Meeting report: mitochondrial DNA and cancer epidemiology.
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DNA, Mitochondrial↗
Biomedical subjects
Claudio Franceschi
Publications and source records attributed to Claudio Franceschi.
Inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans.
A large part of the aging phenotype, including immunosenescence, is explained by an imbalance between inflammatory and anti-inflammatory networks, which results in the low grade chronic pro-inflammatory status we proposed to call inflammaging. Within this perspective, healthy aging and longevity are likely the result not only of a lower propensity to mount inflammatory responses but also of efficient anti-inflammatory networks, which in normal aging fail to fully neutralize the inflammatory processes consequent to the lifelong antigenic burden and exposure to damaging agents. Such a global imbalance can be a major driving force for frailty and common age-related pathologies, and should be addressed and studied within an evolutionary-based systems biology perspective. Evidence in favor of this conceptualization largely derives from studies in humans. We thus propose that inflammaging can be flanked by anti-inflammaging as major determinants not only of immunosenescence but eventually of global aging and longevity.
Aging↗
Resistance to apoptosis of HCW-2 cells can be overcome by curcumin- or vincristine-induced mitotic catastrophe.
The term mitotic catastrophe has recently become widely used to describe a form of death affecting many cancer cells, which, because of severe DNA or mitotic spindle damage, are not able to bypass mitosis. We show here that cells of the HL-60-derived HCW-2 line highly resistant to apoptosis, upon treatment with curcumin or vincristine, undergo mitotic catastrophe that is finalized by caspase 3 activation and oligonucleosomal DNA degradation. Curcumin is a natural dye, derived from Curcuma longa that has been shown to induce cell death in many cancer cells. Both treatments decrease cell proliferation and cell survival, arrest cells in G2/M phase of cell cycle and induce morphological changes characterized by cell enlargement and micronucleation. "Catastrophic" cells comprise a separate subpopulation with less than 4C DNA, as evidenced by flow and scanning cytometry. This subpopulation is MPM-2 positive. Thymidine block increased the number of cell arrested in the G2/M phase of cell cycle and curcumin effectiveness as an inducer of mitotic catastrophe. Curcumin, but not vincristine, acts on HCW-2 cells by inhibiting the expression of survivin, a modulator of cell division and apoptosis in cancer. Altogether our results show that apoptosis resistance can be overcome by inducing mitotic catastrophe in HCW-2 cells.
Apoptosis↗
Alpha1-antitrypsin heterozygosity plays a positive role in attainment of longevity.
Genes involved in cardiovascular diseases (CVD) play an opposite role in human longevity. The alpha1-antitrypsin (AAT) is a serine-protease inhibitor required for the prevention of proteolytic tissue damage, by neutrophil elastase. The role of AAT in CVD has not been definitively assessed and its effect on longevity has not yet fully been studied. To clarify these points, we have studied the distribution of AAT allele variants in 3 cohorts: 127 young patients affected by acute myocardial infarction (AMI), 255 young controls and 143 centenarians from Sicily. The Z allele frequency was most frequent in centenarians (13.3%), intermediate in healthy young controls (3.1%) and less frequent in AMI patients (1.2%) (P = 0.0000001). The heterozygous MZ genotype was significantly over represented in centenarians (38/143) and under represented in AMI patients (3/127) with intermediate values in young controls (16/255) (P = 0.0000001). After adjustment for well-recognized AMI risk factors, the MZ genotype still predicted a significant negative risk factor for developing AMI in the Sicilian population. Thus, our data show a positive role of MZ heterozygosity in attainment of successful ageing linked to the positive effects of this genotype versus the cardiovascular ischemic diseases.
Adult↗
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↗
Family clustering in Sardinian longevity: a genealogical approach.
This paper aims to discuss the validation and family determinants affecting the longevity of Sardinian centenarians, using a genealogical approach. This preliminary study presents the first results of a genealogical tree reconstruction of selected centenarians aged 105 and over, from certain areas. These are mostly situated in the province of Nuoro, an area with the highest rate of centenarians and where the female-to-male sex ratio tends to be male-biased. An accurate centenarian age validation was performed that required a meticulous examination of numerous civil status records and parish registers. An important finding was that longevity occurs among the ascendants of a particular branch of the family. The data used are still provisional but, should it apply to other validated cases, it would provide empirical evidence of a genetic component in longevity. A more thorough examination of the data available may yield deeper insights into the role played by endogamy and consanguinity.
Aged, 80 and over↗
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↗
Genetic polymorphisms of inflammatory cytokines and myocardial infarction in the elderly.
