30 results on '"Silvana Valensin"'
Search Results
2. Memory and Selectivity in Evolving Scale-Free Immune Networks.
- Author
-
Paolo Tieri, Silvana Valensin, Claudio Franceschi, Carlo Morandi, and Gastone C. Castellani
- Published
- 2003
- Full Text
- View/download PDF
3. Quantifying the relevance of different mediators in the human immune cell network.
- Author
-
Paolo Tieri, Silvana Valensin, Vito Latora, Gastone C. Castellani, Massimo Marchiori, Daniel Remondini, and Claudio Franceschi
- Published
- 2005
- Full Text
- View/download PDF
4. A Theoretical Model for 'in machina' Experiments on Immunosenescence
- Author
-
Gianni A. Di Caro and Silvana Valensin
- Subjects
Cognitive science ,History and Philosophy of Science ,Computer science ,General Neuroscience ,Immunosenescence ,General Biochemistry, Genetics and Molecular Biology - Published
- 2006
5. Inflamm-aging: An Evolutionary Perspective on Immunosenescence
- Author
-
Enzo Ottaviani, Claudio Franceschi, Maria De Luca, Giovanna De Benedictis, Fabiola Olivieri, Massimiliano Bonafè, and Silvana Valensin
- Subjects
Aging ,Longevity ,Inflammation ,Disease ,General Biochemistry, Genetics and Molecular Biology ,Network theory of aging ,Proinflammatory cytokine ,Evolution, Molecular ,Immune system ,History and Philosophy of Science ,Stress, Physiological ,medicine ,Animals ,Humans ,Interleukin-6 ,Macrophages ,General Neuroscience ,Stressor ,Immunosenescence ,Eukaryotic Cells ,Pleiotropy (drugs) ,Immune System ,Immunology ,medicine.symptom ,Psychology - Abstract
In this paper we extend the “network theory of aging,” and we argue that a global reduction in the capacity to cope with a variety of stressors and a concomitant progressive increase in proinflammatory status are major characteristics of the aging process. This phenomenon, which we will refer to as “inflamm-aging,” is provoked by a continuous antigenic load and stress. On the basis of evolutionary studies, we also argue that the immune and the stress responses are equivalent and that antigens are nothing other than particular types of stressors. We also propose to return macrophage to its rightful place as central actor not only in the inflammatory response and immunity, but also in the stress response. The rate of reaching the threshold of proinflammatory status over which diseases/disabilities ensue and the individual capacity to cope with and adapt to stressors are assumed to be complex traits with a genetic component. Finally, we argue that the persistence of inflammatory stimuli over time represents the biologic background (first hit) favoring the susceptibility to age-related diseases/disabilities. A second hit (absence of robust gene variants and/or presence of frail gene variants) is likely necessary to develop overt organ-specific age-related diseases having an inflammatory pathogenesis, such as atherosclerosis, Alzheimer's disease, osteoporosis, and diabetes. Following this perspective, several paradoxes of healthy centenarians (increase of plasma levels of inflammatory cytokines, acute phase proteins, and coagulation factors) are illustrated and explained. In conclusion, the beneficial effects of inflammation devoted to the neutralization of dangerous/harmful agents early in life and in adulthood become detrimental late in life in a period largely not foreseen by evolution, according to the antagonistic pleiotropy theory of aging.
- Published
- 2006
6. 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
- Author
-
Angelo Di Iorio, Giovanna De Benedictis, Fabiola Olivieri, Giuseppe Paolisso, Miriam Capri, Stefano Salvioli, Calogero Caruso, Silvana Valensin, Daniela Monti, Francesca Marchegiani, Maurizio Cardelli, Luca Cavallone, Claudio Franceschi, FRANCESCHI C, OLIVIERI F, MARCHEGIANI F, CARDELLI M, CAVALLONE L, CAPRI M, SALVIOLI S, VALENSIN S, DE BENEDICTIS G, DI IORIO A, CARUSO C, PAOLISSO G, MONTI, Franceschi C., Olivieri F., Marchegiani F., Cardelli M., Cavallone L., Capri M., Salvioli S., Valensin S., De Benedictis G., Di Iorio A., Caruso C., Paolisso G., Monti D., Franceschi, C, Olivieri, F, Marchegiani, F, Cardelli, M, Cavallone, L, Capri, M, Salvioli, S, Valensin, S, DE BENEDICTIS, G, DI IORIO, A, Caruso, C, Paolisso, Giuseppe, and Monti, D.
- Subjects
Adult ,Senescence ,Aging ,Candidate gene ,Genotype ,media_common.quotation_subject ,Longevity ,Biology ,Models, Biological ,Genome ,Immune system ,Humans ,Insulin ,Insulin-Like Growth Factor I ,Gene ,Aged ,media_common ,Aged, 80 and over ,Inflammation ,Genetics ,Polymorphism, Genetic ,Aryldialkylphosphatase ,Interleukin-6 ,Age Factors ,Immunity ,Hedgehog signaling pathway ,Interleukin-10 ,Oxidative Stress ,Multigene Family ,Function (biology) ,Interleukin-1 ,Signal Transduction ,Developmental Biology - Abstract
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.
- Published
- 2005
7. 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
- Author
-
Cristiana Barbi, Miriam Capri, Daniela Monti, Giovanna De Benedictis, Gianluca Storci, Stefano Salvioli, Fabiola Olivieri, Efstathios S. Gonos, Massimiliano Bonafè, Claudio Franceschi, and Silvana Valensin
- Subjects
Adult ,Gerontology ,Cholestenone 5 alpha-Reductase ,Aging ,Future studies ,Longevity ,Genes, BRCA1 ,Apoptosis ,Biology ,Demographic data ,Biochemistry ,Glutathione transferase ,Endocrinology ,Gene Frequency ,Risk Factors ,Neoplasms ,Genetics ,medicine ,Humans ,Genetic Predisposition to Disease ,Molecular Biology ,Aged ,Glutathione Transferase ,NADPH-Ferrihemoprotein Reductase ,Polymorphism, Genetic ,Individual susceptibility ,Cancer ,Cell Biology ,Middle Aged ,Genes, p53 ,medicine.disease ,Oldest old ,Apolipoproteins ,Genes, ras ,Cancer incidence ,Human longevity ,Lipoproteins, HDL ,Oxidoreductases - Abstract
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.
