Biomedical subjects

Giovanna De Benedictis

Publications and source records attributed to Giovanna De Benedictis.

18 recordsLinked to original sources

PubMed2006

Sex and age specificity of susceptibility genes modulating survival at old age.

OBJECTIVE: We aimed to investigate the influence of the genetic variability of candidate genes on survival at old age in good health. METHODS: First, on the basis of a synthetic survival curve constructed using historic mortality data taken from the Italian population from 1890 onward, we defined three age classes ranging from 18 to 106 years. Second, we assembled a multinomial logistic regression model to evaluate the effect of dichotomous variables (genotypes) on the probability to be assigned to a specific category (age class). Third, we applied the regression model to a cross-sectional dataset (10 genes; 972 subjects selected for healthy status) categorized according to age and sex. RESULTS: We found that genetic factors influence survival at advanced age in good health in a sex- and age-specific way. Furthermore, we found that genetic variability plays a stronger role in males than in females and that, in both genders, its impact is especially important at very old ages. CONCLUSIONS: The analyses presented here underline the age-specific effect of the gene network in modulating survival at advanced age in good health.

Adolescent↗

PubMed2006

The unusual genetics of human longevity.

In no species other than humans do cultural, social, and biological factors interact with each other in modulating complex phenotypes. Thus, the identification of genetic factors that affect human longevity is a true challenge. The model of centenarians provides us a unique opportunity to tackle this challenge. In this Perspective, we discuss some recent findings (the impact of geography and demography on the longevity phenotype, the relationship between longevity and homozygosity, the role of the nuclear-mitochondrial genome cross-talk) by which new ideas are suggested, such as the concept of a complex allele timing as a pivotal process in modulating the probability of achieving longevity.

Demography↗

PubMed2006

Mitochondrial DNA involvement in human longevity.

The main message of this review can be summarized as follows: aging and longevity, as complex traits having a significant genetic component, likely depend on a number of nuclear gene variants interacting with mtDNA variability both inherited and somatic. We reviewed the data available in the literature with particular attention to human longevity, and argued that what we hypothesize for aging and longevity could have a more general relevance and be extended to other age-related complex traits such as Alzheimer's and Parkinson's diseases. The genetics which emerges for complex traits, including aging and longevity, is thus even more complicated than previously thought, as epistatic interactions between nuclear gene polymorphisms and mtDNA variability (both somatic and inherited) as well as between mtDNA somatic mutations (tissue specific) and mtDNA inherited variants (haplogroups and sub-haplogroups) must be considered as additional players capable of explaining a part of the aging and longevity phenotype. To test this hypothesis is one of the main challenge in the genetics of aging and longevity in the next future.

Cell Nucleus↗

PubMed2006

Gene expression of cytokines and cytokine receptors is modulated by the common variability of the mitochondrial DNA in cybrid cell lines.

Some lines of evidence indicate that common polymorphisms of mitochondrial DNA (mtDNA) act as susceptibility factors in complex traits, such as age-related common diseases. There is also evidence that the cell capability to compensate ravages caused by intrinsic or extrinsic stress factors could contribute to some of these diseases. The cross-talk between nuclear and mitochondrial genome may link the above observations if we assume that the transcription of stress-responder nuclear genes is modulated according to the mtDNA common variability. Cytokines and cytokine receptors are key molecules in stress response. We could, therefore, check the above hypothesis by analyzing expression patterns of cytokine and cytokine receptor genes in response to stress in cell lines sharing the same nuclear genome but different mtDNA. By using a cybrid model (143B.TK- osteosarcoma cells depleted of their own mtDNA and repopulated with foreign mitochondria) we show that the transcription patterns of some of such genes are specifically modulated by the variability of the mitochondrial genome not only under stress conditions (interleukin-6) but also at basal conditions (interleukin-1beta and tumor necrosis factor receptor 2). These findings provide a first experimental evidence of a relationship between mtDNA common variability and expression pattern of stress responder nuclear genes in human cells.

Cell Fusion↗

PubMed2006

The genetics of human longevity.

Aging is due to a complex interaction of genetic, epigenetic, and environmental factors, but a strong genetic component appears to have an impact on survival to extreme ages. In order to identify "longevity genes" in humans, different strategies are now available. In our laboratory, we performed association studies on a variety of "candidate" polymorphisms in Italian centenarians. Many genes/polymorphisms gave negative results, while others showed a positive association with human longevity and a sometimes-positive association with unsuccessful aging (myocardial infarction, Alzheimer's disease, and type 2 diabetes). Results regarding genes involved in inflammation (IL-1 cluster, IL-6, IL-10, TNF-alpha, TGF-beta, TLR-4, PPARgamma), insulin/IGF-1 signaling pathway and lipid metabolism (apolipoproteins, CETP, PON1), and oxidative stress (p53, p66(shc)) will be described. In addition, a strong role of the interaction between nuclear and mitochondrial genomes (mtDNA haplogroups and the C150T mutation) emerged from our findings. Thus, the genetics of human longevity appears to be quite peculiar in a context where antagonistic pleiotropy can play a major role and genes can have a different biological role at different ages.

