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Biomedical subjects

Claudio Franceschi

Publications and source records attributed to Claudio Franceschi.

At least 73 records · Page 4Linked to original sources
PubMed2004

The -174G/C polymorphism of IL-6 is useful to screen old subjects at risk for atherosclerosis or to reach successful ageing.

High levels of IL-6 are coupled with impaired immune efficiency, morbidity and mortality in ageing. Elderly men with GG (C-) genotype in -174 locus of IL-6 promoter are disadvantaged for longevity due to higher IL-6 than CG or CC (C+) carriers. As IL-6 increases in atherosclerosis, the study of the polymorphism of IL-6 may be a useful tool in identifying old subjects at risk for atherosclerosis. Thus, we divided old men into C+ and C- genotypes. Natural killer (NK) cell cytotoxicity, IL-6, IL-10, TNF-alpha, MTmRNA and zinc ion bioavailability were also evaluated and compared with nonagenarians and old patients affected by carotid stenosis. Old C- patients display, other than elevated IL-6, higher IL-10, TNF-alpha and MTmRNA coupled with impaired NK cell cytotoxicity and lower zinc ion bioavailability than C+ patients. The same trend is observed in old subjects with C- phenotype. Nonagenarians with C+ genotype show less inflammation, low MTmRNA, satisfactory NK cell cytotoxicity and good zinc bioavailability than long-living individuals with C- genotype. A higher degree of bilateral carotid stenosis is observed in C- patients than in C+ patients (88 vs 52%). Therefore, C- genotype is coupled with chronic inflammation, impaired immune efficiency, low zinc ion bioavailability and high MTmRNA. As such, C- genotype is a risk factor for the appearance of severe atherosclerosis. Thus, the polymorphism of IL-6, together with the analysis of zinc turnover and immune parameters, is of a great clinical relevance in order to genetically identify old subjects at risk in developing severe atherosclerosis and, at the same time, to predict subjects predestined to successful ageing. As a consequence, more convenient therapies may be prepared for a complete recovery.

Aged↗
PubMed2004

Gender specific association of genetic variation in peroxisome proliferator-activated receptor (PPAR)gamma-2 with longevity.

Long-lived subjects have been shown to have peculiar anthropometric features (i.e. lower body mass index (BMI)) and metabolic parameters (i.e. improved insulin sensitivity). Life style and a genetic background potentially protective against the age-related metabolic derangement might contribute to such a particular phenotype. Peroxisome proliferator-activated receptor (PPAR)gamma-2 is an important regulator of adipose tissue metabolism, insulin sensitivity and inflammatory response. Thus, the potential role of genetic variability at Pro/Ala loci of PPARG gene on longevity was studied in 222 long-lived subjects and 250 aged subjects. We found a different Pro/Ala genotype frequency distribution between long-lived and aged men subjects, long-lived men having an increased frequency of Pro/Ala genotype (20 vs 8.5%); no differences was found when allele and genotype distribution of Pro/Ala gene polymorphism were analyzed in the two age group of women. Interestingly, subjects with Pro/Ala polymorphism had significantly lower BMI than Ala/Ala and Pro/Pro polymorphism. In conclusion, our study demonstrated that paraoxonase Pro/Ala gene polyporphism is associated with human longevity. Such an effect is probably due to the effect of Pro/Ala polymorphism on body composition and appears to be gender specific.

Adult↗
PubMed2004

Different contribution of EBV and CMV infections in very long-term carriers to age-related alterations of CD8+ T cells.

