resistant to low (prefreezing) and freezing temperature extremes. Both selected and control populations were found to be susceptible to prefreezing (1.5 degrees C) and freezing temperatures (0 degree C) here, but adults and pupae of the long-lived populations generally survived better in both situations, and at all durations of exposure. The resistance of individuals improved with acclimatization, but was superior in the long-lived populations whether thermal decline was rapid or stepwise. Cold resistant, long-lived populations also had significantly higher in vitro levels of glycerol, a cryoprotectant metabolite produced from glycogen. However, while adults and pupae of long-lived stocks were more resistant to cold, larvae of those stocks were more sensitive and survived relatively poorly at every length of exposure and acclimation. This surprising result implies that larvae maintain lower levels of cryoprotectant substances. Upon becoming pupae, however, stage-specific capabilities for environmental resistance and long life emerge. This conclusion agrees with a prior study of these stocks indicating that the uptake and use of nutrients in developing larvae are restricted in long-lived populations.

Acclimatization↗
PubMed1999

Extended longevity lines of Drosophila melanogaster: characterization of oocyte stages and ovariole numbers as a function of age and diet.

Vitellogenic and previtellogenic oocyte stages, as well as ovariole numbers, were characterized in the selected (O) lines of D. melanogaster that have been selected for late-life reproduction and extended longevity. On day 4 post-eclosion, O females had more ovarioles than control (B) females, but this difference diminished at older ages. From days 4 to 24, O females showed a marked increase in average vitellogenic oocyte stage, whereas this parameter did not increase in B females as they aged. The previtellogenic gradient of oocyte maturation declined in both B and O females. Specifically, terminal previtellogenic stages were lost with advancing age, and this loss occurred relatively gradually in O females regardless of food regime. Among the reproductive traits assessed, differential persistence of the previtellogenic gradient of maturation is most strongly associated with selected versus control line differences in longevity.

Aging↗
PubMed2001

Longevity and the epsilon2 allele of apolipoprotein E: the Finnish Centenarians Study.

BACKGROUND: Whether and which genetic factors affect human longevity is unclear. This study assesses the association between the epsilon2 allele of apolipoprotein E (APOE), a putative longevity gene, and extremely old age. METHODS: This study is based on all centenarians living in Finland in 1991. Subjects were 179 persons (28 men and 151 women) aged 100 years and older (response rate, 97%). RESULTS: The percentages of epsilon2-allele carriers in persons aged 100 to 101, 102 to 103, and 104 years and older were 9% (10/117), 21% (9/42), and 25% (5/20; gender-adjusted p for trend = .01), respectively. The effect was particularly strong in women: 8% (8/100), 18% (6/33), and 28% (5/18; p for trend = .01) by age group, respectively. Low cell numbers prevented clear conclusions being drawn for men. Seventeen percent (30/179) of the adult Finnish population were carriers of the epsilon4 allele, a figure lower than expected, and stable by age group. CONCLUSIONS: Carriers of the epsilon2 allele of APOE might be predisposed to reach extremely old age.

Aged↗
PubMed2001

Epidemiologic data on the relationships of caloric intake, energy balance, and weight gain over the life span with longevity and morbidity.

Animal experiments have shown that calorically restricted (CR) animals weigh less and live longer than their ad libitum-fed peers. Are these observations applicable to human beings? This is an important question because the prevalence of obesity in America has increased markedly over recent years. We examine whether there are physiologic effects that occur with CR in humans that could plausibly explain the observed longevity of laboratory animals associated with CR. We also review epidemiologic data from observational and interventional studies on the relationships of caloric intake, energy balance, and weight gain with age-related diseases and longevity. Additionally, data on whether long-term, sustained maintenance of weight loss is feasible, as well as the degree of CR achieved in clinical trials, are summarized. Finally, we provide recommendations regarding further epidemiologic research that will help clarify unanswered questions in these areas.

Energy Intake↗
PubMed2002

Different age-specific demographic profiles are generated in the same normal-lived Drosophila strain by different longevity stimuli.

We review the empirical data obtained with our normal-lived Ra control strain of Drosophila and show that this one genome is capable of invoking at least three different responses to external stimuli that induce the animal to express one of three different extended longevity phenotypes, each of which arises from one of three different antagonistic molecular mechanisms of stress resistance. The phenotypes are distinguished by different age-specific mortality patterns. Depending on the selected mechanism, the genome may respond by expressing a delayed onset of senescence (type 1), an increased early survival (type 2), or an increased late survival (type 3) phenotype, suggesting their different demographic effects. We suggest that the different demographic effects stem in part from the differential ability of each selection regime to reallocate the organism's energy from reproduction to somatic maintenance. These data document the complexity of the aging process and argue for a relationship between molecular mechanisms and longevity phenotypes.

Aging↗
PubMed2002

Fertility and life span: late children enhance female longevity.