- Published
- 2002
8. A Stochastic Model for CD8+T Cell Dynamics in Human Immunosenescence: Implications for Survival and Longevity
- Author
-
Fabio Luciani, Paolo Sansoni, Giorgio Turchetti, Massimiliano Bonafè, Silvana Valensin, Rosanna Vescovini, Claudio Franceschi, and Francesco Fagnoni
- Subjects
Statistics and Probability ,Aging ,T cell ,Longevity ,CD8-Positive T-Lymphocytes ,Biology ,Lymphocyte Activation ,General Biochemistry, Genetics and Molecular Biology ,Immune system ,Antigen ,medicine ,Humans ,Cytotoxic T cell ,Lymphocyte Count ,Antigens ,Survival analysis ,Stochastic Processes ,General Immunology and Microbiology ,Applied Mathematics ,Models, Immunological ,General Medicine ,Immunosenescence ,T lymphocyte ,medicine.anatomical_structure ,Modeling and Simulation ,Immunology ,General Agricultural and Biological Sciences ,CD8 - Abstract
We propose here a stochastic model for the CD 8+T lymphocyte dynamics on the long time-scale of the human lifespan. Our purpose has been to test the hypothesis, recently proposed on the basis of our experimental data (Fagnoni et al., 2000), that the depletion of virgin CD8+T lymphocytes can be considered a reliable biomarker related to the risk of death. This hypothesis is embedded in a more general theory of immunosenescence according to which the accumulation of antigen experienced (AE) T cells and the concomitant exhaustion of antigen non-experienced (ANE) T cells with age, mostly due to the chronic lifelong exposure to antigens, is a major characteristic of the remodeling of the human immune system with age. In our model we considered a deterministic balance of ANE and AE T cell concentrations plus a stochastic forcing, which describes the chronic antigenic stress fluctuations, assuming a mean genetically determined capability of individuals to respond to antigens. The major results of our model is the validation of the above-mentioned hypothesis, since the model is capable of fitting the experimental data concerning the changes of ANE T cell concentration over age, and at the same time to reproduce survival curves similar to the demographic ones. Furthermore, the stochastic process results in being responsible for the peculiar shape of the survival curves.
- Published
- 2001
9. Decreased susceptibility to oxidative stress-induced apoptosis of peripheral blood mononuclear cells from healthy elderly and centenarians
- Author
-
Claudio Franceschi, Cristiana Barbi, Daniela Monti, Elisabetta Straface, Massimiliano Bonafè, Andrea Cossarizza, Mauro Piacentini, Silvana Valensin, Miriam Capri, Stefano Salvioli, Walter Malorni, Giovannella Baggio, and Barbara Botti
- Subjects
Adult ,Senescence ,Aging ,Programmed cell death ,Time Factors ,Tissue transglutaminase ,Drug Resistance ,Apoptosis ,apoptosis ,centenarians ,aging ,oxidative stress ,2-deoxy-D-ribose ,longevity ,Biology ,medicine.disease_cause ,Peripheral blood mononuclear cell ,Monocytes ,Membrane Potentials ,medicine ,Humans ,Aged ,Aged, 80 and over ,chemistry.chemical_classification ,Reactive oxygen species ,Cell Death ,Deoxyribose ,Dipeptides ,Intracellular Membranes ,Immunosenescence ,Acetylcysteine ,Mitochondria ,Oxidative Stress ,Proto-Oncogene Proteins c-bcl-2 ,chemistry ,Immunology ,biology.protein ,Oxidation-Reduction ,Oxidative stress ,Developmental Biology - Abstract
The susceptibility to undergo apoptosis of fresh human peripheral blood mononuclear cells (PBMCs) from three groups of healthy donors of different ages: young people (19-40 years), old people (65-85 years) and centenarians was assessed. Apoptosis was induced by 2-deoxy-D-ribose (dRib), an agent which induces apoptosis in quiescent PBMCs by interfering with cell redox status and mitochondrial membrane potential (MMP). Our major finding is that an inverse correlation emerged between the age of the donors and the propensity of their PBMCs to undergo dRib-induced apoptosis. PBMCs from old people and centenarians also showed an increased resistance to dRib-induced glutathione depletion and a decreased tendency to lose MMP. The anti-apoptotic molecule Bcl-2 was similarly expressed in PBMCs from the three age groups. Moreover, the plasma level of the stable product of transglutaminase, epsilon(gamma-glutamyl)lysine isodipeptide, a marker of total body apoptotic rate, was decreased in centenarians compared to young and elderly people. On the whole, these findings suggest that physiological aging is characterised by a decreased tendency to undergo apoptosis, a phenomenon likely resulting from adaptation to lifelong exposure to damaging agents, such as reactive oxygen species, and may contribute to one of the major phenomena of immunosenescence, i.e. the progressive accumulation of memory/effector T cells.
- Published
- 2001
10. [Untitled]
- Author
-
M. DeLuca, G. De Benedictis, Silvana Valensin, Anatoli I. Yashin, Massimiliano Bonafè, James W. Vaupel, Qihua Tan, and Claudio Franceschi
- Subjects
Genetics ,Aging ,Candidate gene ,education.field_of_study ,Population ,Confounding ,Population genetics ,Computational biology ,Biology ,Genetic determinism ,Life expectancy ,Geriatrics and Gerontology ,Gene–environment interaction ,Allele ,education ,Gerontology - Abstract
New approaches are needed to explore the different ways in which genes affect the human life span. One needs to assess the genetic effects themselves, as well as gene-environment interactions and sex dependency. In this paper, we present a new model that combines both genotypic and demographic information in the estimation of the genetic influence on life spans. Based on Cox's proportional hazard assumption, the model measures the risks for each gene as well as for gene-environment and gene-sex interactions, while controlling for confounding factors. A two-step MLE is introduced to obtain a non-parametric form of the baseline hazard function. The model is applied to genotypic data from Italian centenarian studies to estimate relative risks of candidate genes, risks due to interactions and initial frequencies of different genes in the population. Results from models that either do or do not take into consideration individual heterogeneity are compared. It is shown that ignoring the existence of heterogeneity can lead to a systematic underestimation of genetic effects and effects due to interactions.
- Published
- 2001
11. The network and the remodeling theories of aging: historical background and new perspectives
- Author
-
Silvana Valensin, Daniela Monti, Giuseppe Paolisso, Massimiliano Bonafè, Anatoli I. Yashin, G. De Benedictis, Claudio Franceschi, Franceschi, C, Valensin, S, Bonafe, M, Paolisso, Giuseppe, Yashin, Ai, Monti, D, and DE BENEDICTIS, G.
- Subjects
Inflammation ,Gerontology ,Aging ,media_common.quotation_subject ,Longevity ,Saccharomyces cerevisiae ,Cell Biology ,Immunosenescence ,Biology ,Biological Evolution ,Biochemistry ,Network theory of aging ,Mice ,Multicellular organism ,Endocrinology ,Immune System ,Genetics ,Animals ,Humans ,Molecular Biology ,Neuroscience ,Heat-Shock Proteins ,media_common - Abstract
Two general theories, i.e. “the network theory of aging” (1989) and “the remodeling theory of aging” (1995), as well as their implications, new developments, and perspectives are reviewed and discussed. Particular attention has been paid to illustrate: (i) how the network theory of aging fits with recent data on aging and longevity in unicellular organisms (yeast), multicellular organisms (worms), and mammals (mice and humans); (ii) the evolutionary and experimental basis of the remodeling theory of aging (immunological, genetic, and metabolic data in healthy centenarians, and studies on the evolution of the immune response, stress and inflammation) and its recent development (the concepts of “immunological space” and “inflamm-aging”); (iii) the profound relationship between these two theories and the data which suggest that aging and longevity are related, in a complex way, to the capability to cope with a variety of stressors.