Aging is accompanied by a complex dynamics of CD8+ T cell subsets whose origin is unclear. To evaluate the impact of Epstein-Barr virus (EBV) and cytomegalovirus (CMV) chronic infections on CD8+ T cells in far advanced age, we studied CD8+ T cells frequencies and phenotype in nonagenarians and centenarians by HLA-A*0201- and HLA-B*0702-tetramers incorporating epitopes specific of both viruses along with viral replication. The results demonstrate that EBV and CMV infections induce quantitatively and qualitatively different CD8+ T-cell responses in advanced aging. The frequency and absolute number of CD8+ T cells specific for one lytic and two latent EBV-epitopes, were relatively low and mostly included within CD8+ CD28+ cells. By contrast, CMV infection was characterized by highly variable numbers of CD8+ T cells specific for two differently restricted CMV-epitopes that, in some subjects, were strikingly expanded. Moreover, the great majority of anti-CMV CD8+ T cells did not bear CD28 antigen. Notwithstanding the expansion of CMV-specific CD8+ lymphocytes, CMV-DNA detection in blood samples was invariably negative. Altogether, we suggest that CMV, but not EBV, can sustain chronic activation of the HLA-class I restricted effector arm in elderly that might have detrimental effects on age-associated diseases.

Aged↗
PubMed2004

Identification of a geographic area characterized by extreme longevity in the Sardinia island: the AKEA study.

High prevalence and low female/male ratio for validated centenarians are observed in Sardinia and these findings appear to be thus far unique to this island. Moreover a specific region on the island is characterized by exceptional male longevity. We calculated the extreme longevity index (ELI), defined as the percentage of persons born in Sardinia between 1880 and 1900, who became centenarians. A gaussian smoothing method was used in order to identify the so-called 'Blue Zone', where longevity is concentrated in the central-eastern part of the island and covers all the mountainous areas of central Sardinia. The estimated life expectancy in the 'Blue Zone' is longer than in the remaining territory of the island especially for men and the male to female ratio among centenarians born in this area is 1.35 compared to 2.43 in the rest of Sardinia. The specific mechanism by which persons living in this territory were more likely to reach extreme longevity remains unknown but it is interesting to note that most of the 'longevity hot spots' identified in various regions of the world over the years have been located in mountainous geographical areas even if none of these longevity regions have been fully validated. An alternative and interesting hypothesis is that the high rate of inbreeding determined by frequent marriages between consanguineous individuals and low immigration rates have progressively decreased the variability of the genetic pool and facilitated the emergence of genetic characteristics that protect individuals from diseases that are major causes of mortality particularly in older individuals. Given the exceptionally high prevalence of male centenarians in the 'Blue Zone', it is reasonable to assume that either the environmental characteristics or the genetic factors, or both, exert their favorable effect more strongly in men than in women. Thus, the mechanism involved may be modulated by the hormonal milieu, or may be associated with genes located in the sex chromosomes.

Aged↗
PubMed2004

Association of the mitochondrial DNA haplogroup J with longevity is population specific.

Evidences are accumulating on the effects of the variability of mitochondrial DNA (mtDNA) on many complex traits. In particular, mtDNA haplogroup J has been reported to increase the individual chance to attain longevity in northern Italians, Northern Irish and Finns. However, since the genetic contribution to longevity may be population specific, we wanted to verify if haplogroup J does affect longevity also in a southern European population having a different genetic and environmental history. We analysed a population sample (883 subjects, 371 males and 521 females; age range 18-108 years) from southern Italy for the presence of haplogroup J. No frequency increase of this mtDNA haplogroup was found in the older cohorts, suggesting that, in this population, haplogroup J does not play a significant role in longevity. This finding shows that, as for other genetic factors, the association of mtDNA inherited variability with longevity is population specific.

Adolescent↗
PubMed2004

50 Hz sinusoidal magnetic fields do not affect human lymphocyte activation and proliferation in vitro.

In the last 30 years, an increasing public concern about the possible harmful effects of electromagnetic fields generated by power lines and domestic appliances has pushed the scientific community to search for a correct and comprehensive answer to this problem. In this work the effects of exposure to 50 Hz sinusoidal magnetic fields, with a magnetic flux density of 0.05 mT and 2.5 mT (peak values), were studied on human peripheral blood mononuclear cells (PBMCs) collected from healthy young and elderly donors. Cell activation and proliferation were investigated by using flow cytometry techniques and 3H-TdR incorporation assays, respectively. The results obtained indicated that exposure to the fields altered neither DNA synthesis nor the capacity of lymphocytes to enter the activation phase and progress into the cell cycle. Thus, the conclusions are that two important functional phases of human lymphocytes, such as activation and proliferation, are not affected by exposures to 50 Hz magnetic fields similar to those found under power lines.

