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Biomedical subjects

Claudio Franceschi

Publications and source records attributed to Claudio Franceschi.

At least 109 records · Page 6Linked to original sources
PubMed2003

Polymorphic variants of insulin-like growth factor I (IGF-I) receptor and phosphoinositide 3-kinase genes affect IGF-I plasma levels and human longevity: cues for an evolutionarily conserved mechanism of life span control.

Current literature indicates that abrogation of the IGF-I response pathway affects longevity in Caenorhabditis elegans, and that the down-regulation of IGF-I gene expression is associated with an extension of the life span in mice. In this paper we tested the hypothesis that polymorphic variants of IGF-I response pathway genes, namely IGF-IR (IGF-I receptor; G/A, codon 1013), PI3KCB (phosphoinositol 3-kinase; T/C, -359 bp; A/G, -303 bp), IRS-1 (insulin receptor substrate-1; G/A, codon 972), and FOXO1A (T/C, +97347 bp), play a role in systemic IGF-I regulation and human longevity. The major finding of this investigation was that subjects carrying at least an A allele at IGF-IR have low levels of free plasma IGF-I and are more represented among long-lived people. Moreover, genotype combinations at IGF-IR and PI3KCB genes affect free IGF-I plasma levels and longevity. These findings represent the first indication that free IGF-I plasma levels and human longevity are coregulated by an overlapping set of genes, contributing to the hypothesis that the impact of the IGF-I/insulin pathway on longevity is a property that has been evolutionarily conserved throughout the animal kingdom.

Adolescent↗
PubMed2003

Low vitamin D status, high bone turnover, and bone fractures in centenarians.

The oldest olds, including centenarians, are increasing worldwide and, in the near future, will represent a consistent part of the population. We have studied bone status and metabolism in 104 subjects over 98 yr of age to evaluate possible interventions able to avoid fragility fractures and disability. Ninety females and 14 males not affected by any acute disease were considered. After a complete clinical assessment, blood was drawn for evaluating bone turnover markers, and performance tests together with skeletal ultrasonography (either at the phalanges or at the heel) were performed. We found that 38 subjects had sustained a total of 55 fractures throughout their lives, and 75% of these were fragility fractures. Twenty-eight fractures occurred at the proximal femur, with 14 after the age of 94 yr. Serum 25-hydroxyvitamin D was undetectable in 99 of 104 centenarians. PTH and serum C-terminal fragment of collagen type I were elevated in 64 and 90% of centenarians, respectively, with a trend toward hypocalcemia. Bone alkaline phosphatase levels were close to the upper limit. Serum IL-6 was elevated in 81% of centenarians and was positively correlated with PTH and negatively correlated with serum calcium. Serum creatinine was not correlated with PTH. Bone ultrasonography showed that most centenarians had low values, and ultrasonographic parameters were correlated with resorption markers. We conclude that the extreme decades of life are characterized by a pathophysiological sequence of events linking vitamin D deficiency, low serum calcium, and secondary hyperparathyroidism with an increase in bone resorption and severe osteopenia. These data offer a rationale for the possible prevention of elevated bone turnover, bone loss, and consequently the reduction of osteoporotic fractures and fracture-induced disability in the oldest olds through the supplementation with calcium and vitamin D.

Activities of Daily Living↗
PubMed2003

Von Willebrand factor in Italian centenarians.

BACKGROUND AND OBJECTIVES: Subjects with blood type O have lower concentration of von Willebrand factor (VWF) than those with type A, B or AB. Since we recently observed that laboratory signs of marked hypercoagulability are compatible with health and longevity in Italian centenarians, we determined VWF and blood groups in healthy centenarians to see whether levels of this marker of endothelial perturbation were altered and whether its correlation with blood groups was similar to that among the general population. DESIGN AND METHODS: In 74 centenarians and in 110 controls (55<45 years old; 55>45 years old), we studied VWF antigen (VWF:Ag), ristocetin co-factor activity (VWF:Rco), multimeric pattern of VWF and cleaving protease (VWF:CP), and plasmin-antiplasmin complexes (PAP). RESULTS: The levels of VWF:Ag and VWF:Rco in centenarians were significantly higher than in controls without significant difference between blood group O or non-O. Fifty-one percent of centenarians have a reduction of the relative proportion of high molecular weight multimers (HMV); furthermore VWF:CP was lower and PAP significantly higher than in young controls. INTERPRETATION AND CONCLUSIONS: The loss of large VWF multimers in 51% of centenarians could depend on degradation protease(s) in the circulation. VWF, a well-known independent predictor of atherothrombotic disease, was increased in centenarians, independently of the blood group, confirming the previous results of a state of hypercoagulability. The finding that the VWF:CP levels are low when VWF levels are high in centenarians could be a corollary of the previous described paradox of successful aging, adding another marker of increased risk of atherothrombosis to the scenario.