- Published
- 2000
12. Do men and women follow different trajectories to reach extreme longevity?
- Author
-
Maurizio Cardelli, Maurizio Motta, Liana Spazzafumo, Paolo Sansoni, R. Rapisarda, Rosamaria Lisa, A.M. Franzone, C. Viticchi, Massimiliano Bonafè, L. Amadio, G. Sartoni, R. Mattace, L. Ferrucci, Paola Gueresi, G. De Benedictis, Silvana Valensin, R. Morresi, Fabiola Olivieri, Luca Deiana, Gabriella Pini, Cristiana Barbi, Luca Cavallone, Claudio Franceschi, Gianni Pes, Luciano Motta, M. Berardelli, Claudia Gemelli, Francesca Marchegiani, Maria Speranza Desole, Andrea Cossarizza, L. Troiano, Daniela Monti, Ciriaco Carru, Giovanni Passeri, S. Giunta, G. Baggio, Francesco Lescai, and Rosalia Stecconi
- Subjects
Gerontology ,Aging ,Mortality rate ,Incidence (epidemiology) ,media_common.quotation_subject ,Longevity ,Haplotype ,Gender ,Biology ,Social group ,Multicenter study ,Centenarians ,Sex ,Geriatrics and Gerontology ,media_common ,Human mitochondrial DNA haplogroup ,Sex characteristics - Abstract
Gender accounts for important differences in the incidence and prevalence of a variety of age-related diseases. Considering people of far advanced age, demographic data document a clear-cut prevalence of females compared to males, suggesting that sex-specific mortality rates follow different trajectories during aging. In the present investigation, we report data from a nationwide study on Italian centenarians (a total of 1162 subjects), and from two studies on centenarians living in two distinct zones of Italy, i.e., the island of Sardinia (a total of 222 subjects) and the Mantova province (Northern Italy) (a total of 43 subjects). The female/male ratio was about 2:1 in Sardinia, 4:1 in the whole of Italy, and about 7:1 in the Mantova province. Thus, a complex interaction of environmental, historical and genetic factors, differently characterizing the various parts of Italy, likely plays an important role in determining the gender-specific probability of achieving longevity. Gender differences in the health status of centenarians are also reported, and an innovative score method to classify long-lived people in different health categories, according to clinical and functional parameters, is proposed. Our data indicate that not only is this selected group of people, as a whole, highly heterogeneous, but also that a marked gender difference exists, since male centenarians are less heterogeneous and more healthy than female centenarians. Immunological factors regarding the age-related increase in pro-inflammatory status, and the frequency of HLA ancestral haplotypes also show gender differences that likely contribute to the different strategies that men and women seem to follow to achieve longevity. Concerning the different impact of genetic factors on the probability of reaching the extreme limits of the human life-span, emerging evidence (regarding mtDNA haplogroups, Thyrosine Hydroxilase, and IL-6 genes) suggests that female longevity is less dependent on genetics than male longevity, and that female centenarians likely exploited a healthier life-style and more favorable environmental conditions, owing to gender-specific cultural and anthropological characteristics of the Italian society in the last 100 years.
- Published
- 2000
13. p53 Codon 72 Polymorphism and Longevity: Additional Data on Centenarians from Continental Italy and Sardinia
- Author
-
Sandro Sorbi, Fabiola Olivieri, Ciriaco Carru, Daniela Monti, Paola Gueresi, Massimiliano Bonafè, M. Morellini, Paolo Sansoni, Leonarda Troiano, Rosamaria Lisa, Luigi Ferrucci, Rosario Mattace, Luca Deiana, Maurizio Berardelli, Daniela Mari, Giovanni Passeri, Giovannella Baggio, Gabriella Pini, Francesca Marchegiani, Cristiana Barbi, Loredana Amadio, Maurizio Cardelli, Silvana Valensin, Giovanna De Benedictis, Maria Giovanna Tucci, Giovanni Mario Pes, Luca Cavallone, Simona Giovagnetti, Claudio Franceschi, and Maria De Luca
- Subjects
Aging ,media_common.quotation_subject ,Longevity ,Cancer and aging ,Biology ,Neoplasms ,Centenarians ,Ethnicity ,Genetics ,Humans ,Genetic Predisposition to Disease ,Genetics(clinical) ,Allele ,Letters to the Editor ,Codon ,Genetics (clinical) ,media_common ,Aged ,Aged, 80 and over ,P53 ,Cancer risk factors ,Polymorphism, Genetic ,Haplotype ,Case-control study ,Age Factors ,Genes, p53 ,Genotype frequency ,Haplotypes ,Italy ,Human longevity ,Case-Control Studies ,Sample Size ,Codon 72 polymorphism - Abstract
In a previous letter (Bonafe et al. 1999) we tested the hypothesis that polymorphic variants of p53 have an impact on human longevity, by comparing p53 codon 72 allelic and genotypic frequency distributions between young people and centenarians. A nonsignificant difference emerged between the groups, and several explanations were offered. Following the reply letter of Sun et al. (in this issue), we would like to argue with some of their comments and to provide new data regarding centenarians from continental Italy and Sardinia.
- Published
- 1999
- Full Text
- View/download PDF
14. Design, recruitment, logistics, and data management of the GEHA (Genetics of Healthy Ageing) project
- Author
-
C. Gilbault, G. Pelicci, Marian Beekman, Axel Skytthe, Serena Dato, A. Skouteri, Konstantinos Voutetakis, Luca Deiana, Ciriaco Carru, Ewa Sikora, Claudio Franceschi, Friederike Flachsbart, Leena Peltonen, James W. Vaupel, P. Laiho, Joanna Collerton, V. Bezrukov, Stefan Schreiber, Michel Poulain, Karen Davies, Irene Maeve Rea, Mikko Hurme, Giuseppe Passarino, Federica Sevini, Katarzyna Broczek, Outi Törnwall, Antti Hervonen, Elisa Cevenini, Hélène Blanché, Bernard Jeune, Maria Scurti, Rodolfo Cotichini, Jean-Marie Robine, Erica Haimes, A.J.M. de Craen, Thomas B. L. Kirkwood, R. Masciulli, José Remacle, Lene Christiansen, Dorota Janiszewska, F. Balard, Almut Nebel, A. Leon, P.E. Slagboom, Lars Bolund, A. Marchisio, Liana Spazzafumo, Marja Jylhä, Virgilia Toccaceli, G. De Benedictis, Markus Perola, Olivier Toussaint, Jutta Gampe, M A Stazi, Silvana Valensin, Peter Kristensen, Kaare Christensen, Efstathios S. Gonos, University of Southern Denmark (SDU), University of Bologna/Università di Bologna, Laboratoire Lorrain de Sciences Sociales (2L2S), Université de Lorraine (UL), Institut National de la Santé et de la Recherche Médicale (INSERM), Netherlands Consortium for Healthy Ageing, Leiden University Medical Center (LUMC), Universiteit Leiden-Universiteit Leiden, Institute of Gerontology [Kiev], Fondation Jean Dausset - Centre d’Etudes du Polymorphisme Humain [Paris] (CEPH), Beijing Genomics Institute [Shenzhen] (BGI), Institute of Human Genetics [Aarhus], Nencki Institute of Experimental Biology, Polska Akademia Nauk = Polish Academy of Sciences (PAN), Medical University of Warsaw - Poland, Università degli Studi di Sassari = University of Sassari [Sassari] (UNISS), Odense University Hospital (OUH), Newcastle University [Newcastle], Istituto Superiore di Sanità (ISS), Universiteit Leiden, Università della Calabria [Arcavacata di Rende] (Unical), Institute of Clinical Molecular Biology, Kiel University, Max Planck Institute for Demographic Research (MPIDR), Max-Planck-Gesellschaft, Université Catholique de Louvain = Catholic University of Louvain (UCL), National Hellenic Research Foundation [Athens], Tampere School of Public Health, University of Tampere [Finland], University of Aarhus, The National Institute for Health and Welfare, National Institute for Health and Welfare [Helsinki], Research Innovation [Italy], IFOM Institute of Milan, Queen's University [Belfast] (QUB), Eppendorf Array Technologies, CERMES3 - Centre de recherche Médecine, sciences, santé, santé mentale, société (CERMES3 - UMR 8211 / U988 / UM 7), École des hautes études