Adult↗
PubMed2004

The G/C915 polymorphism of transforming growth factor beta1 is associated with human longevity: a study in Italian centenarians.

Sequence variations in a variety of pro- or anti-inflammatory cytokine genes have been found to influence successful aging and longevity. Because of the role played by the transforming growth factor beta1 (TGF-beta1) cytokine in inflammation and regulation of immune responses, the variability of the TGF-beta1 gene may affect longevity by playing a role in inflamm-aging. Two polymorphisms, G/A -800 and C/T -509, located in the 5' region, and two missense polymorphisms, T/C 869 and G/C 915 which change (Leu > Pro)10 and (Arg > Pro)25, respectively, located in the signal peptide, were analysed in 419 subjects from Northern and Central Italy, including 172 centenarians and 247 younger controls. In addition, the effects of the TGF-beta1 genetic variability on plasma levels of the biologically active form (naturally processed) of this cytokine were studied in 143 randomly selected subjects, including 73 centenarians. Significant differences were found at the +915 site as far as the C allele and GC genotype were concerned, both of them being lower in centenarians than in young controls (P=0.034 and 0.028, respectively), but none of the other tested genetic variants was significantly different between centenarians and controls. Moreover, a particular haplotype combination (G -800/C -509/C 869/C 915) was notably lower in centenarians than in younger individuals (P=0.007). Finally, active TGF-beta1 plasma levels were significantly increased in the elderly group, but no relationship with TGF-beta1 genotypes was observed. These results suggest that, at least in this population, the variability of the TGF-beta1 gene influences longevity and that the age-related increase in plasma levels of active TGF-beta1 seems not to be genetically regulated.

Adolescent↗
PubMed2004

Diverse effect of inflammatory markers on insulin resistance and insulin-resistance syndrome in the elderly.

OBJECTIVES: To evaluate the potential association between different inflammatory markers and insulin resistance (IR), as well as insulin-resistance syndrome (IRS) in a large, population-based study of older, nondiabetic persons. DESIGN: Cross-sectional study. SETTING: Outpatient clinic in Greve in Chianti and Bagno a Ripoli (Italy). PARTICIPANTS: One thousand one hundred forty-six nondiabetic subjects ranging in age from 22 to 104. MEASUREMENTS: Anthropometric measurements; plasma fasting levels of glucose, insulin, and cholesterol (total, high-density lipoprotein, low-density lipoprotein); homeostasis model assessment to estimate degree of insulin resistance; tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), soluble IL-6 receptor (sIL-6R), interleukin receptor antagonist (IL-1ra), and C-reactive protein (CRP) plasma concentrations; diastolic, systolic, and mean arterial blood pressure; and echo-color-Doppler duplex scanning examination of carotid arteries. RESULTS: Insulin resistance correlated with age (r=0.102; P<.001) and plasma levels of TNF-alpha (r=0.082; P=.007), IL-1ra (r=0.147; P<.001), IL-6 (r=0.133; P<.001), sIL-6R (r=-0.156; P<.001), and CRP (r=0.83; P<.001). Subjects in the upper tertile of IR degree were older and had higher serum levels of TNF-alpha, IL-1ra, and IL-6 and lower levels of sIL-6R than subjects in the lowest tertile. Independent of age, sex, body mass index, waist-to-hip ratio, triglycerides, drug intake, diastolic blood pressure, smoking habit, and carotid atherosclerotic plaques, higher IL-6 (t=2.987; P=.003) serum concentrations were associated with higher IR, whereas sIL-6R levels (t=-5.651; P<.001) were associated with lower IR. Furthermore, IL-1ra concentrations (t=2.448; P=.015) were associated with IRS, and higher sIL-6R plasma levels continued to correlate negatively with IRS. CONCLUSION: Different inflammatory markers are associated with a diverse effect on IR and IRS in elderly nondiabetic subjects.

Adult↗
PubMed2004

Aging, longevity, inflammation, and cancer.