Adult↗
PubMed2003

-174 G>C polymorphism of interleukin 6 gene promoter affects interleukin 6 serum level in patients with colorectal cancer.

PURPOSE: Experimental data suggest that interleukin 6 (IL-6) plays an important role in the development and progression of metastasis from colorectal cancer (CRC), and -174 G>C polymorphism has been identified recently in the IL-6 gene promoter. Therefore, the aim of the present study was to investigate the significance of this type of polymorphism in patients with CRC. EXPERIMENTAL DESIGN: Using enzyme immunoassay, IL-6 concentrations were measured in preoperative serum samples from 65 stage I-IV CRC patients. DNA was extracted from peripheral blood mononuclear cells, and -174 G>C polymorphism detected using PCR, followed by NlaIII restriction enzyme digestion and electrophoresis. RESULTS: The median IL-6 serum level was 0.14 pg/ml in patients with stage I-III disease versus 0.41 pg/ml in patients with stage IV disease (P < 0.001). DNA amplification was possible in 62 cases. On grouping genotypes at the -174 G>C locus as C+ (CC and CG) and C- (GG), a significant association was observed between the type of polymorphism and IL-6 serum level: the median value for IL-6 was 0.14 pg/ml in C+ patients (n = 32) and 0.32 pg/ml in C- patients (n = 30; P = 0.034). Moreover, in patients with hepatic metastasis the median level of IL-6 was 0.23 pg/ml in C+ patients (n = 9) and 0.96 pg/ml in C- patients (n = 9; P = 0.004). CONCLUSIONS: In patients with CRC, the -174 G>C polymorphism status of the IL-6 gene promoter affects the IL-6 serum level, particularly in the presence of hepatic metastasis.

Adult↗
PubMed2002

p53 codon 72 genotype affects apoptosis by cytosine arabinoside in blood leukocytes.

A wide difference in the susceptibility to undergo in vitro apoptosis exists among individuals, and this fact has potential implications in predicting the in vivo response to apoptotic agents, such as those employed in chemotherapy. In this report, we addressed the question whether the natural variability at p53 locus (the proline-arginine substitution at codon 72) affects the capacity of peripheral-blood mononuclear cells from healthy subjects to undergo in vitro apoptosis in response to the cytotoxic drug cytosine arabinoside. We found that cells from subjects carrying the arginine/arginine genotype undergo in vitro apoptosis at a higher extent in comparison to those from arginine/proline subjects. This finding suggests that naturally occurring genetic variability at p53 gene explains part of the inter-individual difference in the in vitro susceptibility to a chemotherapeutic drug, thus resulting as an eligible predictor marker of in vivo response to chemotherapy and its adverse effects.

Adult↗
PubMed2002

Chronic inflammation and the effect of IGF-I on muscle strength and power in older persons.

Deregulation of the inflammatory response plays a major role in the age-related decline of physical performance. The causal pathway leading from inflammation to disability has not been fully clarified, but several researches suggest that interleukin-6 (IL-6) causes a reduction of physical performance in elderly through its effect on muscle function. In vitro studies demonstrated that IL-6 inhibits the secretion of insulin-like growth factor I (IGF-I) and its biological activity, suggesting that the negative effect of IL-6 on muscle function might be mediated through IGF-I. We evaluated the joint effect of IGF-I and IL-6 on muscle function in a population-based sample of 526 persons with a wide age range (20-102 yr). After adjusting for potential confounders, such as age, sex, body mass index, IL-6 receptor, and IL-6 promoter polymorphism, IL-6, IGF-I, and their interaction were significant predictors of handgrip and muscle power. In analyses stratified by IL-6 tertiles, IGF-I was an independent predictor of muscle function only in subjects in the lowest IL-6 tertile, suggesting that the effect of IGF-I on muscle function depends on IL-6 levels. This mechanism may explain why IL-6 is a strong risk factor for disability.