Adaptor Proteins, Signal Transducing↗

PubMed2005

What evidence is there for the existence of individual genes with antagonistic pleiotropic effects?

Classical evolutionary theory predicts the existence of genes with antagonistic effects on longevity and various components of early-life fitness. Quantitative genetic studies have provided convincing evidence that such genes exist. However, antagonistic pleiotropic effects have rarely been attributed to individual loci. We examine several classes of longevity-assurance genes: those involved in regulation of the gonad; the insulin-like growth factor pathway; free-radical scavenging; heat shock proteins and apoptosis. We find initial evidence that antagonistic pleiotropic effects are pervasive in each of these classes of genes and in various model systems--although most studies lack explicit studies of fitness components. This is particularly true of human studies. Very little is known about the early-life fitness effects of longevity loci. Given the possible medical importance of such effects we urge their future study.

Animals↗

PubMed2005

Genes involved in immune response/inflammation, IGF1/insulin pathway and response to oxidative stress play a major role in the genetics of human longevity: the lesson of centenarians.

In this paper, we review data of recent literature on the distribution in centenarians of candidate germ-line polymorphisms that likely affect the individual chance to reach the extreme limit of human life. On the basis of previous observations on the immunology, endocrinology and cellular biology of centenarians we focused on genes that regulate immune responses and inflammation (IL-6, IL-1 cluster, IL-10), genes involved in the insulin/IGF-I signalling pathway and genes that counteract oxidative stress (PON1). On the whole, data indicate that polymorphisms of these genes likely contribute to human longevity, in accord with observations emerging from a variety of animal models, and suggest that a common core of master genes and metabolic pathways are responsible for aging and longevity across animal species. Moreover, in the concern of our plan to discover new genetic factors related to longevity, we explored the possibility to by-pass the need of an a-priori choice of candidate genes, extending the search to genes and genomic regions of still unknown function. Alu sequences may be considered as good markers of highly variable and potentially unstable loci in functionally important genomic regions. We extensively screened Alu-rich genomic sites and found a new genomic region associated with longevity.

Adult↗

PubMed2005

A novel VNTR enhancer within the SIRT3 gene, a human homologue of SIR2, is associated with survival at oldest ages.

SIR2 genes control life span in model organisms, playing a central role in evolutionarily conserved pathways of aging and longevity. We wanted to verify whether similar effects may act in humans too. First, we searched for variability in the human sirtuin 3 gene (SIRT3) and discovered a VNTR polymorphism (72-bp repeat core) in intron 5. The alleles differed both for the number of repeats and for presence/absence of potential regulatory sites. Second, by transient transfection experiments, we demonstrated that the VNTR region has an allele-specific enhancer activity. Third, by analyzing allele frequencies as a function of age in a sample of 945 individuals (20-106 years), we found that the allele completely lacking enhancer activity is virtually absent in males older than 90 years. Thus the underexpression of a human sirtuin gene seems to be detrimental for longevity as it occurs in model organisms.

Adult↗

PubMed2004

A study of the average effect of the 3'APOB-VNTR polymorphism on lipidemic parameters could explain why the short alleles (<35 repeats) are rare in centenarians.

BACKGROUND: In studies on the genetics of human aging, we observed an age-related variation of the 3'APOB-VNTR genotypic pool (alleles: Short, S, <35 repeats; Medium, M, 35-39 repeats; Long, L, >39 repeats) with the homozygous SS genotype showing a convex frequency trajectory in a healthy aging population. This genotype was rare in centenarians, thus indicating that the S alleles are unfavorable to longevity, while common in adults, thus indicating a protective role at middle age. This apparent paradox could be due to possible effects exerted by the above polymorphism on lipidemic parameters. Aim of the work was to get insights into these puzzling findings METHODS: We followed a double strategy. Firstly, we analyzed the average effects of S (alphaS), M (alphaM), and L (alphaL) alleles on lipidemic parameters in a sample of healthy people (409 subjects aged 20-102 years) recruited in Calabria (southern Italy). The (alphaS), (alphaM), and (alphaL) values were estimated by relating 3'APOB-VNTR genotypes to lipidemic parameters, after adjustment for age, sex and body mass index (multiple regression). Then, we analyzed the S alleles as susceptibility factors of Cardiovascular Atherosclerotic Disease (CD) in CD patients characterized either by low serum HDL-Cholesterol or by high serum LDL-Cholesterol (CD-H and CD-L patients, 40 and 40 subjects respectively). The Odds Ratios (OR) were computed for carriers of S alleles in CD-H and CD-L patients matched for origin, sex and age with controls extracted from the sample of healthy subjects. RESULTS: By the analysis of the healthy sample group we found that the S alleles lower the average values of serum Total Cholesterol (alphaS = -5.98 mg/dL with [-11.62/-0.74] 95% confidence interval) and LDL-Cholesterol (alphaS = -4.41 mg/dL with [-8.93/-0.20] 95% confidence interval) while the alleles M and L have no significant effect on the lipidemic phenotype. In line with these findings, the analysis of CD patients showed that the S alleles are protective as for CD-L (O.R. = 0.55 with [0.21/0.98] 95% confidence interval) while neutral as for CD-H (O.R. = 0.75 with [0.32/1.60] 95% confidence interval). CONCLUSION: On the whole, the S alleles would be advantageous in adults (by protecting from CD-L) while dangerous in the elderly, probably by lowering serum cholesterol below a critical threshold. This could explain the convex frequency trajectory of SS genotypes previously observed in a healthy aging population.

