The allele (A) -110 in the promoter region of the HSP70-1 gene is unfavorable to longevity in women

Heat shock proteins (HSPs) are crucial for maintenance of cell homeostasis and survival both during and after various stresses. The capability to cope with stress is believed to affect the chance of health and survival at organismal level. We have investigated whether the gene pool relevant to the (A/C)_-110 polymorphism in the promoter region of the HSP70-1 gene changes as the population ages and survival selection occurs. A total of 591 southern Italian subjects were enrolled in the study (263 males and 328 females; age range 18–109 years), free of clinically manifest diseases and with normal haemato-chemical parameters. A significant age-related decrease of the frequency of allele (A)_-110 was observed in females. The probability ratio of 0.403 (95% confidence interval [0.163, 0.910]) computed by considering female centenarians as cases and young women (18–49 years old) as controls showed that the (A)_-110 allele is unfavorable to longevity in females.This revised version was published online in October 2005 with corrections to the Cover Date.     

Plasma fibronectin in French centenarians

Plasma fibronectin was shown to increase with age, the difference between individuals (the SD of the mean) also increases with age. Fibronectin is highly sensitive to proteolytic degradation and several of the degradation products were shown to have noxious effects as proper proteolytic activity, activation of IL-1 and collagenase expression and also activation of fibronectin biosynthesis. It was therefore interesting to compare the plasma fibronectin values of centenarians in relatively good health with an elderly population in a geriatric hospital, somewhat younger (70-96 years) but with a variety of pathologies. A third population of men and women between 59 and 70 in good health (the EVA-epidemiological study) was also used for comparison. Plasma fibronectin was determined by a specific and highly sensitive Elisa assay. Fibronectin fragments were characterized by immunoblot. It could be shown that plasma fibronectin in centenarians had a lower distribution with lower average values than the geriatric population. Fibronectin fragments could be demonstrated in the plasma of a selection of geriatric patents but not in the plasma of centenarians. These results suggest a more moderate increase of plasma fibronectin in the relatively healthy centenarians as compared to a younger but pathological population. They also show that the plasma fibronectin of the investigated centenarians was better protected from proteolytic degradation than in the geriatric population. The above results also confirm the contention that epigenetic mechanisms such as an age-dependent increase of fibronectin synthesis and degradation and the potential noxious effects of degradation products may well play an important role in the age-dependent decline of physiological functions.     

Life-long sustained mortality advantage of siblings of centenarians

Although survival to old age is known to have strong environmental and behavioral components, mortality differences between social groups tend to diminish or even disappear at older ages. Hypothesizing that surviving to extreme old age entails a substantial familial predisposition for longevity, we analyzed the pedigrees of 444 centenarian families in the United States. These pedigrees included 2,092 siblings of centenarians, whose survival was compared with 1900 birth cohort survival data from the U.S. Social Security Administration. Siblings of centenarians experienced a mortality advantage throughout their lives relative to the U.S. 1900 cohort. Female siblings had death rates at all ages about one-half the national level; male siblings had a similar advantage at most ages, although diminished somewhat during adolescence and young adulthood. Relative survival probabilities for these siblings increase markedly at older ages, reflecting the cumulative effect of their mortality advantage throughout life. Compared with the U.S. 1900 cohort, male siblings of centenarians were at least 17 times as likely to attain age 100 themselves, while female siblings were at least 8 times as likely.     

The tumor necrosis factor alpha -308G>A polymorphism is associated with dementia in the oldest old

OBJECTIVES: To test the hypothesis that the tumor necrosis factor (TNF) -308 G>A promoter gene polymorphism is a risk factor in age-related dementia and longevity. DESIGN: A cross-sectional and a longitudinal study. SETTING: A population-based sample of Danish centenarians. PARTICIPANTS: One hundred-year-old Danes (n=122) from "The Longitudinal Study of Danish Centenarians." Octogenarians (n=174) and healthy volunteers aged 18 to 30 (n=47) served as reference groups. METHODS: Whether the distribution of TNF -308 GG/GA/AA genotypes were different in centenarians than in younger age groups was investigated (Fischer exact test). Furthermore, whether the TNF -308 G>A polymorphism was associated with the prevalence of dementia (logistic regression analysis), the plasma level of TNF-alpha (analysis of variance), and mortality in the following 5 years (Cox regression analysis) within the cohort of centenarians was tested. RESULTS: The distribution of TNF -308 genotypes was not different across the three different age groups, but the GA genotype was associated with decreased prevalence of dementia in centenarians. The few centenarians with AA carrier status had higher mortality risk and tended to show higher plasma levels of TNF-alpha, but the significance was questionable due to a low number of subjects with this genotype. CONCLUSION: It is possible that the TNF -308 A allele is maintained during aging because subjects who are heterozygous for this polymorphism possess the optimal inflammatory response with regard to protection against age-related neurodegeneration.     