Cancer rates increase sharply with age in both sexes, and the majority of cases of cancer occur in patients over the age of 65 years. However, the incidence and mortality for cancer level off around 85-90 years of age, followed by a plateau, or even a decline in the last decades of life. Therefore, it seems reasonable to conclude that centenarians are endowed with a peculiar resistance to cancer. Tumor progression is a complex process that depends on interactions between tumor and host cells. One aspect of the host response, the inflammatory response, is of particular interest because it includes the release of proinflammatory cytokines, some of which may promote tumor growth and hence influence survival. Data in the literature reviewed in this paper suggest that some kind of solid tumors are affected by regulatory cytokine genotypes. In particular proinflammatory genotypes characterized by a low IL-10 producer or a high IL-6 producer seem to be associated with a worse clinical outcome. On the other hand, recent evidence has linked IL-10 and IL-6 cytokine polymorphisms to longevity. In fact, those individuals who are genetically predisposed to produce high levels of IL-6 have a reduced capacity to reach the extreme limits of human life, whereas the high IL-10-producer genotype is increased among centenarians. This opposite effect of IL-6 and IL-10 common gene polymorphisms in cancer and longevity is intriguing. These data prompt considerations of the role that antagonistic pleiotropy plays in disease and in longevity. Inflammatory genotypes may be both friends and enemies. In fact, they are an important and necessary part of the normal host responses to pathogens, but the overproduction of inflammatory cytokines might cause immune-inflammatory diseases and eventually death. In fact, our immune system has evolved to control pathogens, so proinflammatory responses are likely to be evolutionarily programmed to resist fatal infections, and a high IL-6 or a low IL-10 production is associated with increased resistance to pathogens. However, decreased level of IL-6 or increased level of IL-10 might better control inflammatory responses and cancer development. These conditions might result in an increased chance of long-life survival in an environment with a reduced antigen (i.e., pathogen) load.

Adult↗
PubMed2004

The immune system in the elderly: activation-induced and damage-induced apoptosis.

Apoptosis is a complex cell-death process that allows cells to die in a controlled fashion. Our overall health relies to a great extent on the proper balance between the normal removal of damaged or unneeded cells via apoptosis and proliferation of the cells that comprise our body. Increasing evidence suggests that apoptosis is involved in many physiological processes and pathological conditions. It plays an important role during development, in maintaining tissue homeostasis, in responding to cellular damage, and in preventing neoplastic diseases. Apoptosis is a key regulator of clonotypic diversity generation during lymphocyte ontogenesis and is essential for the proper function of the immune system, controlling lymphocyte activation and clonal expansion following antigenic stimulation. There are various types of apoptosis, induced by different kinds of stimuli and in cells and tissues of different natures. On the basis of the nature of the apoptosis-inducing stimuli, two main apoptotic pathways can be identified: an activation-induced apoptosis, initiated by a variety of signals, such as the binding of ligands to their death-promoting receptors on the cell surface, and a damage-induced apoptosis, triggered by a damage to the nucleous or other cellular components. Apoptosis is markedly involved in many changes characteristic of immunosenescence, such as thymic involution, alteration of T-cell repertoire, accumulation of memory/effector cells, and autoimmunity. The intense investigation of the age-related changes occurring in cell-death phenomena and on their precise impact on aging has resulted in controversial data. During senescence, the activation-induced and damage-induced apoptotic pathways could be differentially modulated, with variable impacts on the aging process. Changes in either of these two main apoptotic networks that may occur during aging could lead to disease. A correct modulation of apoptosis may be useful for prolonging the lifespan or at least reducing age-related degenerative and inflammatory pathologies and neoplastic diseases whose incidence increases with age. Careful study of literature together with personal experience in the field of senescence causes us to propose a new reading register that better explains and integrates many of the apparently discordant results.

Aged↗
PubMed2004

In vitro exposure of human lymphocytes to 900 MHz CW and GSM modulated radiofrequency: studies of proliferation, apoptosis and mitochondrial membrane potential.

