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PubMed2006

The association between birthweight and longevity in the rat is complex and modulated by maternal protein intake during fetal life.

Maternal protein restriction in rat pregnancy has been suggested to reduce lifespan of the resulting offspring by inducing fetal growth retardation, followed by postnatal catch-up growth. We tested the hypothesis that lifespan could be programmed in both males and females by exposure to undernutrition at specific stages of fetal development. Protein restriction throughout gestation significantly reduced lifespan in both males and females. Low birthweight increased longevity, whilst rapid postnatal growth had a detrimental effect. There was no evidence that undernutrition programmed lifespan through oxidative processes in the major organs. Fetal programming is an important contributor to the ageing process.

Animals↗
PubMed2004

Modest implication of interleukin-6 promoter polymorphisms in longevity.

The multifunctional interleukin-6 has been suggested to contribute to a chronic low-grade inflammatory status, thereby conferring susceptibility to age-related pathological conditions as well as functional decline and increased mortality. Several polymorphisms have been identified in the interleukin-6 promoter, but investigation of the effect of these on interleukin-6 levels and disease susceptibility have led to contradictory results. This study investigates the significance of the three single-point polymorphisms (-597G/A, -572G/C and -174G/C) and the AT-stretch polymorphism (-373(A)n(T)m) in ageing, by comparison of the frequency of each single polymorphism separately as well as the entire promoter haplotype in a total of 1710 Danish subjects ranging in age from 47 to 100 years. We found a modest, but significant, increase in the frequency of interleukin-6 -174GG homozygotes with age suggesting that this genotype is advantageous for longevity.

Adolescent↗
PubMed2005

Do deficiencies in growth hormone and insulin-like growth factor-1 (IGF-1) shorten or prolong longevity?

Present knowledge on the effects of growth hormone (GH) and insulin-like growth factor-I (IGF-I) deficiency on aging and lifespan are controversial. Studying untreated patients with either isolated GH deficiency due to GH gene deletion, patients with multiple pituitary hormone deficiency due to PROP-1 gene mutation and patients with isolated IGF-I deficiency due to deletions or mutations of the GH receptor gene (Laron syndrome); it was found, that these patients despite signs of early aging (wrinkled skin, obesity, insulin resistance and osteopenia) have a long life span reaching ages of 80-90 years. Animal models of genetic GH deficiencies such as Snell mice (Pit-1 gene mutations) the Ames mice (PROP-1 gene mutation) and the Laron mice (GH receptor gene knock-out) have a statistically significant higher longevity compared to normal controls. On the contrary, mice transgenic for GH and acromegalic patients secreting high amounts of GH have premature death. Those data raise the question whether pharmacological GH administration to adults is deleterious, in contrast to policies advocating such therapies.

Aged↗
PubMed2005

Strategies to enhance longevity and independent function: the Jerusalem Longitudinal Study.

PURPOSE: To analyze the impact of medical and social factors on survival and function from age 70 to 82 and point to possible genetic basis for differences. MATERIALS AND METHODS: Longitudinal, cohort study of a representative sample of Jerusalem residents, born 1920-1921. At age 70, 463 subjects underwent a thorough interview eliciting social determinants as well as a medical history and examination and laboratory investigation. At age 77,265 of the survivors, 71%, were re-examined. In 2002, all death certificates in Israel were reviewed. End points were performance of basic and advanced tasks with ease at age 77 and survival to age 82 or life span in subjects who had succumbed. The independent influence of each factor was tested using logistic regression. RESULTS: 89.6% of women were alive after 6 years and 77.4% after 12. Survival for men was 79.9% and 59.8%, respectively. Social factors predominated in the correlation with longer life: financial security, p=.0004; volunteer activity, p=.0002; regular exercise, p=.0002; positive self-assessed health, p<.0001; and activities of daily living (ADL) independence, p<.0001. Less striking but significant correlation for longevity was noted for avoiding naps, p=.04 and instrumental activities of daily living (IADL) independence, p=.048. Medical conditions associated with increased mortality included diabetes, p<.0001; coronary artery disease, p=.0002; impaired vision, p=.0007; and renal insufficiency, p=.008. Anemia and disturbed sleep did not independently correlate with mortality while the association with hypertension did not reach statistical significance, p=.056. In a regression to determine the independent impact of medical and social factors on mortality, unimpaired renal function, good vision, avoiding afternoon naps, volunteer or compensated work, physical activity and IADL independence all correlated with improved survival. Moreover, good vision, volunteer work or work for pay and physical activity were independently associated with continued ADL independence after 7 years. CONCLUSIONS: These findings highlight the ability of social, economic and functional factors to modify genetic influence on survival and function. Increased physical and social activity is an important tool to lengthen the span of robust function. The role of heredity in determining function and mortality may be expressed through diverse pathways.