Comparison of the heat shock response in ethnically and ecologically different human populations.

In response to heat shock or other metabolic insults, an increased expression of different heat shock proteins (hsps) and, in particular, members of the hsp70 family is observed in human cells. Using two-dimensional electrophoresis, we compared the pattern of hsp70 synthesis in human fibroblast cell lines isolated from two contrasting groups of individuals. The first group was represented by native Turk-men living in the hot desert of Middle Asia; the second group consisted of Russians living in moderate climatic regions of European Russia. This analysis has shown that fibroblasts isolated from Turkmen after severe heat shock exhibited intensive synthesis of all hsps in parallel with synthesis of many other cellular proteins, while only trace synthesis of hsps was observed in the second group (Russians). Surprisingly, Northern analysis of RNA synthesis failed to reveal any differences between the two groups after heat shock treatment. When survival of fibroblasts after severe heat shock treatment was assessed by colony formation assay, the cells of the first group exhibited significantly higher survival rates.     

The effects of hyperthermia on human hepatocellular carcinoma stem and mature cancer cells

Introduction and objectivesHepatocellular carcinoma (HCC) can recur following radiofrequency ablation and other hyperthermic treatment modalities. Cancer stem cells (CSCs) are a subpopulation of HCC cells that are difficult to eradicate and largely responsible for tumor recurrences. Thus, the principal objective of this study was to determine whether human HCC CSCs are relatively thermal-resistant compared to non-stem or mature cancer cells (MCCs).Materials and methodsEpithelial cell adhesion molecule (EpCAM) positive enriched CSCs and EpCAM⁻ MCCs were derived from a human HCC cell line using fluorescence activated cell sorting. Each cell population was exposed to 65 °C heat for 0–16 min and survival documented at various time points.ResultsCell survival curves were similar in CSC and MCCs throughout the 16 min heat exposure period. Maximum killing was obtained after 12–14 min of heat exposure. Cytoprotective, heat shock proteins-70 (HSP70) and -90 (HSP90) mRNA expression were not disproportionately increased in CSCs.ConclusionsThese results suggest that human HCC CSCs are not more thermal resistant than MCCs and therefore, do not support the hypothesis that HCC recurrences following hyperthermic treatment reflect CSC thermal-resistance.     

X-linked genetic factors regulate hematopoietic stem-cell kinetics in females

X inactivation makes females mosaics for 2 cell populations, usually with an approximate 1:1 distribution. Skewing of this distribution in peripheral blood cells is more common among elderly women. The depletion of hematopoietic stem cells followed by random differentiation may explain the acquired skewing with age. However, an animal model suggests that selection processes based on X-linked genetic factors are involved. We studied peripheral blood cells from 71 monozygotic twin pairs aged 73 to 93 years and from 33 centenarians, and we found that with age, 1 of the cell populations becomes predominant for most women. We also observed a strong tendency for the same cell line to become predominant in 2 co-twins. This suggests that X-linked genetic factors influence human hematopoietic stem cell kinetics. The fact that females have 2 cell lines with different potentials could be one of the reasons women live longer than men.     

The centenarians in Shanghai City and its genetic analysis

To understand centenarians and seek a genetic principle of human age, we carried out a survey of centenarians in Shanghai City in 1990. There were 11,857,478 people in Shanghai City. Among them, 72 are centenarians, giving a ratio of 0.606/100,000. Eleven of the centenarians were males and 61 were females; the ratio of males to females was 0.18. The average age was 101.6 years; the oldest was 107. The father and/or mother of 40 (70.2%) died at 70 or older; 17 (29.8%) had parents who died before age 70. We propose that age is determined by genetic factors. The 72 centenarians have a total of 314 sons and daughters. Two hundred and forty-two of these died naturally at ages shown below:

Have centenarians had younger parents than the others?

This work, based on a matched case-control design, tests the assumption that centenarians were conceived by parents younger than the parents of individuals who had lifespan close to mean life duration. The centenarians are paired with controls of the same sex, born at the same place and at the same time in order to avoid traditional biases related to mortality peaks or secular trend of increase in life expectancy. The parental age at the time of the birth registration of 320 centenarians born in France between 1875 and 1890 and deceased between 1990 and 1999 is collected, as well as the one of 603 controls of the same sex whose births were recorded immediately before or after those of the future centenarians on the birth registers of the cities concerned. No difference is found between the parental age of parents of centenarians and of controls. In particular, no difference is found for females. Recent studies showed--from genealogical data--that the life expectancy of a female would be much reduced if her father was old at the time of her conception. Our study does not indicate a negative effect of a higher paternal age on the longevity of daughters.     