en sciences sociales (EHESS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Istituto Nazionale Ricovero e Cura Anziani, Université de Namur [Namur] (UNamur), European Project: 26813,GEHA, University of Bologna, Istituto Superiore di Sanita [Rome], University of Calabria, The Queen’s University of Belfast, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-École des hautes études en sciences sociales (EHESS), Skytthe A., Valensin S., Jeune B., Cevenini E., Balard F., Beekman M., Bezrukov V., Blanche H., Bolund L., Broczek K., Carru C., Christensen K., Christiansen L., Collerton J.C., Cotichini R., de Craen A.J., Dato S., Davies K., De Benedictis G., Deiana L., Flachsbart F., Gampe J., Gilbault C., Gonos E.S., Haimes E., Hervonen A., Hurme M.A., Janiszewska D., Jylha M., Kirkwood T.B., Kristensen P., Laiho P., Leon A., Marchisio A., Masciulli R., Nebel A., Passarino G., Pelicci G., Peltonen L., Perola M., Poulain M., Rea I.M., Remacle J., Robine J.M., Schreiber S., Scurti M., Sevini F., Sikora E., Skouteri A., Slagboom P.E., Spazzafumo L., Stazi M.A., Toccaceli V., Toussaint O., Tornwall O., Vaupel J.W., Voutetakis K., Franceschi C., GEHA consortium [Pini Elisa, Palmas Maria Giustina, Panourgia Maria Panagiota], balard, frédéric, and GEnetics for Healthy Aging - GEHA - 26813 - OLD
- Subjects
Research design ,Gerontology ,Male ,Questionnaires ,Aging ,Genetic Linkage ,[SDV]Life Sciences [q-bio] ,Genome-wide association study ,Biochemistry ,Nonagenarian sib pairs ,[SHS]Humanities and Social Sciences ,0302 clinical medicine ,Endocrinology ,Cognition ,Surveys and Questionnaires ,80 and over ,Medicine ,ComputingMilieux_MISCELLANEOUS ,media_common ,Genetics ,Aged, 80 and over ,0303 health sciences ,Life style ,Longevity ,Middle Aged ,HEALTHY AGING ,[SDV] Life Sciences [q-bio] ,Europe ,Research Design ,Extreme longevity tracking ,Female ,[SHS] Humanities and Social Sciences ,media_common.quotation_subject ,Article ,03 medical and health sciences ,Healthy ageing ,Humans ,Family ,Molecular Biology ,Life Style ,030304 developmental biology ,Genetic association ,Aged ,nonagenarian sib pair ,business.industry ,Patient Selection ,Cell Biology ,Multicenter study ,business ,030217 neurology & neurosurgery ,Genome-Wide Association Study - Abstract
In 2004, the integrated European project GEHA (Genetics of Healthy Ageing) was initiated with the aim of identifying genes involved in healthy ageing and longevity. The first step in the project was the recruitment of more than 2500 pairs of siblings aged 90years or more together with one younger control person from 15 areas in 11 European countries through a coordinated and standardised effort. A biological sample, preferably a blood sample, was collected from each participant, and basic physical and cognitive measures were obtained together with information about health, life style, and family composition. From 2004 to 2008 a total of 2535 families comprising 5319 nonagenarian siblings were identified and included in the project. In addition, 2548 younger control persons aged 50-75years were recruited. A total of 2249 complete trios with blood samples from at least two old siblings and the younger control were formed and are available for genetic analyses (e.g. linkage studies and genome-wide association studies). Mortality follow-up improves the possibility of identifying families with the most extreme longevity phenotypes. With a mean follow-up time of 3.7years the number of families with all participating siblings aged 95years or more has increased by a factor of 5 to 750 families compared to when interviews were conducted. Thus, the GEHA project represents a unique source in the search for genes related to healthy ageing and longevity. In 2004, the integrated European project GEHA (Genetics of Healthy Ageing) was initiated with the aim of identifying genes involved in healthy ageing and longevity. The first step in the project was the recruitment of more than 2500 pairs of siblings aged 90years or more together with one younger control person from 15 areas in 11 European countries through a coordinated and standardised effort. A biological sample, preferably a blood sample, was collected from each participant, and basic physical and cognitive measures were obtained together with information about health, life style, and family composition. From 2004 to 2008 a total of 2535 families comprising 5319 nonagenarian siblings were identified and included in the project. In addition, 2548 younger control persons aged 50-75years were recruited. A total of 2249 complete trios with blood samples from at least two old siblings and the younger control were formed and are available for genetic analyses (e.g. linkage studies and genome-wide association studies). Mortality follow-up improves the possibility of identifying families with the most extreme longevity phenotypes. With a mean follow-up time of 3.7years the number of families with all participating siblings aged 95years or more has increased by a factor of 5 to 750 families compared to when interviews were conducted. Thus, the GEHA project represents a unique source in the search for genes related to healthy ageing and longevity.
- Published
- 2011
15. Systems biology and longevity: an emerging approach to identify innovative anti-aging targets and strategies
- Author
-
Stefano Salvioli, Paolo Tieri, Miriam Capri, Elena Bellavista, Alexey Zaikin, Mirko Francesconi, Francesco Lescai, Aurelia Santoro, Silvana Valensin, Daniela Monti, Michele Mishto, Claudio Franceschi, Elisa Cevenini, J. P. de Magalhaes, Gastone Castellani, Cevenini E., Bellavista E., Tieri P., Castellani G., Lescai F., Francesconi M., Mishto M., Santoro A., Valensin S., Salvioli S., Capri M., Zaikin A., Monti D., de Magalhaes J.P., and Franceschi C.
- Subjects
Senescence ,Aging ,Process (engineering) ,Systems biology ,media_common.quotation_subject ,Longevity ,Genomics ,Computational biology ,Longevity, physiology ,Biology ,Protein degradation ,Models, Biological ,03 medical and health sciences ,0302 clinical medicine ,Drug Discovery ,Humans ,Organism ,030304 developmental biology ,media_common ,Pharmacology ,Genetics ,0303 health sciences ,Systems Biology ,Age Factors ,Phenotype ,Aging, physiology ,Drug Design ,030217 neurology & neurosurgery - Abstract
Human aging and longevity are complex and multi-factorial traits that result from a combination of environmental, genetic, epigenetic and stochastic factors, each contributing to the overall phenotype. The multi-factorial process of aging acts at different levels of complexity, from molecule to cell, from organ to organ systems and finally to organism, giving rise to the dynamic "aging mosaic". At present, an increasing amount of experimental data on genetics, genomics, proteomics and other -omics are available thanks to new high-throughput technologies but a comprehensive model for the study of human aging and longevity is still lacking. Systems biology represents a strategy to integrate and quantify the existing knowledge from different sources into predictive models, to be later tested and then implemented with new experimental data for validation and refinement in a recursive process. The ultimate goal is to compact the new acquired knowledge into a single picture, ideally able to characterize the phenotype at systemic/organism level. In this review we will briefly discuss the aging phenotype in a systems biology perspective, showing four specific examples at different levels of complexity, from a systemic process (inflammation) to a cascade-process pathways (coagulation) and from cellular organelle (proteasome) to single gene-network (PON-1), which could also represent targets for anti-aging strategies.