Cardiovascular diseases (CVD), such as myocardial infarction (MI), are major causes of disability and mortality in the elderly. The increasing burden of CVD in ageing industrialized populations requires intensive research in order to improve preventive and therapeutic strategies especially in old people and if possible slow the processes of cardiovascular disease generation and progression. Ageing is accompanied by an age-dependent up-regulation of the inflammatory response, due to chronic antigenic stress stimulation, which potentially triggers the onset of inflammatory diseases, especially CVD. However, the exact mechanisms are still poorly understood. Since CVD are caused by interactions between genetic and environmental factors, a possible approach to their prevention is to identify the potential genetic component of inflammatory cardiovascular risk factors, providing the basis for personalized lifestyle modification and improved pharmacological therapy. Some common gene polymorphisms associated with high production of inflammatory molecules have been associated with atherosclerosis. Therefore, controlling inflammation might play a protective role against CVD, especially in ageing. Although a large number of studies of pro- and anti-inflammatory gene variants in association with CVD and MI exists, the emerging data are quite conflicting and do not provide definitive evidence for a role of these polymorphisms in the pathogenesis of MI. In this paper we review the evidence for a possible role of genetic polymorphisms of the most important inflammatory cytokines (IL-6, TNF-alpha, IL-10) and immune receptors (CD14 receptor and TLR-4) in modulating the incidence or the prognosis of MI, with a special focus in ageing population.
Aged↗
p66(Shc) gene has a pro-apoptotic role in human cell lines and it is activated by a p53-independent pathway.
p66(Shc) protein has been proposed to be an indispensable factor for p53-dependent, mitochondria-mediated apoptosis in mice. Here, we show that p66(Shc) plays a pro-apoptotic role also in cell lines of human origin such as SaOs-2 and HeLa, where p53 is either absent or inactivated, thus, suggesting that p66(Shc) pro-apoptotic role is independent from the presence of a functional form of p53. The active form of p66(Shc) is phosphorylated in Serine 36. We confirm the importance of Serine 36 phosphorylation for p66(Shc) pro-apoptotic role, and our results suggest that the kinase involved in this process is activated independently from p53.
Adaptor Proteins, Signal Transducing↗
Inflammation markers predicting frailty and mortality in the elderly.
Greater numbers of individuals are living to older ages. A major concern at both individual and population levels is how to live these years at a high functional level. If we had physiological markers to identify those at risk for progressive functional decline and impeding death, therapies could be targeted towards these individuals to prevent adverse outcomes. Senescence is presently considered as the consequence of lifelong antigenic stress impinging upon the individual genetic background. We might consider inflammation markers as synthetic measures of lifelong attrition combined with genetic tendency to develop an inflammatory phenotype. Such biomarkers are the most powerful predictors of frailty and mortality in the elderly available today. The aim of this review is to translate results from the research on ageing into a practical view, suggesting new tools for the clinical approach to older people.
Aged↗
Gene expression changes in human cells after exposure to mobile phone microwaves.
Possible biological effects of mobile phone microwaves were investigated in vitro. In this study, which was part of the 5FP EU project REFLEX (Risk Evaluation of Potential Environmental Hazards From Low-Energy Electromagnetic Field Exposure Using Sensitive in vitro Methods), six human cell types, immortalized cell lines and primary cells, were exposed to 900 and 1800 MHz. RNA was isolated from exposed and sham-exposed cells and labeled for transcriptome analysis on whole-genome cDNA arrays. The results were evaluated statistically using bioinformatics techniques and examined for biological relevance with the help of different databases. NB69 neuroblastoma cells, T lymphocytes, and CHME5 microglial cells did not show significant changes in gene expression. In EA.hy926 endothelial cells, U937 lymphoblastoma cells, and HL-60 leukemia cells we found between 12 and 34 up- or down-regulated genes. Analysis of the affected gene families does not point towards a stress response. However, following microwave exposure, some but not all human cells might react with an increase in expression of genes encoding ribosomal proteins and therefore up-regulating the cellular metabolism.
Cell Line↗
Immunoproteasome and LMP2 polymorphism in aged and Alzheimer's disease brains.
In this study, we investigated the presence and role of immunoproteasome and its LMP2 subunit polymorphism at codon 60 in Alzheimer's disease (AD). Immunoproteasome was present in brain areas such as hippocampus and cerebellum and localized in neurons, astrocytes and endothelial cells. A higher expression of immunoproteasome was found in brain of AD patients than in brain of non-demented elderly, being its expression in young brain negligible or absent. Furthermore, AD affected regions showed a partial decrease in proteasome trypsin-like activity. The study of LMP2 polymorphism (R/H) showed that it does not influence LMP2 expression (neither the mRNA nor mature protein) in brain tissue. However, control brain areas of AD patients carrying the RR genotype showed an increased proteasome activity in comparison with RH carriers. To test whether this effect of the genotype might be related to AD onset we performed a genetic study, which allowed us to exclude an association of LMP2 codon 60 polymorphism with AD onset, despite its influence on the proteasome activity in human brain.
Adult↗
Analysis of HLA-DQA, HLA-DQB frequencies in a group of Sardinian centenarians.
Human leukocyte antigen (HLA) alleles, regulating type and intensity of the immune response, might influence life expectancy. In previous case-control studies the authors have demonstrated that both HLA-DR and -DQ alleles are not associated with longevity in the Sardinian population. On the other hand, association studies are subjected (as part of the homogeneity of the population in terms of geographic origin) to a number of possible confounding factors. Therefore, the authors typed the HLA-DQA1 and HLA-DQB1 alleles in 24 sibs (age range 85 to 97) of 17 centenarians by PCR-SSP. Sib pair analysis showed nonsignificant differences between the observed and expected percentage of DQA* or DQB1* allele sharing. Therefore, these data strengthen the view that class II HLA genes have a marginal effect, if any, on the complex longevity trait.