Cortisol can be pro- or anti-apoptotic in sea bream cells: potential role of HSP70 induction for cytoprotection

Cortisol, and heat shock protein 70 (HSP70) are known to perform key roles as part of the fish stress response. In the present study, two in vitro systems were used to investigate a possible cortisol-HSP70-apoptosis regulatory relationship. Using a developed silver sea bream fibroblast cell line (SSF), cortisol was found to induce HSP70 synthesis with a concomitant protection against camptothecin induced apoptosis. The induction of HSP70 synthesis using azetidine was also found to protect SSF against apoptosis. A primary culture of silver sea bream macrophages (SSM) displayed reduced HSP70, underwent apoptosis and displayed reduced phagocytic activity upon exposure to cortisol. The effect of cortisol on HSP70 expression in both SSF and SSM were blocked by the glucocorticoid antagonist, RU486. Treatment of SSM with azetidine protected against apoptosis and also enhanced phagocytic activity. The data from this study demonstrates for the first time that cortisol can be either anti- apoptotic or pro-apoptotic in different fish cells and such actions can be mediated via HSP70 induction or suppression respectively.     

Interleukin 6-174 G/C promoter gene polymorphism in centenarians: no evidence of association with human longevity or interaction with apolipoprotein E alleles

The C allele at position -174 in the promoter of the interleukin 6 (IL-6) gene has been associated with reduced gene expression and reduced plasma levels of IL-6. Given that IL-6 tracks with functional disability and age-related diseases, there may be attrition or reduction in the frequency of the homozygous subjects, who produce higher IL-6 serum levels, in older survivors in a population. In fact, a marked reduction of the IL-6*G/*G genotype was recently demonstrated in male though not female Italian centenarians compared with younger age groups. First aim of the present study was to investigate whether there was evidence of an association among IL-6 -174 G/C promoter polymorphism and extreme longevity in a population of 81 centenarians compared with a control group of 122 middle-aged healthy subjects (mean age: 51+/-18 SD; range: 19-73 years), from Apulia (Southern Italy). Secondly, we also tested possible interaction of apolipoprotein E (APOE) alleles with the IL-6 -174 G/C promoter polymorphism in view of our recent findings for reduced APOE epsilon4 allele in centenarians. No differences have been found in the IL-6 -174 G/C promoter allele and genotype frequencies between centenarians and controls nor was there any observed interaction with APOE alleles that are also reputed to be linked to longevity. Regional genetic differences in conjunction with differing environmental factors may explain in part previous results suggesting a role of this polymorphism in longevity.     

Protective effects of heat shock protein 70 induced by geranylgeranylacetone on oxidative injury in rat intestinal epithelial cells

OBJECTIVE: Geranylgeranylacetone (GGA), an anti-ulcer agent, has recently been demonstrated to protect a variety of cells and tissues via induction of heat shock protein (HSP)70 against numerous stresses. We investigated whether GGA induces HSP70 and protects against an oxidative stressor, monocrolamine (NH(2)Cl), in a rat intestinal epithelial cell line (IEC-18). MATERIAL AND METHODS: IEC-18 cells pretreated with GGA (0.1-10 microM) were subjected to injury induced by NH(2)Cl. Cell viability was assessed, and endogenous HSP70 levels were determined by enzyme-linked immunosorbent assay in IEC-18 cells. RESULTS: Treatment with GGA (0.1-10 microM) was found rapidly to elevate HSP70 levels and to protect against NH(2)Cl-induced injury in IEC-18 cells. Furthermore, quercetin, an inhibitor of HSP70 synthesis, diminished the protective effects of GGA in IEC-18 cells upon NH(2)Cl-caused injury. CONCLUSIONS: The results of this study suggest that GGA plays an important role in defense mechanisms against oxidative injury in the intestine, primarily via induction of HSP70.     