- Published
- 2010
16. Capturing Degeneracy in the Immune System
- Author
-
Claudio Franceschi, Paolo Tieri, Stefano Salvioli, Jonathan Loroni, Daniel Remondini, Gastone Castellani, and Silvana Valensin
- Subjects
Immune system ,Risk analysis (engineering) ,Artificial immune system ,Computer science ,Resource constraints ,Degeneracy (biology) ,Immune receptor ,Organism - Abstract
For host survival, the immune system (IS) is required to deliver high-level, specific and continuous performance, dealing with a very complex universe of stimuli and functions, as well as physical and resource constraints. From this perspective, the immune system needs an effective strategy to assure the requested operational functions, to survive and to evolve. The concept of degeneracy discussed in this chapter, is the ability of some immune receptors to bind many types of ligands and it would appear to be a fundamental characteristic for immune system functioning as well as a formidable weapon in the architecture of complex biological structures and systems. In this chapter, we will discuss how degeneracy acts as a strategy to optimize the necessary trade-off between the inescapable promiscuity of receptors and ligands, with the necessity to produce a specific response, and how the degeneracy principle acts to set up a memory of each immunological event, thus contributing to the fitness of the organism, and how degeneracy can be considered among the underlying causes for the evolution and robustness of the IS.
- Published
- 2007
17. Complexity of anti-immunosenescence strategies in humans
- Author
-
Michela Pierini, Serena Altilia, Federica Sevini, Francesco Lescai, Silvana Valensin, Rita Ostan, Claudio Franceschi, Daniela Monti, Laura Bucci, Miriam Capri, Stefano Salvioli, Capri M., Monti D., Salvioli S., Lescai F., Pierini M., Altilia S., Sevini F., Valensin S., Ostan R., Bucci L., and Franceschi C.
- Subjects
Aging ,T-Lymphocytes ,Biomedical Engineering ,Medicine (miscellaneous) ,Cytomegalovirus ,Cytomegalovirus, immunology ,Bioengineering ,Thymus Gland ,Biology ,Immune System, growth /&/ development ,Biomaterials ,Immune system ,Antigen ,Thymus Gland, immunology ,Cytotoxic T cell ,Humans ,Involution (medicine) ,Cytomegalovirus Infections, immunology ,Progenitor cell ,Antigens ,Inflammation ,Thymic involution ,Inflammation, immunology ,T-Lymphocytes, immunology ,CD28 ,General Medicine ,Immunosenescence ,Aging, immunology ,Biological Evolution ,Immune System ,Immunology ,Cytomegalovirus Infections ,Antigens, immunology - Abstract
Immunosenescence is characterized by three main aspects: (i) the shrinkage of the T cell repertoire and the accumulation of oligoclonal expansions (megaclones) of memory/effector cells directed toward ubiquitary infectious agents; (ii) the involution of the thymus and the exhaustion of naive T cells; and (iii) a chronic inflammatory status called inflamm-aging. We present here possible strategies to counteract these main aspects of immunosenescence in humans with particular attention to the reduction of antigenic load by pathogens, such as CMV, and the normalization of intestinal microflora, the possible utilization of IL-7 to reverse thymic involution, the purging of megaclones, the forced expression of CD28 on T lymphocytes, the reduction of inflamm-aging and the administration of nutrients such as vitamin D. Possible drawbacks of all these strategies are discussed. Finally, the complexity of a rejuvenation approach is stressed, with particular attention to the inhibitory role played by the "old microenvironment" on the performance of progenitor cells, the best candidate to counteract the decline in regenerative potential characteristic of organs and tissues from old organisms.
- Published
- 2006
18. A general learning rule for network modeling of neuroimmune interactome
- Author
-
Gastone Castellani, Paolo Tieri, Silvana Valensin, Ferdinando Bersani, Ettore Verondini, Claudio Franceschi, Daniel Remondini, Apolloni, B, Marinaro, M, Necosia, G, Tagliaferri, R, D. Remondini, P. Tieri, S. Valensin, E. Verondini, C. Franceschi, F. Bersani, and G. Castellani
- Subjects
Input/output ,SELECTION ,Artificial neural network ,Computer science ,business.industry ,IMMUNE NETWORK ,MEMORY ,Network theory ,Network topology ,Interactome ,Set (abstract data type) ,CONNECTIVITY ,Learning rule ,Artificial intelligence ,PLASTICITY ,business ,SYSTEM ,Network model - Abstract
We propose a network model in which the communication between its elements (cells, neurons and lymphocytes) can be established in various ways. The system evolution is driven by a set of equations that encodes various degrees of competition between elements. Each element has an “internal plasticity threshold” that, by setting the number of inputs and outputs, determines different network global topologies.
- Published
- 2006
19. Inflamm-aging, Cytokines and aging: State of the art, new hypotheses on the role of mitochondria and new perspectives from systems biology
- Author
-
Enzo Ottaviani, Claudio Franceschi, Daniela Monti, Silvana Valensin, Paolo Tieri, Stefano Salvioli, Miriam Capri, Salvioli S., Capri M., Valensin S., Tieri P., Monti D., Ottaviani E., and Franceschi C.
- Subjects
Senescence ,Aging ,Systems biology ,media_common.quotation_subject ,In silico ,medicine.medical_treatment ,pro-inflammatory cytokines ,aging ,Physiology ,Disease ,Computational biology ,Biology ,Heat shock protein ,Drug Discovery ,medicine ,Animals ,Humans ,Phylogeny ,media_common ,Inflammation ,Pharmacology ,Polymorphism, Genetic ,Innate immune system ,Systems Biology ,Longevity ,Mitochondria ,Cytokine ,Cytokines - Abstract
In this article we summarise present knowledge on the role of pro-inflammatory cytokines on chronic inflammation leading to organismal aging, a phenomenon we proposed to call "inflamm-aging". In particular, we review genetic data regarding polymorphisms of genes encoding for cytokines and proteins involved in natural immunity (such as Toll-like Receptors and Heat Shock Proteins) obtained from large population studies including young, old and very old people in good health status or affected by age-related diseases such as Alzheimer's Disease and Type II Diabetes. On the whole, despite some controversial results, the available data are in favour of the hypothesis that pro-inflammatory cytokines play an important role in aging and longevity. Further, we present a possible hypothesis to reconcile energetic dysfunction, including mitochondria, and inflamm-aging. New perspectives for future studies, including phylogenetic studies in animal models and in silico studies on mathematical and bioinformatic models inspired by the systems biology approach, are also proposed.