Activities of Daily Living↗
PubMedDate not supplied

Cholesteryl ester transfer protein (CETP) I405V polymorphism and longevity in Italian centenarians.

A common polymorphism (I405V) in exon 14 of the cholesteryl ester transfer protein (CETP) gene has been recently associated to healthy aging in Ashkenazi Jewish. In order to study this genetic effect in long-lived individuals with a different ethnicity, we analyzed the allele and genotype distributions of the CETP polymorphism a sample of Italian centenarians. Our result does not confirm the association between the I405V CETP variation and the healthy aging phenotype described in the Ashkenazi Jewish population and suggests that other gene environment interactions contribute to longevity.

Aged↗
PubMed2005

Maximum longevities of chemically protected and non-protected fishes, reptiles, and amphibians support evolutionary hypotheses of aging.

Evolutionary hypotheses of aging predict that species with low rates of mortality from extrinsic sources, such as predation, should senesce more slowly and have longer maximum life spans than related species with higher rates of extrinsic mortality. We tested this prediction by synthesizing information on maximum body lengths and life spans in captivity of 1193 species of chemically protected (venomous or poisonous) and non-chemically protected fishes, snakes, caudatans (salamanders and newts), and anurans (frogs and toads). In every phylogenetic group maximum longevity was positively correlated with body size and, when size was controlled for statistically, chemically protected species and genera usually had longer maximum life spans than non-protected species. These results reemphasize the importance of life history traits, particularly protection from predation, in the evolution of senescence.

Animals↗
PubMed2005

Cellular replicative capacity correlates primarily with species body mass not longevity.

Although the limited replicative capacity of human fibroblasts in culture is frequently used as a model for aging, a question of major interest is whether the relationship between in vitro fibroblast proliferative capacity and species longevity is primary or secondary to a relationship with species body size. In this report we establish that body mass is the primary correlative of proliferative potential rather than species life-span.

Adolescent↗
PubMed2006

Extended longevity mechanisms in short-lived progeroid mice: identification of a preservative stress response associated with successful aging.

Semantic distinctions between "normal" aging, "pathological" aging (or age-related disease) and "premature" aging (otherwise known as segmental progeria) potentially confound important insights into the nature of each of the complex processes. Here we review a recent, unexpected discovery: the presence of longevity-associated characteristics typical of long-lived endocrine-mutant and dietary-restricted animals in short-lived progeroid mice. These data suggest that a subset of symptoms observed in premature aging, and possibly normal aging as well, may be indirect manifestations of a beneficial adaptive stress response to endogenous oxidative damage, rather than a detrimental result of the damage itself.

Aging↗
PubMed2006

Inflammatory networks in ageing, age-related diseases and longevity.