Adult↗
PubMed2002

Inhibitory effect of the peptide epitalon on the development of spontaneous mammary tumors in HER-2/neu transgenic mice.

Female FVB/N HER-2/neu transgenic mice from the age of 2 months were subcutaneously injected with saline, the peptide Epitalon(R) (Ala-Glu-Asp-Gly) or with the peptide Vilon(R) (Lys-Glu) in a single dose of 1 microg/mouse for 5 consecutive days every month. Epitalon treatment reduced the cumulative number and the maximum size of tumors (p < 0.05). Furthermore, the number of mice bearing 1 mammary tumor was increased, whereas the number of mice bearing 2 or more mammary tumors was reduced in Epitalon-treated in comparison to saline-treated animals (p < 0.05). The size but not the number of lung metastases was reduced in Epitalon-treated compared to saline-treated mice (p < 0.05). The treatment with Vilon produced significant negative effects when compared to the control group, with an increased incidence of mammary cancer development (p < 0.05), a shorter mean latent period of tumors (p < 0.05) and an increased cumulative number of tumors (p < 0.05). A 3.7-fold reduction in the expression of HER-2/neu mRNA was found in mammary tumors from HER-2/neu transgenic mice treated with Epitalon compared to control animals. The expression of mRNA for HER-2/neu was also partially reduced in Vilon-treated mice, but it remained significantly higher in Vilon- than in Epitalon-treated animals (1.9-fold increase). The data demonstrate the inhibitory effect of Epitalon in the development of spontaneous mammary tumors in HER-2/neu mice, suggesting that a downregulation of HER-2/neu gene expression in mammary adenocarcinoma may be responsible, at least in part, for the antitumor effect of the peptide.

Animals↗
PubMed2002

T cells and aging, January 2002 update.

Age-related changes in the immune system may contribute to morbidity and mortality due to decreased resistance to infection and, possibly, certain cancers in the aged. Many studies mostly performed in mice, rats and man but also including monkeys and dogs have established that age-associated immune decline is characterized by decreases in both humoral and cellular responses. The former may be largely a result of the latter, because observed changes both in the B cell germline-encoded repertoire and the age-associated decrease in somatic hypermutation of the B cell antigen receptors are now known to be critically affected by helper T cell aging. As antigen presenting cell (APC) function appears to be well-maintained in the elderly, this review will focus on the T cell. Factors contributing to T cell immunosenescence may include a) altered production of T cell progenitors (stem cell defects, stromal cell defects), b) decreased levels of newly-generated mature T cells (thymic involution), c) aging of resting immune cells, d) disrupted activation pathways in immune cells (stimulation via the T cell receptor for antigen, costimulation, apoptosis control), e) replicative senescence of clonally expanding cells. This review aims to consider the current state of knowledge on the scientific basis for and potential clinical relevance of those factors in immunosenescence in humans. Experiments in other species will be touched upon with the proviso that there are clearly differences between them, especially between humans and rodents, but exactly what those differences are is not completely clear. Given its potential importance and the increasing proportion of elderly people the world over, coupled with the realisation that whereas mortality is decreasing, morbidity may not be decreasing in parallel (1), a better understanding of the causes and impact of immunosenescence may offer the possibility of identifying where prevention or delay of onset, as well as therapeutic intervention, might be beneficial. Amelioration of the effects of dysregulated immune responses in the elderly by replacement therapy, supplementation therapy or other approaches may result in an enhancement of their quality of life, and significant reductions in the cost of medical care in old age.

Aging↗
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↗
PubMed2002

A centenarian-only approach for assessing gene-gene interaction in human longevity.

In this study, we introduce a centenarian-only approach to the assessment of gene-gene interaction that contributes to human longevity. This approach corresponds to the non-traditional case-only method in the genetic study of gene and disease associations. We first describe how the method can be implemented to screen for gene-gene interaction in human longevity. Then we apply the method to centenarian data collected from an Italian centenarian study in order to detect the interactions between the REN gene and the mitochondrial haplotypes. A significant interaction between REN gene allele 10 and the mitochondrial H haplotype, which may favour longevity, was found. Important features of the application in human longevity studies are highlighted and discussed. Since centenarians constitute a special population representing successful ageing, the centenarian-only approach will be an important tool in the search for major genes that contribute to human longevity.