- Published
- 2006
20. Genes, Ageing and Longevity in Humans: Problems, Advantages and Perspectives
- Author
-
Laura Celani, Stefano Salvioli, Miriam Capri, Francesca Marchegiani, G. De Benedictis, Calogero Caruso, Aurelia Santoro, Michele Mishto, Claudio Franceschi, Maurizio Cardelli, Giuseppe Paolisso, Efstathios S. Gonos, Fabiola Olivieri, Elena Bellavista, Elisa Cevenini, Laura Invidia, Daniela Monti, Federica Sevini, Francesco Lescai, Silvana Valensin, Salvioli S., Olivieri F., Marchegiani F., Cardelli M., Santoro A., Bellavista E., Mishto M., Invidia L., Capri M., Valensin S., Sevini F., Lescai F., Gonos E., Caruso C., Paolisso G., De Benedictis G., Monti D., Franceschi C., SALVIOLI S, OLIVIERI F, MARCHEGIANI F, CARDELLI M, SANTORO A, BELLAVISTA E, MISHTO M, INVIDIA L, CAPRI M, VALENSIN S, SEVINI F, CEVENINI E, CELANI L, LESCAI F, GONOS E, CARUSO C, PAOLISSO G, DE BENEDICTIS G, MONTI D, FRANCESCHI C, Salvioli, S, Olivieri, F, Marchegiani, F, Cardelli, M, Santoro, A, Bellavista, E, Mishto, M, Invidia, L, Capri, M, Valensin, S, Sevini, F, Cevenini, E, Celani, L, Lescai, F, Gonos, E, Caruso, C, Paolisso, Giuseppe, DE BENEDICTIS, G, Monti, D, and Franceschi, C.
- Subjects
Mitochondrial DNA ,Aging ,Proteasome Endopeptidase Complex ,Nuclear gene ,Apolipoproteins, genetics ,Insulin-Like Growth Factor I, genetics ,media_common.quotation_subject ,Apolipoprotein E4 ,Longevity ,Biology ,Genetic polymorphisms, ageing, longevity, centenarians, association studies, mitochondrial DNA ,Biochemistry ,DNA, Mitochondrial ,Inflammation, genetics ,Apolipoprotein E4, genetics ,Cytokines, genetics ,Animals ,Humans ,Allele ,Insulin-Like Growth Factor I ,Longevity, genetics ,Gene ,media_common ,Genetic association ,Genetics ,Aged, 80 and over ,Inflammation ,Polymorphism, Genetic ,Aryldialkylphosphatase ,Superoxide Dismutase ,Superoxide Dismutase, genetics ,General Medicine ,Clusterin, genetics ,Poly(ADP-ribose) Polymerases, genetics ,Aging, genetics ,Apolipoproteins ,Clusterin ,Tumor Suppressor Protein p53, genetics ,Genes ,Evolutionary biology ,Trait ,Cytokines ,Gene pool ,Poly(ADP-ribose) Polymerases ,Tumor Suppressor Protein p53 ,Aryldialkylphosphatase, genetics ,DNA, Mitochondrial, genetics ,Proteasome Endopeptidase Complex, physiology - Abstract
Many epidemiological data indicate the presence of a strong familial component of longevity that is largely determined by genetics, and a number of possible associations between longevity and allelic variants of genes have been described. A breakthrough strategy to get insight into the genetics of longevity is the study of centenarians, the best example of successful ageing. We review the main results regarding nuclear genes as well as the mitochondrial genome, focusing on the investigations performed on Italian centenarians, compared to those from other countries. These studies produced interesting results on many putative "longevity genes". Nevertheless, many discrepancies are reported, likely due to the population-specific interactions between gene pools and environment. New approaches, including large-scale studies using high-throughput techniques, are urgently needed to overcome the limits of traditional association studies performed on a limited number of polymorphisms in order to make substantial progress to disentangle the genetics of a trait as complex as human longevity.
- Published
- 2006
21. The genetics of human longevity
- Author
-
Daniela Monti, Federica Sevini, Stefano Salvioli, Giovanna De Benedictis, Claudio Franceschi, Graham Pawelec, Miriam Capri, Laura Celani, Silvana Valensin, Efstathios S. Gonos, Capri M., Salvioli S., Sevini F., Valensin S., Celani L., Monti D., Pawelec G., De Benedictis G., Gonos E.S., and Franceschi C.
- Subjects
Aging ,PPARγ ,medicine.disease_cause ,Genome ,Pleiotropy ,Insulin ,Insulin-Like Growth Factor I ,p53, p66shc ,Aged, 80 and over ,Genetics ,Mutation ,General Neuroscience ,TLR-4 ,Apolipoprotein ,Longevity gene ,Interleukin-10 ,Multigene Family ,IL-10 ,Signal Transduction ,TGF-β ,Src Homology 2 Domain-Containing, Transforming Protein 1 ,Longevity ,Context (language use) ,Biology ,General Biochemistry, Genetics and Molecular Biology ,History and Philosophy of Science ,CETP ,medicine ,Humans ,Epigenetics ,PON1 ,Gene ,Adaptor Proteins, Signal Transducing ,Glycoproteins ,Genetic association ,Inflammation ,IL-6 ,insulin/IGF-1 ,Polymorphism, Genetic ,Aryldialkylphosphatase ,Interleukin-6 ,Tumor Necrosis Factor-alpha ,IL-1 cluster ,Lipid Metabolism ,Cholesterol Ester Transfer Proteins ,PPAR gamma ,Toll-Like Receptor 4 ,Oxidative Stress ,Apolipoproteins ,Shc Signaling Adaptor Proteins ,TNF-α ,Tumor Suppressor Protein p53 ,Carrier Proteins ,Interleukin-1 ,Human mitochondrial DNA haplogroup - Abstract
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.