Inflammation is considered a response set by the tissues in response to injury elicited by trauma or infection. It is a complex network of molecular and cellular interactions that facilitates a return to physiological homeostasis and tissue repair. The individual response against infection and trauma is also determined by gene variability. Ageing is accompanied by chronic low-grade inflammation state clearly showed by 2-4-fold increase in serum levels of inflammatory mediators. A wide range of factors has been claimed to contribute to this state; however, the most important role seems to be played by the chronic antigenic stress, which affects immune system thorough out life with a progressive activation of macrophages and related cells. This pro-inflammatory status, interacting with the genetic background, potentially triggers the onset of age-related inflammatory diseases as atherosclerosis. Thus, the analysis of polymorphisms of the genes that are key nodes of the natural immunity response might clarify the patho-physiology of age-related inflammatory diseases as atherosclerosis. On the other hand, centenarians are characterized by marked delay or escape from age-associated diseases that, on average, cause mortality at earlier ages. In addition, centenarian offspring have increased likelihood of surviving to 100 years and show a reduced prevalence of age-associated diseases, as cardiovascular disease (CVD) and less prevalence of cardiovascular risk factors. So, genes involved in CVD may play an opposite role in human longevity. Thus, the model of centenarians can be used to understand the role of these genes in successful and unsuccessful ageing. Accordingly, we report the results of several studies in which the frequencies of pro-inflammatory alleles were significantly higher in patients affected by infarction and lower in centenarians whereas age-related controls displayed intermediate values. These findings point to a strong relationship between the genetics of inflammation, successful ageing and the control of cardiovascular disease at least in men, in which these studies were performed. These data are also briefly discussed in the light of antagonistic pleiotropy theory and in order to pursuit a pharmacogenomics approach.

Aging↗
PubMed2026

To longevity and beyond: A systems view of aging and stress resilience.

Aging is a dynamic and time-dependent process characterized by progressive functional decline across biological systems. Key hallmarks, including genomic instability, telomere attrition, loss of proteostasis, mitochondrial dysfunction, and immunosenescence, have been widely described, each reflecting distinct yet interconnected mechanistic frameworks. Rather than acting in isolation, these processes arise from complex interactions among cellular stressors, impaired repair mechanisms, and the cumulative burden of maladaptive responses. This system-level perspective explains the inter-individual variability in aging trajectories. Centenarians represent an extreme and informative model of successful aging, in which the balance between damage accumulation and repair is shifted toward the maintenance of physiological function. Their exceptional longevity is supported by coordinated genetic, epigenetic, metabolic, and immunological adaptations that enhance resilience to age-related stressors. Here, we summarize the biological drivers and theoretical frameworks of aging within an integrative context, focusing on mechanisms associated with extended healthspan in centenarians. We also examine the contribution of major animal models, highlighting their complementary roles in elucidating conserved and species-specific aging pathways. Overall, aging outcomes reflect a dynamic equilibrium between damage and repair processes. Understanding how this balance is modulated in long-lived individuals may inform strategies to promote healthy aging and delay the onset of age-related diseases.

Humans↗
PubMed2004

Increasing longevity by decreasing sympathetic stress--early beta receptor blockade pharmacotherapy.

Consideration regarding human aging and sympathetic nervous system activity suggests that old age represents a hyperadrenergic state. With advancing age the sympathetically mediated stress on the body, specifically the cardiovascular system, may outweigh the benefits an intact sympathetic nervous system conveys for short-term survival. Beta blockers temper the effects of the sympathetic nervous system by slowing heart rate and decreasing blood pressure. Recently, beta blockers have been shown to improve outcome and survival following surgery and myocardial infarction, have beneficial effects in patients with heart failure, and may have an antiatherosclerotic effect. We propose that instituting beta receptor blockade pharmacotherapy at an early age will increase longevity by countering the adverse effects of sympathetically mediated stress.

Adrenergic beta-Antagonists↗
PubMed2005

The empirical relationship between longevity and physical stature may be obscured by unobserved genetic diversity in the optimal metabolic rate.

It is hypothesized that an inheritable "optimal" metabolic rate is associated with the lowest attainable mortality risk, greatest attainable height (in youth) and a desirable body weight. Positive deviations from this rate are reflected in overweight and higher mortality, negative deviations in shorter stature (stunting), low body mass index (BMI), and higher mortality. In a heterogeneous population the optimal rate may differ among genotypes, and those with a higher optimal rate are the ones who can translate more energy intake into growth in height such that under optimal net-nutritional intake, they are able to reach a greater final adult height with a lower body mass index than genotypes with a lower optimal rate. Hence, the optimal height and weight - in terms of longevity - may differ substantially among genotypes, so that an empirical estimation of the relationship may be blurred in a heterogeneous society. Conversely, the "true" association (within genotypes) may be stronger than the measured one, which may have some implications for the contribution of the secular increase in human height to the rise in life expectancy or the optimal BMI in persons who experienced stunting in youth.