Aged↗
PubMed2002

Genetic analysis of Paraoxonase (PON1) locus reveals an increased frequency of Arg192 allele in centenarians.

Human Paraoxonase (PON1) is a High-Density Lipoprotein (HDL)-associated esterase that hydrolyses lipo-peroxides. PON1 has recently attracted attention as a protective factor against oxidative modification of LDL and may therefore play an important role in the prevention of the atherosclerotic process. Two polymorphisms have been extensively studied: a Leucine (L allele) to Methionine (M allele) substitution at codon 55, and a Glutamine (A allele) to Arginine (B allele) substitution at codon 192. We have examined these two aminoacidic changes in 579 people aged 20 to 65 years old, and 308 centenarians. We found that the percentage of carriers of the B allele at codon 192 (B+ individuals) is higher in centenarians than in controls (0.539 vs 0.447), moreover we found that among the B+ individuals, the phenomenon was due to an increase of people carrying M alleles at codon 55 locus. In conclusion, we propose that genetic variability at PON1 locus affects survival at extreme advanced age.

Adult↗
PubMed2002

LL-paraoxonase genotype is associated with a more severe degree of homeostasis model assessment IR in healthy subjects.

The LL genotype among subjects with paraoxonase (PON) polymorphism Met-Leu 54 has been shown to be associated with elevated risk of coronary heart disease. Indeed, insulin resistance (IR) is a well known cardiovascular risk factor that is likely attributable to a genetic background, lifestyle, and environmental factors such oxidative stress. Because subjects sharing the LL genotype have a more elevated degree of oxidative stress, one cannot rule out that in those subjects a more severe degree of IR can occur. Thus, the possible relationship between PON gene polymorphism and degree of IR was investigated. In 213 healthy subjects, the degree of IR was assessed by the homeostasis model assessment, and the Met-Leu 54 PON polymorphism was detected. The frequency was 0.366 for the LL genotype, 0.469 for the LM genotype, and 0.164 for the MM genotype. Comparing the three genotype groups, LL genotype had the more severe degree of IR, compared with LM (P < 0.01) and MM (P < 0.01) genotypes. No difference between LM and MM genotypes was found (P = 0.49). Subjects carrying the LL genotype were associated with the IR syndrome picture more than individuals carrying the M allele because they were more overweight and had the highest levels of triglycerides and blood pressure and the lowest values of plasma high-density lipoprotein cholesterol. In a multivariate stepwise regression analysis, LL genotype was a significant predictor of IR, independent of age, sex, body mass index, fasting plasma triglycerides, and high-density lipoprotein cholesterol (P < 0.001). In conclusion, the presence of LL PON genotype is associated with a more severe degree of IR. Thus, IR might be the possible missing link between Met-Leu 54 PON polymorphism and the increased cardiovascular risk.

Aryldialkylphosphatase↗
PubMed2002

Numerical and functional alterations of circulating gammadelta T lymphocytes in aged people and centenarians.

The aim of this study was to evaluate the peripheral representation, in vitro expansion, cytokine production, and cytotoxicity of gammadelta T lymphocytes from 104 healthy subjects ranging in age from 19 to 103 years. We demonstrated that the absolute number of circulating gammadelta(+) T cells was reduced significantly in old people and centenarians in comparison with young subjects as a consequence of the age-related decreased lymphocyte number. The decrease was a result of an age-dependent reduction of Vdelta2 T cells, whereas the absolute number of Vdelta1 T cells was unaffected by age. As a consequence, the Vdelta2/Vdelta1 ratio was inverted in old subjects and centenarians. A higher percentage of gammadelta(+) T cells producing tumor necrosis factor alpha was found in old donors and centenarians, whereas no age-related difference was observed in interferon -gamma production. After a 10-day in vitro expansion, a twofold lower expansion index of gammadelta T cells, and particularly of a Vdelta2, but not of a Vdelta1 subset, was found in old people and centenarians in comparison with young subjects. The cytotoxicity of sorted gammadelta T cells was preserved in old people and centenarians. The alteration of gammadelta T cells could contribute to the age-related derangement of T cell-mediated, adoptive responses and may represent a new characteristic of immunosenescence.

Adult↗
PubMedDate not supplied

Effect of metformin on life span and on the development of spontaneous mammary tumors in HER-2/neu transgenic mice.