The aim of this study was to investigate the nonthermal effects of radiofrequency (RF) fields on human immune cells exposed to a Global System for Mobile Communication (GSM) signal generated by a commercial cellular phone and by a sinusoidal non-modulated signal. To assess whether mobile phone RF-field exposure affects human immune cell functions, peripheral blood mononuclear cells (PBMCs) from healthy donors were exposed in vitro to a 900 MHz GSM or continuous-wave (CW) RF field 1 h/day for 3 days in a transverse electromagnetic mode (TEM) cell system (70-76 mW/kg average specific absorption rate, SAR). The cells were cultured for 48 or 72 h, and the following end points were studied: (1) mitogen-induced proliferation; (2) cell cycle progression; (3) spontaneous and 2-deoxy-D-ribose (dRib)-induced apoptosis; (4) mitochondrial membrane potential modifications during spontaneous and dRib-induced-apoptosis. Data obtained from cells exposed to a GSM-modulated RF field showed a slight decrease in cell proliferation when PBMCs were stimulated with the lowest mitogen concentration and a slight increase in the number of cells with altered distribution of phosphatidylserine across the membrane. On the other hand, cell cycle phases, mitochondrial membrane potential and susceptibility to apoptosis were found to be unaffected by the RF field. When cells were exposed to a CW RF field, no significant modifications were observed in comparison with sham-exposed cells for all the end points investigated.

Adult↗
PubMed2003

Long-term immune-endocrine effects of bereavement: relationships with anxiety levels and mood.

Psychological, endocrine and immune parameters were measured over a 6-month period in 14 healthy subjects who underwent an unpredictable acute emotional stress (e.g. sudden death of a loved one) compared with 14 controls who did not. Probands were profoundly stressed as assessed 10 days after bereavement by their scores on the Hamilton Rating Scales of Anxiety and Depression, adrenocorticotropin and cortisol plasma concentrations, and non-suppression in response to dexamethasone. Functional alterations of immune parameters, such as responsiveness of peripheral blood lymphocytes to mitogens, were found 40 days after bereavement. Despite a normal number of circulating lymphocyte subsets, the functional activity of natural killer (NK) cells was markedly reduced at day 40. Changes in the intracellular concentration of beta-endorphin in peripheral blood mononuclear cells correlated with anxiety and depression scores. Controls showed no changes in psychometric, endocrine and immune measures during the 6-month study. Cluster analysis revealed two groups of bereaved subjects with different patterns of immune and endocrine changes: (1) Five subjects, characterized by harm-avoidant temperament and long-lasting dysphoric mood, showed reduced responsiveness of peripheral blood lymphocytes to mitogens, decreased NK cell activity and non-suppression in response to dexamethasone that persisted for 6 months. (2) Nine subjects showed significant changes only during the early phase after bereavement. Our data suggest that the immunological consequences of stress do not simply overlap with psychological and endocrine alterations, and are particularly severe and long-lasting in a subgroup of subjects, indicating the importance of individual variability in the capacity to cope with stress.

Adaptation, Psychological↗
PubMed2003

Retention of the p53 codon 72 arginine allele is associated with a reduction of disease-free and overall survival in arginine/proline heterozygous breast cancer patients.

PURPOSE: The arginine to proline substitution at codon 72 represents a common aminoacidic polymorphism of the p53 protein. Recent data suggest that p53 codon 72 may modulate the response to cancer therapy. The aim of this study was to test the hypothesis that the p53 codon 72 genotype, evaluated in the tumor tissue and in the disease-free lymph node, is related to differences in disease-free and overall survival among breast cancer-affected patients. EXPERIMENTAL DESIGN: We assessed the p53 codon 72 genotype in DNA from disease-free lymph nodes and neoplastic tissues obtained from 67 women affected by breast cancer who underwent surgical resection at the Bologna Breast Cancer Surgical Unit from 1993 to 1995. RESULTS: We found that the retention of the p53 codon 72 arginine allele in the tumor tissue of proline/arginine heterozygous breast cancer patients is associated with statistically significant reduced disease-free and overall survivals. CONCLUSIONS: Our findings suggest that the genotyping for p53 codon 72 locus in both the tumor tissue and in the lymph node of breast cancer patients could contribute to identify a subset of arginine/proline heterozygous patients who have a reduced survival that is associated with the specific retention of the arginine allele in the tumor tissue.