Adolescent↗
PubMed2005

Longevity-associated mitochondrial DNA 5178 C/A polymorphism is associated with fasting plasma glucose levels and glucose tolerance in Japanese men.

Mitochondrial DNA 5178 cytosine/adenine (Mt5178 C/A) polymorphism is reportedly associated with longevity in the Japanese population, and the Mt5178A genotype may resist the onset of type 2 diabetes. To investigate whether Mt5178 C/A polymorphism is associated with glucose tolerance, we conducted a cross-sectional study using the 75-g oral glucose tolerance test (OGTT) in which non-diabetic Japanese male subjects were classified into three subgroups by body mass index (BMI): BMI<22 (n=91); 22< or =BMI<25 (n=138); and BMI> or =25 (n=67). The frequency of Mt5178A was significantly lower among 'BMI<22' subjects exhibiting impaired fasting glucose and impaired glucose tolerance than among those with normal glucose tolerance. In the 'BMI<22' group, fasting plasma glucose (FPG) levels and plasma glucose levels at 60 and 120 min after glucose load (OGTT-1h and OGTT-2h, respectively) were significantly lower in the Mt5178A genotype than in the Mt5178C genotype. After adjusting for age, BMI, habitual smoking, habitual drinking and family history of diabetes, FPG levels and OGTT-2h levels were still significantly lower in the Mt5178A genotype than in the Mt5178C genotype. However, after adjusting for covariates, in both the '22< or =BMI<25' and 'BMI> or =25' groups, FPG levels were significantly higher in the Mt5178A genotype than in the Mt5178C genotype. Differences in the effect of alcohol consumption on FPG levels and glucose tolerance between the Mt5178 C/A genotypes were observed. The present results suggest that Mt5178 C/A polymorphism may be associated with FPG levels and glucose tolerance in middle-aged Japanese men.

Blood Glucose↗
PubMed2004

Polymorphic metabolic susceptibility genes and longevity: a study in octogonarians.

In order to investigate possible associations of genetic variants in genes of xenobiotic metabolism with longevity, we compared allele frequencies and genotype distributions of polymorphic genes between 205 octogenarians and a non-cancer reference group of 294 persons aged less than 80 years. We analyzed common sequence variations in the cytochrome P-450 genes CYP1A1 T461N, 3801 T > C and CYP1B1 V432L, and in the glutathione S-transferase genes GSTM1 (deletion), GSTT1 (deletion), and GSTP1 (I105V). In octogenarians, the CYP1B1 432L allele was less prevalent than in the reference group (allele frequency 0.49 versus 0.60; odds ratio, OR, 0.63, 95% confidence limits (CI) 0.40-1.00). Octogenarians turned out to have marginally significant more GSTM1 negatives (frequency 0.56 versus 0.48; OR 1.41, 95% CI 0.97-2.05), but less GSTT1 deficient genotypes (frequency 0.14 versus 0.21; OR 0.64; 95% CI 0.38-1.06). In octogenarians without cancer, GSTT1 negative carriers were less prevalent than in the aged with cancer (frequency 0.12 versus 0.27; OR 2.81; 95% CI 1.00-7.38). Polymorphic metabolic susceptibility genes could become relevant for processes of aging when toxic defense mechanisms decline.

Adolescent↗
PubMed2005

Does longevity of adult Wuchereria bancrofti increase with decreasing intensity of parasite transmission? Insights from clinical observations.