The relation between fertility and postmenopausal longevity is investigated for a sample of 1635 women from a historical (17th to 18th century) French-Canadian cohort who lived past the age of 50 years. We find that increased fertility is linked to increased rather than decreased postreproductive survival. Postreproductive life expectancy extension is found to be tied to late births. This finding sheds new light on the cost of reproduction and may be viewed as supporting a new paradigm that states that reproductive potential drives remaining longevity. The emerging reproductive potential concept complements the well-established cost of reproduction hypothesis. Alternative explanations for the observed association are also explored. A specific finding is that the degree to which mortality increases for 50-year-old mothers as a result of senescence is closely tied to the logarithm of the age of their youngest child. For example, 50-year-old mothers experience a mortality decrease of 38% and an increase of remaining lifetime of 3.93 years for every 10-fold decrease in the age of their youngest child. This amount of gain in remaining life expectancy would apply to a mother with a two-year-old child as compared with a mother with a 20-year-old offspring. We also find evidence for the existence of vulnerable periods in human life history that are characterized by phases of heightened mortality and are found to be tied to reproduction and senescence.

Child, Preschool↗
PubMed2005

A new field record for bat longevity.

A new longevity record has been established for a free-living bat-41 years for a male Brandt's bat, Myotis brandtii. The exceptional longevity of bats generally, and this species in particular, should make bats of special interest for researchers studying mechanisms of slow aging.

Aging↗
PubMed2005

Housing density does not influence the longevity effect of calorie restriction.

This study examined the effect of housing density on the longevity-extending and disease-delaying actions of calorie restriction (CR). Singly or multiply housed (four per cage) mice were either fed ad libitum (AL) or were on CR beginning at 2 months. All CR mice were fed 40% less food than were multiply housed AL mice. CR increased median longevity by 19%, and housing density had no effect on this increase. CR also reduced neoplastic lesions in both housing groups, but lymphoma, the most common neoplasm, was reduced more in singly than in multiply housed mice. Singly housed AL mice ate 40% more food than did multiply housed AL mice, but weighed the same and lived as long as multiply housed AL mice. These results indicate that CR can extend life span as effectively in multiply as in singly housed mice, even though housing density can differentially affect the cancer-reducing effect of CR.

Animals↗
PubMed2006

Oxidation-resistant membrane phospholipids can explain longevity differences among the longest-living rodents and similarly-sized mice.

Underlying causes of species differences in maximum life span (MLS) are unknown, although differential vulnerability of membrane phospholipids to peroxidation is implicated. Membrane composition and longevity correlate with body size; membranes of longer-living, larger mammals have less polyunsaturated fatty acid (PUFA). We determined membrane phospholipid composition of naked mole-rats (MLS > 28.3 years) and similar-sized mice (MLS = 3-4 years) by gas-liquid chromatography to assess if the approximately 9x MLS difference could be explained. Mole-rat membrane composition was unchanged with age. Both species had similar amounts of membrane total unsaturated fatty acids; however, mice had 9 times more docosahexaenoic acid (DHA). Because this n-3PUFA is most susceptible to lipid peroxidation, mole-rat membranes are substantially more resistant to oxidative stress than are mice membranes. Naked mole-rat peroxidation indices, calculated from muscle and liver mitochondrial membranes, concur with those predicted by MLS rather than by body size, suggesting that membrane phospholipid composition is an important determinant of longevity.

Animals↗
PubMed2006

A polymorphism of the YTHDF2 gene (1p35) located in an Alu-rich genomic domain is associated with human longevity.

The uneven distribution of Alu repetitive elements in the human genome is related to specific functional properties of genomic regions. We report the identification of a locus associated with human longevity in one of the chromosomal regions with the highest density of Alu elements, in 1p35. The locus, corresponding to a (TG)n microsatellite in the YTHDF2 gene, was identified by characterizing an "anonymous" marker detectable through inter-Alu fingerprinting, which previously evidenced an increased homozygosity in centenarians. After genotyping 412 participants of different ages, including 137 centenarians, we confirmed the increased homozygosity in centenarians at this locus, and observed a concomitantly increased frequency of the most frequent allele and the corresponding homozygous genotype. Remarkably, the same genotype was associated with increased YTHDF2 messenger RNA levels in immortalized lymphocytes. Finally, YTHDF2 messenger RNA resulted to be mainly expressed in testis and placenta. The data suggest a possible role of this locus in human longevity.

Adolescent↗
PubMed2006

Sex differences in the association of apolipoprotein E and angiotensin-converting enzyme gene polymorphisms with healthy aging and longevity: a population-based study from Southern Italy.

We investigated the association of sex and age with the occurrence of apolipoprotein E (apoE) and angiotensin-converting enzyme (ACE) genotypes in healthy aging and longevity in 1344 healthy individuals and 64 centenarians. As compared to participants younger than 60 years, a significant higher frequency of the apoE/epsilon2 was observed in men aged 60-90 years (p <.001) and in centenarians (p <.001). Logistic regression analysis confirmed this outcome in both participants aged 60-90 years (odds ratio [OR] = 1.897; 95% confidence interval [CI], 1.227-2.931) and centenarians (OR = 3.263; 95% CI, 1.860-5.722). A further significant association of ACE/D allele and age was observed in centenarians (OR = 2.135; 95% CI, 1.253-3.636). Heterosis was also observed at the ACE locus. No relationship between apoE and ACE polymorphism was found. These findings suggest a role of sex in the association of apoE and ACE gene polymorphisms with healthy aging and longevity.

Aged↗