- Published
- 2006
22. Quantifying the relevance of different mediators in the human immune cell network
- Author
-
Paolo Tieri, Vito Latora, Claudio Franceschi, Massimo Marchiori, Daniel Remondini, Silvana Valensin, Gastone Castellani, TIERI P, VALENSIN S, LATORA V, CASTELLANI G., MARCHIORI M, REMONDINI D, FRANCESCHI C., P. Tieri, S. Valensin, V. Latora, G. Castellani, M. Marchiori, D. Remondini, and C. Franceschi
- Subjects
Statistics and Probability ,Chemokine ,Cell type ,medicine.medical_treatment ,animal diseases ,Molecular Networks (q-bio.MN) ,Antigen-Presenting Cells ,Inflammation ,chemical and pharmacologic phenomena ,Antigen-Antibody Complex ,Cell Communication ,Biochemistry ,Immune system ,Immunity ,medicine ,Humans ,Quantitative Biology - Molecular Networks ,Computer Simulation ,Lymphocytes ,NETWORK ,Molecular Biology ,Innate immune system ,biology ,CYTOKINES ,Models, Immunological ,biochemical phenomena, metabolism, and nutrition ,Acquired immune system ,Immunity, Innate ,Computer Science Applications ,Computational Mathematics ,Cytokine ,Computational Theory and Mathematics ,Gene Expression Regulation ,FOS: Biological sciences ,Immunology ,biology.protein ,bacteria ,medicine.symptom ,Inflammation Mediators ,IMMUNE SYSTEM ,Neuroscience ,Signal Transduction - Abstract
Immune cells coordinate their efforts for the correct and efficient functioning of the immune system (IS). Each cell type plays a distinct role and communicates with other cell types through mediators such as cytokines, chemokines and hormones, among others, that are crucial for the functioning of the IS and its fine tuning. Nevertheless, a quantitative analysis of the topological properties of an immunological network involving this complex interchange of mediators among immune cells is still lacking. Here we present a method for quantifying the relevance of different mediators in the immune network, which exploits a definition of centrality based on the concept of efficient communication. The analysis, applied to the human immune system, indicates that its mediators significantly differ in their network relevance. We found that cytokines involved in innate immunity and inflammation and some hormones rank highest in the network, revealing that the most prominent mediators of the IS are molecules involved in these ancestral types of defence mechanisms highly integrated with the adaptive immune response, and at the interplay among the nervous, the endocrine and the immune systems., Comment: 10 pages, 3 figures
- Published
- 2004
- Full Text
- View/download PDF
23. The unexpected contribution of immunosenescence to the leveling off of cancer incidence and mortality in the oldest old
- Author
-
Vincenzo Marigliano, Claudio Franceschi, Massimiliano Bonafè, Walter Gianni, and Silvana Valensin
- Subjects
Senescence ,Aged, 80 and over ,Aging ,Incidence ,T-Lymphocytes ,Cancer ,Hematology ,T lymphocyte ,Immunosenescence ,Biology ,medicine.disease ,Natural killer cell ,Immune system ,medicine.anatomical_structure ,Oncology ,Cancer incidence ,Ageing ,Immune System ,Neoplasms ,Immunology ,medicine ,Humans ,Aged - Abstract
In this paper the hypothesis that some features of immunosenescence might impact on the levelling off of cancer incidence and mortality in the oldest old will be considered. In fact, the term immunosenescence suggests that a progressive loss of immune system (IS) function occurs with aging. However, the age-related modifications of the IS can be more properly acknowledged as a 'remodeling' characterized by profound structural changes, which modify the functional properties of IS. We suggest that the expansion with age of natural killer cells (NK) and of T cells which progressively acquire phenotypes intermediate between T lymphocytes and NK cells, together with the age-related changes in the production of inflammatory/anti-inflammatory cytokines, such as INFgamma and IL-4, might create an environment unfavorable for neoplastic growth in the oldest old. In this perspective, studies on immunosenescence likely provide insights on mechanisms responsible for the individual capacity to escape from the life-threatening consequences of cancer outgrowth.
- Published
- 2001
24. Neuroinflammation and the genetics of Alzheimer's disease: the search for a pro-inflammatory phenotype
- Author
-
Fabiola Olivieri, Massimiliano Bonafè, Federico Licastro, G. De Benedictis, Francesco Lescai, Silvana Valensin, Luigi M.E. Grimaldi, Claudio Franceschi, and Daniela Monti
- Subjects
Aging ,Interleukin-6, biosynthesis/genetics ,Disease ,Alpha 1-antichymotrypsin ,Pathogenesis ,Neuritis ,Alzheimer Disease ,Medicine ,Humans ,Neuritis, genetics ,Interleukin 6 ,Neuroinflammation ,Aged ,Alzheimer Disease, etiology/genetics/immunology ,biology ,business.industry ,Interleukin-6 ,Interleukin ,Immunosenescence ,Middle Aged ,Phenotype ,Inflammation Mediators, metabolism ,Aging, genetics/immunology ,Immunology ,biology.protein ,Cytokines, biosynthesis ,Interleukin-1, biosynthesis/genetics ,Cytokines ,Geriatrics and Gerontology ,Inflammation Mediators ,business ,Interleukin-1 - Abstract
The role of interleukin 1 (IL-1) and interleukin 6 (IL-6) in the pathogenesis of Alzheimer's disease (AD) is reviewed within the framework of "inflamm-aging", i.e., the characteristic chronic pro-inflammatory status which develops in old age, and neuroinflammation, i.e., the peculiar inflammatory process which is present in the brain of AD patients. In particular, the data suggesting that several IL-1 and IL-6 gene polymorphisms can contribute to the risk of developing AD are reviewed. The possibility as well as the difficulty in identifying a pro-inflammatory phenotype, and its importance for the prevention, diagnosis and therapy of AD and other age-related pathologies are discussed.
- Published
- 2001
25. Immunogenetics of longevity. Is major histocompatibility complex polymorphism relevant to the control of human longevity? A review of literature data
- Author
-
Silvana Valensin, Domenico Lio, Massimiliano Bonafè, Giuseppina Candore, Calogero Caruso, Claudio Franceschi, and Giuseppina Colonna Romano
- Subjects
Genetics ,Aging ,Polymorphism, Genetic ,media_common.quotation_subject ,Haplotype ,Longevity ,Human leukocyte antigen ,Immunogenetics ,Biology ,Major histocompatibility complex ,Histocompatibility ,Major Histocompatibility Complex ,Mice ,Immune system ,Antigen ,HLA Antigens ,Immunology ,biology.protein ,Animals ,Humans ,Genetic Predisposition to Disease ,Developmental Biology ,media_common - Abstract
Literature data suggest that human longevity may be directly correlated with optimal functioning of the immune system. Therefore, it is likely that one of the genetic determinants of longevity resides in those polymorphisms for the immune system genes that regulate immune responses. Accordingly, studies performed on mice have suggested that the Major Histocompatibility Complex (MHC), known to control a variety of immune functions, is associated with the life span of the strains. In the last 25 years, a fair number of cross-sectional studies that searched for the role of HLA (the human MHC) genes on human longevity by comparing HLA antigen frequencies between groups of young and elderly persons have been published, but conflicting findings have been obtained. In fact, the same HLA antigens are increased in some studies, decreased in others and unchanged in others. On the whole, that could lead us to hypothesize that the observed age-related differences in the frequency of HLA antigens are due to bias. In our opinion, this hypothesis is real for most studies owing to major methodological problems. However, some studies that do not meet these biases have shown an association between longevity and some HLA-DR alleles or HLA-B8,DR3 haplotype, known to be involved in the antigen non-specific control of immune response. Thus, HLA studies in man may be interpreted to support suggestions derived from the studies on congenic mice on MHC effects on longevity. However, in mice the association may be by way of susceptibility to lymphomas whereas, in human beings, the effect on longevity is likely, via infectious disease susceptibility. Longevity is associated with positive or negative selection of alleles (or haplotypes) that respectively confer resistance or susceptibility to disease(s), via peptide presentation or via antigen non-specific control of the immune response.