Potentiation of baroreceptor reflex response by heat shock protein 70 in nucleus tractus solitarii confers cardiovascular protection during heatstroke

BACKGROUND: Whereas hypotension and bradycardia seen during the onset of heatstroke may be protected by prior induction of heat shock protein 70 (HSP70) in the brain, the underlying mechanism is not fully understood. We evaluated the hypothesis that HSP70 may confer cardiovascular protection during heatstroke by potentiating the baroreceptor reflex (BRR) control of peripheral hemodynamic performance. METHODS AND RESULTS: Adult male Sprague-Dawley rats subjected to a brief hyperthermic heat shock (HS; 42 degrees C for 15 minutes) induced discernible expression of HSP70 in the bilateral nucleus tractus solitarii (NTS), the terminal site in the brain stem for primary baroreceptor afferents. This HSP70 expression was detected at 8 hours, peaked at 24 hours, and returned to baseline by 48 hours after HS. Brief hyperthermia also significantly potentiated the BRR response in a temporal profile that correlated positively with changes in HSP70 expression at the NTS. Prior HS also appreciably alleviated hyperthermia, severe hypotension, and bradycardia manifested during the onset of heatstroke (45 degrees C for 60 minutes) elicited 24 hours later. Microinjection bilaterally of anti-HSP70 antiserum (1:20) into the NTS or denervation of the sinoaortic baroreceptor afferents significantly reversed the enhancement of BRR response and cardiovascular protection during heatstroke induced by prior HS. CONCLUSIONS: These results suggest that HS-induced expression of HSP70 in the NTS may alleviate severe hypotension and bradycardia exhibited during the onset of heatstroke by potentiating both the sensitivity and capacity of BRR response.     

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.     

人肝癌细胞膜上HSP70的表达

用流式细胞仪和Cell-ELISA检测了 4株人肝癌细胞膜上HSP70的表达。结果表明正常情况下人肝癌细胞膜上HSP70的表达较低 ,经热处理后表达增加 (P <0 0 1)并显示出细胞之间的差异 (P <0 0 1)。推测其低表达可能与肝癌细胞逃逸机体免疫监视有关 ,对制定肝癌的防治对策有重要的指导意义。     

Age changes and differences in personality traits and states of the old and very old

The purpose of this study was to examine stability and change in personality traits and states for 3 age groups: centenarians, octogenarians, and sexagenarians. One hundred seventy-nine older adults participated in the 2-wave study. Results concerning age-group differences indicated that centenarians scored higher in Suspiciousness but lower in Intelligence and Stress when compared with the other 2 age groups. Octogenarians were lower in the personality traits Intelligence, Dominance, and Conscientiousness when compared with sexagenarians. Octogenarians were lower in the personality state Arousal, but higher on Regression. Results from the longitudinal analyses for centenarians indicated lower scores for Sensitivity, but higher scores for Radicalism (both personality traits), as well as higher scores of Fatigue and Depression (personality states) at follow-up. For the younger 2 age groups, age changes included higher scores for Sensitivity and Suspiciousness (personality traits). Stability scores for traits and states were considerably lower for centenarians when compared with the younger age groups.     

The prevalence of cardiovascular risk factors among centenarians is low: risk factors in centenarians.

BACKGROUND: The presence of major cardiovascular risk factors was investigated in a group of centenarians. METHODS: The following risk factors: sex, smoking, overweight, diabetes, hypertension and hypercholesterolemia were analysed in 93 centenarians and compared with data obtained from 90 individuals age 40-60 years. RESULTS: Smoking, overweight and hypercholesterolemia were found statistically more often in a younger population, whereas hypertension was diagnosed more frequently in centenarians. No or one risk factor were found in 55.4% of centenarians and in 14.2% of younger subjects. CONCLUSIONS: Centenarians are characterized by a much better cardiovascular risk profile than middle-aged individuals. This indicates that longevity is related to low cardiovascular risk.     

Effect of Heat Shock on Neuronal Cultures: Importance of Protein Synthesis and HSP72 Induction for Induced Tolerance and Survival

In this study the effects of 30 min heat-shock, ranging from 42°C to 46°C, on survival, protein synthesis and HSP72 expression were investigated in primary rat neuronal cultures. Heat-shock of 44°C resulted in a complete, but transient inhibition of protein synthesis which recovered within 24 h. 46°C heat-shock resulted in an irreversible inhibition of protein synthesis and complete neuronal loss within 24 h. Cycloheximide treatment of neuronal cultures resulted in aggravation of neuronal cell damage after heatshock of 44°C, indicating that the capacity for recovery of the overall protein synthesis is an important survival factor. In addition, the reduction of neuronal cell damage mediated by heat conditioning was abolished by cycloheximide treatment, indicating that the function of new proteins is important for induced thermotolerance. Induction of the strictly inducible member of the heat-shock protein 70kDa family, HSP72, was found in those few astrocytes which were contaminating the neuronal cell cultures, but not in neurons. These results indicate that newly synthesised proteins other than HSP72 are likely to mediate neuronal protection following heat shock in our experiments. These findings raise the possibility that induced tolerance may not necessarily be mediated by HSP72.