Studies in mammals have led to the suggestion that hyperglycemia and hyperinsulinemia are important factors both in aging and in the development of cancer. Insulin/insulin-like growth factor 1 (IGF-1) signaling molecules that have been linked to longevity include DAF-2 and InR and their homologues in mammals, and inactivation of the corresponding genes is followed by increased life span in nematodes, fruit flies and mice. It is possible that the life-prolonging effects of calorie restriction are due to decreasing IGF-1 levels. A search of pharmacological modulators of insulin/IGF-1 signaling pathway (which mimetic effects of life span extending mutations or calorie restriction) could be a perspective direction in regulation of longevity. The chronic treatment of female transgenic HER-2/neu mice with metformin (100 mg/kg in drinking water) slightly decreased the food consumption but failed in reducing the body weight or temperature, slowed down the age-related rise in blood glucose and triglycerides level, as well as the age-related switch-off of estrous function, prolonged the mean life span by 8% (p < 0.05), the mean life span of last 10% survivors by 13.1%, and the maximum life span by 1 month in comparison with control mice. The demographic aging rate represented by the estimate of respective Gompertz's parameter was decreased 2.26 times. The metformin-treatment significantly decreased the incidence and size of mammary adenocarcinomas in mice and increased the mean latency of the tumors.

Adenocarcinoma↗
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↗
PubMedDate not supplied

The -174 C/G locus affects in vitro/in vivo IL-6 production during aging.

IL-6 in vitro production, as well as the serum/plasma concentration of the cytokine, increase with age. In the present investigation, a total of 62 individuals (31 males and 31 females), aged from 29 to 93 years of age (mean age of males: 60.4 years; mean age of females: 59.4 years) were assessed for IL-6 plasma concentration, and for IL-6 in vitro production, using supernatants of 4h cultured adherent peripheral blood mononuclear cells (aPBMC). The subjects were examined for a C to G transition at nucleotide -174 of the IL-6 gene promoter (-174 C/G locus), and were classified as C allele carriers (C+) or non-carriers (C-). We found that: (i) aPBMC from C+ individuals produced smaller amounts of IL-6 in vitro than C- individuals; (ii) IL-6 production by aPBMC increased with age in C+ but not in C- subjects; (iii) there was no correlation between IL-6 plasma levels and in vitro IL-6 production by aPBMC; (iv) IL-6 C+ individuals had lower plasma levels than C- individuals, and this phenomenon was significant only in men. On the whole our data indicate that the production of IL-6 is genetically controlled and age- and gender-dependent.

Adult↗
PubMedDate not supplied

Allele frequencies of +874T-->A single nucleotide polymorphism at the first intron of interferon-gamma gene in a group of Italian centenarians.

Ageing is characterized by a pro-inflammatory status which could contribute to the onset of major age-related diseases such as cardiovascular diseases, neurodegeneration, osteoarthritis and osteoporosis, and diabetes. Thus, it can be hypothesized that genetic variations in pro- or anti-inflammatory cytokines might influence successful ageing and longevity. We have studied the distribution of +874T-->A interferon-gamma (IFN-gamma) polymorphisms in a large number of Italian centenarians to evaluate if the two alleles might be differently represented in people selected for longevity. DNA samples were obtained from 174 Italian centenarians (>99 years old, 142 women and 32 men) and from 248 <60-year-old control subjects (90 women and 158 men) matched for geographical distribution. Polymorphisms at +874 were identified by using amplification refractory mutational system methodology. The +874T allele was found less frequently in centenarian women than in centenarian men or in control women whereas no significant differences were observed in the distribution of the two alleles between male or female controls. Allele frequencies in centenarian men were not found significantly different from male controls. Possession of the +874A allele, known to be associated with low IFN-gamma production, significantly increases the possibility to achieve extended longevity, suggesting that the pro-inflammatory status characteristic of ageing may be detrimental for successful ageing. The datum that the allele was significantly increased in female but not male centenarians seems to strengthen the idea that gender may be a major variable in the biology of the ageing process. However, the present data add another piece of evidence to the complex puzzle of genetic and environmental factors involved in controlling life span expectancy in humans. Thus, studies on cytokine gene polymorphisms may promise to individuate a complex network of trans-interactive genes able to influence the type and strength of responses to environmental stressors and as a final result, thereby conditioning individual life expectancy.

Adult↗