To interrupt transmission of Wuchereria bancrofti, a parasite that causes lymphatic filariasis, mass treatment of at-risk populations with antifilarial drugs is recommended for 4-6 years, the minimum estimated adult worm lifespan. Factors associated with adult worm longevity are unknown. In Recife, Brazil, we conducted a retrospective cohort study of 57 men whose adult W. bancrofti were not sensitive to diethylcarbamazine and who were followed with semi-annual physical examinations (to detect intrascrotal nodules, indicative of adult worm death) and ultrasound examinations (to detect the 'filaria dance sign' (FDS), indicative of living adult worms). After 5 years, the FDS remained detectable in 10 (24.4%) of 41 adult worm nests in 25 men from areas of high filariasis transmission intensity and in 30 (90.9%) of 33 nests in 32 men from areas of low transmission (P<0.001). New nodules and adult worm nests were detected only in men from high-transmission areas. Of 30 men who were microfilaria-positive initially and whose FDS remained detectable after 5 years of follow-up, 19 (63.3%) remained microfilaria-positive in 5 ml blood (mean density, 0.4 per ml). In conclusion, survival of adult W. bancrofti is inversely associated with transmission intensity. These findings have implications for filariasis elimination and research.

Adolescent↗
PubMed2006

The L-isoaspartyl-O-methyltransferase in Caenorhabditis elegans larval longevity and autophagy.

The protein L-isoaspartyl-O-methyltransferase, coded by the pcm-1 gene in Caenorhabditis elegans, participates in the repair of age-damaged proteins. We tested the ability of pcm-1-deficient nematodes to survive starvation stress as developmentally-arrested L1 larvae. We found that pcm-1 mutant L1 larvae do not survive as well as wild-type L1 larvae when incubated in M9 medium without nutrients. We then tested whether the starved L1 larvae could continue development when allowed access to food in a recovery assay. A loss of recovery ability with age was observed for all larvae, with little or no difference between the pcm-1 mutant and wild-type N2 larvae. Interestingly, when L1 larvae were starved in cholesterol-containing S medium or M9 medium supplemented with cholesterol, the survival rates of both mutant and wild-type animals nearly doubles, with pcm-1 larvae again faring more poorly than N2 larvae. Furthermore, L1 larvae cultured in these cholesterol-containing media show an increase in Sudan Black staining over animals cultured in M9 medium. The longevity defects of pcm-1 mutants previously seen in dauer larvae and here in L1 larvae suggest a defect in the ability of pcm-1 mutants to recycle and reuse old cellular components in pathways such as autophagy. Using an autophagosomal marker, we found evidence suggesting that the pcm-1 mutation may inhibit autophagy during dauer formation, suggesting that the absence of protein repair may also interfere with protein degradation pathways.

Animals↗
PubMed2006

Multiple sensory G proteins in the olfactory, gustatory and nociceptive neurons modulate longevity in Caenorhabditis elegans.

The life span of the nematode Caenorhabditis elegans is under control of sensory signals detected by the amphid neurons. In these neurons, C. elegans expresses at least 13 Galpha subunits and a Ggamma subunit, which are involved in the transduction and modulation of sensory signals. Here, we show that loss-of-function mutations in the Galpha subunits odr-3, gpa-1 and gpa-9, in the Ggamma subunit gpc-1 and the introduction of extra copies of the Galpha subunit gpa-11 extend the life span of C. elegans. Loss-of-function of odr-3 and extra copies of gpa-11 act synergistically and can together extend life span more than two-fold, indicating that sensory signals play an important role in regulating life span. We show that gpa-1, gpa-11, odr-3 and gpc-1 all signal via the daf-16 FOXO family transcription factor. In addition, odr-3 and gpa-11 might suppress life span extension partially independent of the insulin/IGF-1 like receptor homologue daf-2. Our results suggest that the previously unanticipated nociceptive ASH and/or ADL neurons regulate longevity. We expect that the implication of specific G proteins will eventually contribute to the identification of the sensory cues that determine the rate of aging in C. elegans.

Animals↗
PubMed2001

Mitochondria, aging and longevity--a new perspective.

A new perspective is emerging indicating that mitochondria play a critical role in aging not only because they are the major source and the most proximal target of reactive oxygen species, but also because they regulate stress response and apoptosis. Recent literature indicates that, in response to stress, a variety of molecules translocate to and localise in mitochondria. These molecules are likely to interact with each other, in order to mediate mitochondria/nucleus cross-talk and to regulate apoptosis. We surmise that an integration of signals in multimolecular complexes occurs at mitochondrial level. These phenomena can be of critical importance for human aging and longevity.

Aging↗