Adult↗
PubMed2003

Karyotype instability and anchorage-independent growth in telomerase-immortalized fibroblasts from two centenarian individuals.

Several reports have shown that the ectopic expression of the human telomerase catalytic subunit gene (hTERT) leads to an indefinite extension of the life span of human fibroblasts cultured in vitro without the appearance of cancer-associated changes. We infected two fibroblast strains derived from centenarian individuals with an hTERT containing retrovirus and isolated transduced massive populations (cen2tel and cen3tel). In both populations, hTERT expression reconstituted telomerase activity and extended the life span. In cen2tel, a net telomere lengthening was observed while, in cen3tel, telomeres stabilized at a length lower than that detected in senescent parental cells. Interestingly, both cen2tel and cen3tel cells developed chromosome anomalies, numerical first and structural thereafter. Moreover, cen3tel cells acquired the ability to grow in the absence of solid support, a typical feature of transformed cells. The results we present here highlight an unexpected possible outcome of cellular immortalization driven by telomerase reactivation, and indicate that, in some cases, an artificial extension of cellular replicative capacity can increase the probability of occurrence of genomic alterations, which can lead to cellular transformation.

Agar↗
PubMed2003

Serum IL-1beta levels in health and disease: a population-based study. 'The InCHIANTI study'.

Interleukin-1 plays a role in normal homeostasis and in the inflammatory response which is deemed to be responsible for the development of major chronic diseases that are highly prevalent in the elderly. Aim of this study is to evaluate the factors influencing the serum levels of Interleukin-1 beta, in a large and representative population. Data were from the InCHIANTI project, a study of factors contributing to the decline of mobility in late life, which sampled people living in two sites in the surroundings of Florence. Blood samples were obtained from 1,292 participants and frozen aliquots were stored at -80 degrees C. The serum levels of several cytokines were measured by enzyme linked immunosorbent assay using an ultrasensitive commercial kit. Interleukin-1 beta serum levels were associated with congestive heart failure (p > 0.001) and angina (p = 0.02), with Ca2+ serum levels (p = 0.02), and with a history of dyslipidemia (p = 0.05). We found no association between serum IL-1beta level and age, sex, consumption of cardioactive drugs and serum levels of IL-1Ra, IL-6, sIL-6R, IL-10 and TNF-alpha. Our data could lend support to the hypothesis that IL-1beta is mainly involved in the functional alterations of cardiomyocytes under conditions marked by mononuclear cell infiltration and by downregulation of calcium.

Aging↗
PubMed2003

Strikingly higher frequency in centenarians and twins of mtDNA mutation causing remodeling of replication origin in leukocytes.

The presence of a genetic component in longevity is well known. Here, the association of a mtDNA mutation with a prolonged life span in humans was investigated. Large-scale screening of the mtDNA main control region in leukocytes from subjects of an Italian population revealed a homoplasmic C150T transition near an origin of heavy mtDNA-strand synthesis in approximately 17% of 52 subjects 99-106 years old, but, in contrast, in only 3.4% of 117 younger individuals (P = 0.0035). Evidence was obtained for the contribution of somatic events, under probable nuclear genetic control, to the striking selective accumulation of the mutation in centenarians. In another study, among leukocyte mtDNA samples from 20 monozygotic and 18 dizygotic twins, 60-75 years old, 30% (P = 0.0007) and 22% (P = 0.011), respectively, of the individuals involved exhibited the homoplasmic C150T mutation. In a different system, i.e., in five human fibroblast longitudinal studies, convincing evidence for the aging-related somatic expansion of the C150T mutation, up to homoplasmy, was obtained. Most significantly, 5' end analysis of nascent heavy mtDNA strands consistently revealed a new replication origin at position 149, substituting for that at 151, only in C150T mutation-carrying samples of fibroblasts or immortalized lymphocytes. Considering the aging-related health risks that the centenarians have survived and the developmental risks of twin gestations, it is proposed that selection for a remodeled replication origin, inherited or somatically acquired, provides a survival advantage and underlies the observed high incidence of the C150T mutation in centenarians and twins.

Adolescent↗