3' Flanking Region↗

PubMed2004

Heat shock response by EBV-immortalized B-lymphocytes from centenarians and control subjects: a model to study the relevance of stress response in longevity.

'Successful aging', i.e. the ability to attain old age in relatively good health, is believed to be related to the capability to cope with different environmental stresses. Independently of their specific differentiation, all body cells respond to hyperthermia and other stresses with the production of Heat Shock Proteins (HSPs) that play an important role in cell survival. We investigated the heat shock response in B-lymphoid cell lines from 44 centenarians and 23 younger subjects, by studying both HSP70 synthesis and cell survival after hyperthermic treatment. Interestingly, no significant difference could be found between the two age groups as far as HSP70 synthesis was concerned; moreover, cell lines from centenarians appeared to be less prone to heat-induced apoptosis than lines from younger controls. These results, which are in contrast with previous findings showing an age-related decrease of the HSP70 synthesis and of hyperthermic response, corroborate the above mentioned hypothesis that the biological success of centenarians is due to the preservation of the capability to cope with stresses. An A/C polymorphism identified in the promoter region of HSP70-1 gene had been previously shown to affect the probability to attain longevity in females. To investigate if this effect was related to any influence of this polymorphism on HSP70 protein synthesis the correlation between A/C polymorphism and protein synthesis was investigated. We found that cells from AA centenarian females displayed a lower synthesis of HSP70.

Adult↗

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

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↗

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↗

PubMed2003

The role of IL-1 gene cluster in longevity: a study in Italian population.

In this study, we analysed the polymorphic variants of IL-1alpha (C-T transition at position -889), IL-1beta (C-T transition at position -511) and IL-1 receptor antagonist (Ra) (86-bp repeated sequence in intron 2) in 1131 subjects (453 females and 678 males) from Northern and Central Italy, including 134 centenarians, to evaluate whether IL-1 cluster alleles might be differently represented in people selected for longevity. In addition, IL-1Ra and IL-1beta plasma levels were quantified by ELISA in 130 randomly selected subjects. No significant differences in the genotype and allele frequency distributions were observed between young, elderly and centenarian subjects. IL-1Ra plasma levels showed an age-related increase, whereas IL-1beta plasma levels did not show any detectable age-related trend. Neither IL-1Ra nor IL-1beta plasma levels showed any relationship with genotypes of the three IL-1 genes. These results suggest that no one particular polymorphism in the IL-1 gene cluster yields an advantage for survival in the last decades of life, and that the age-related increase in plasma levels of IL-1Ra seems not to be genetically regulated but a likely safeguard mechanism to buffer the age-associated increased inflammatory state.

Adult↗

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↗

PubMedDate not supplied

What studies on human longevity tell us about the risk for cancer in the oldest old: data and hypotheses on the genetics and immunology of centenarians.

Centenarians are people who escaped from major common diseases, including cancer, and reached the extreme limits of human life-span. The analysis of demographic data indicates that cancer incidence and mortality show a levelling off around the age of 85-90 years, and suggests that oldest old people and centenarians are protected from cancer onset and progression. In this paper, we review data of recent literature on the distribution in centenarians of germ-line polymorphisms, which are supposed to affect the individual susceptibility to cancer (p53, HRAS1, BRCA1, glutathione transferases, cytochrome oxidases, steroid-5 alpha-reductase enzyme type II). Moreover, we add new data on two p53 polymorphisms in a total of 1086 people of different age, including 307 centenarians. In addition, we put forth the hypothesis that the remodelling of the immune system occurring with age is capable of creating a hostile environment for the growth of cancer cells in these exceptional individuals. We conclude that future studies on centenarians regarding the germ-line variability of genes involved in the control of the immune response, including apoptosis (ApoJ), are likely to be of fundamental importance in understanding the basic mechanisms for cancer, aging and their complex relationship.

Adult↗