Aged, 80 and over↗
Association between the HLA-A2 allele and Alzheimer disease.
In the elderly, the most common cause of dementia is Alzheimer disease (AD), which is responsible for the age-related progressive neurodegenerative inflammatory condition mediated by the disease. It has been seen that several genetic and environmental factors are involved in AD onset. Epidemiologic data suggest that some genetic determinants of AD might reside in those polymorphisms that regulate immune inflammatory responses, such as the major histocompatibility complex (MHC). Therefore, several MHC polymorphisms have been in the spotlight of a large number of AD association studies. A possible association of HLA-A2 allele with increased susceptibility to AD has been the subject of debate for more than 20 years, even if the results of these studies, in the various populations, are discordant. Thus, to gain insight in this matter, the authors have studied the HLA-A2 allele for a possible association with sporadic AD in a homogeneous population of Italian patients. For this reason, the distribution of HLA-A2 allele in patients with sporadic AD and controls was analyzed by PCR-SSP assay. The results demonstrated a significant difference in the frequency of HLA-A2 allele between patients with sporadic AD and controls (46% versus 38%). Thus, these data confirm a positive role of HLA-A2 allele in the risk of developing AD. However, some of the observed discrepancies may result from clinical or genetic heterogeneity of the populations under study or methodologic biases. Besides, whenever external agents such as viruses play a role, these might different in the various populations leading to various associations. However, it has to be taken into account that there are many molecular HLA-A2 subtypes with different frequencies in various populations. Therefore, further studies should include molecular typing of HLA-A2 subtypes.
Aged↗
Paraoxonase activity and genotype predispose to successful aging.
The paraoxonase 1 codon 192 R allele has been previously reported to have a role in successful aging. The relationship between PON1 genotypes, enzymatic activity, and mass concentration was evaluated in a group of 229 participants from 22 to 104 years of age, focusing our attention on nonagenarian/centenarian participants. We found a genetic control for paraoxonase activity that is maintained throughout life, also in the nonagenarians/centenarians. This activity decreases significantly during aging and shows different mean values among R and M carriers, where R+ and M- carriers have the significant highest paraoxonase activity. Results from the multinomial regression logistic model show that paraoxonase activity as well as R+ and M- carriers contribute significantly to the explanation of the longevity phenotype. In conclusion, we show that genetic variability at the PON1 locus is related to paraoxonase activity throughout life, and suggest that both parameters affect survival at extreme advanced age.
Adult↗
A polymorphism of the YTHDF2 gene (1p35) located in an Alu-rich genomic domain is associated with human longevity.
The uneven distribution of Alu repetitive elements in the human genome is related to specific functional properties of genomic regions. We report the identification of a locus associated with human longevity in one of the chromosomal regions with the highest density of Alu elements, in 1p35. The locus, corresponding to a (TG)n microsatellite in the YTHDF2 gene, was identified by characterizing an "anonymous" marker detectable through inter-Alu fingerprinting, which previously evidenced an increased homozygosity in centenarians. After genotyping 412 participants of different ages, including 137 centenarians, we confirmed the increased homozygosity in centenarians at this locus, and observed a concomitantly increased frequency of the most frequent allele and the corresponding homozygous genotype. Remarkably, the same genotype was associated with increased YTHDF2 messenger RNA levels in immortalized lymphocytes. Finally, YTHDF2 messenger RNA resulted to be mainly expressed in testis and placenta. The data suggest a possible role of this locus in human longevity.
Adolescent↗
The PON1192RR genotype is associated with a higher prevalence of arterial hypertension.
OBJECTIVE: To investigate whether genetic polymorphism of paraoxonase (PON1192), an enzyme which protects low density lipoprotein from oxidation, is related to the prevalence of arterial hypertension. METHODS: Two groups of carefully selected subjects of both sexes were enrolled and compared. The first group comprised 219 healthy controls (mean age 46.5 +/- 14.7 years) whereas the second comprised 119 hypertensive patients (mean age 47.9 +/- 10.5 years) with untreated essential arterial hypertension. Anthropometric and biochemical parameters were within the normal range in both groups. The PON1192 polymorphism was determined by a polymerase chain reaction-restriction fragment length polymorphism approach. RESULTS: In hypertensive patients, a significant increase of the frequency of PON1192RR genotype with respect to healthy controls (14.3 versus 5.0%, P = 0.003) was found. Logistic regression analyses also showed that the PON1192RR genotype was independently associated with a four-fold increase in susceptibility to arterial hypertension (odds ratio = 4.31; 95% confidence interval = 1.63-11.43, P = 0.003). CONCLUSIONS: The finding that PON1192RR genotype is associated with a higher prevalence of arterial hypertension may contribute to improving the stratification of cardiovascular risk within a population aged 30-60 years. Determination of the PON1192 polymorphism may help to identify those individuals who are prone to developing cardiovascular diseases at an early stage, suggesting the need for close monitoring of cardiovascular risk factors before the onset of cardiovascular disease.
Adult↗
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↗