- Published
- 2001
26. HLA, aging, and longevity: a critical reappraisal
- Author
-
Giuseppina Colonna Romano, Domenico Lio, Silvana Valensin, Claudio Franceschi, Calogero Caruso, Massimiliano Bonafè, and Giuseppina Candore
- Subjects
Male ,Aging ,media_common.quotation_subject ,Immunology ,Longevity ,Human leukocyte antigen ,Major histocompatibility complex ,Evolution of ageing ,HLA-B8 Antigen ,HLA-DR3 Antigen ,Pleiotropy ,HLA Antigens ,Immunology and Allergy ,Humans ,Allele ,media_common ,Aged ,Genetics ,Aged, 80 and over ,biology ,Haplotype ,Homozygote ,General Medicine ,Immunosenescence ,Haplotypes ,biology.protein ,Female - Abstract
Despite a large number of studies, available data do not allow at present to reach definitive and clear conclusions on role of HLA on longevity, owing to major methodological problems, such as serological and molecular typing of different loci, insufficient sample sizes, different inclusion criteria and age cut-off, inappropriate mixing of data referred to people from 58 to over 100 years of age, inappropriate control matching, and neglected consideration of sex-related effects and the different genetic make-up of studied populations. However, within this confused scenario, some data emerge. First, two studies that do not fit the biases above discussed show that some HLA alleles are associated with longevity. However, some of these alleles may confer an increased risk to undergo a variety of diseases. Second, longevity may be associated with an increased homozygosity at HLA loci. Third, an intriguing association between longevity and the 8.1 ancestral haplotype (AH), which has been proven to be associated with a variety of immune dysfunctions and autoimmune diseases, apparently emerges. This association appears to be a sex-specific (males) longevity contributor, and it is particularly interesting, taking into account that a type 2 (early infancy) --> type 1 (adulthood) --> type 2 (aging) shift of cytokine profile occurs lifelong, and that individuals bearing this haplotype show a type 2 immune responsiveness (note that type 1 cytokines mainly enhance cellular responses, whereas type 2 cytokines predominantly enhance humoral responses). On the whole, the (sex specific) association of longevity with alleles or haplotypes of several genes related to risk factors for a variety of diseases (cardiovascular diseases, cancer), including HLA alleles and haplotypes, is not unexpected on the basis of previous studies on the genetics of longevity in centenarians. This association can be interpreted under the perspective of a well known evolutionary theory of aging (antagonistic pleiotropy). This theory predicts that the same gene (or allele or haplotype) can have different roles (positive or negative) in different periods of the life span. Thus, the 8.1 AH should exert a positive effect during the infancy and aging but not in adulthood, when, indeed it is associated to susceptibility to a variety of diseases.
- Published
- 2000
27. Human immunosenescence: the prevailing of innate immunity, the failing of clonotypic immunity, and the filling of immunological space
- Author
-
Claudio Franceschi, Silvana Valensin, and Massimiliano Bonafè
- Subjects
Aging ,T-Lymphocytes ,Biology ,Lymphocyte Activation ,Models, Biological ,Antigen ,Immunity ,Stress, Physiological ,Humans ,Antigens ,Aged ,Aged, 80 and over ,Thymic involution ,Innate immune system ,General Veterinary ,General Immunology and Microbiology ,Effector ,Public Health, Environmental and Occupational Health ,Immunosenescence ,T lymphocyte ,Telomere ,Biological Evolution ,Immunity, Innate ,Infectious Diseases ,Immunology ,Molecular Medicine ,Immunologic Memory ,CD8 ,Cell Division - Abstract
According to the remodeling theory of aging we proposed several years ago, the current data on human immunosenescence depicts a complex scenario where clonotypical immunity deteriorates, while ancestral innate/natural immunity is largely conserved or even up-regulated with age. Under an evolutionary perspective, antigens are the cause of a persistent life-long antigenic stress, responsible for the accumulation of effector CD8+/CD28− T cells, the decrease of naive T cells (CD95−) and the marked shrinkage of T cell repertoire with age. Concomitantly, NK cytotoxicity, chemotaxis, phagocytosis and complement activities remain unaffected or negligibly affected, in comparison to clonotypical immunity. Thus, immunosenescence is not a random deteriorative phenomenon but appears to inversely recapitulate an evolutionary pattern. On the whole, immunosenescence can be envisaged as the result of the continuous challenge of the unavoidable exposure to a variety of potential antigens (viruses, bacteria, but also food and self molecules among others). From this perspective antigens are nothing else than a particular type of stressor and immunosenescence appears to be the price paid to immunological memory, i.e. one of the main characteristics of the most evolutionary recent and sophisticated type of immunity. Together with the age-related thymic involution, and the consequent age-related decrease of thymic output of new T cells, this situation leaves the body practically devoid of virgin T cells, and thus likely more prone to a variety of infectious and non infectious diseases.
- Published
- 2000
28. Biomarkers of immunosenescence within an evolutionary perspective: the challenge of heterogeneity and the role of antigenic load
- Author
-
Silvana Valensin, Francesco Fagnoni, Massimiliano Bonafè, Claudio Franceschi, and Cristiana Barbi
- Subjects
Genetics ,Aging ,Effector ,media_common.quotation_subject ,Longevity ,Genetic Variation ,Cell Biology ,Immunosenescence ,Biology ,Biochemistry ,Biological Evolution ,Telomere ,Endocrinology ,Immune system ,Pleiotropy (drugs) ,Antigen ,Immune System ,Humans ,Stem cell ,Antigens ,Molecular Biology ,Neuroscience ,Biomarkers ,media_common - Abstract
Under an evolutionary perspective, antigens can be considered nothing else than chronic stressors that constituted the major selective pressure for immune system emergence and evolution. In this review, recent data are discussed under the hypothesis that human immunosenescence is the consequence of the continuous attrition caused by chronic antigenic overload/stress. The advantage of this theoretical approach is that a unifying hypothesis is proposed, which tries to fill in the current gap between the conceptualizations concerning the mechanisms which counteract aging and favor longevity in invertebrates and vertebrates. The hypothesis is that the immune system is, at a higher level of biological organization and complexity, the counterpart of the anti-stress response network identified in invertebrates as the major determinant of survival. We argue that some of the most important characteristics of immunosenescence, i.e. the accumulation and the clonal expansion of memory and effector T cells, the reduction/exhaustion of naive T cells, and the shrinkage of T cell repertoire, are compatible with this assumption. Thus, immunosenescence can be envisaged as a global reduction of the "immunological space." Concomitantly, immunosenescence results in the progressive generation of cellular mosaicism which is the consequence of the heterogeneous replicative histories and telomere shortening of T and B cell subsets, as well as hemopoietic stem cells. Most of the parameters affected by immunosenescence appear to be under genetic control, and future research on biomarkers should address this point. On the whole, immunosenescence can be taken as a proof that the beneficial effects of the immune system, devoted to the neutralization of dangerous/harmful agents early in life and in adulthood, turn to be detrimental late in life, in a period largely not foreseen by evolution. This perspective fits with basic assumptions of evolutionary theories of aging, such as antagonistic pleiotropy.
- Published
- 2000
29. Mitochondrial DNA involvement in human longevity
- Author
-
Stefano Salvioli, Federica Sevini, Giuseppina Rose, Claudio Franceschi, Giuseppe Passarino, Miriam Capri, Daniela Monti, Giovanna De Benedictis, Aurelia Santoro, Silvana Valensin, Nicola Raule, Dina Bellizzi, Santoro A., Salvioli S., Raule N., Capri M., Sevini F., Monti D., Bellizzi D., Passarino G., Rose G., De Benedictis G., and Franceschi C.
- Subjects
Mitochondrial DNA ,Mitochondrial Diseases ,Nuclear gene ,DNA Repair ,media_common.quotation_subject ,Longevity ,mtDNA haplogroup ,Biophysics ,Biology ,Alzheimer's Disease ,DNA, Mitochondrial ,Biochemistry ,Haplogroup ,Humans ,Centenarian ,media_common ,Cell Nucleus ,Genetics ,Nuclear–mitochondrial interaction ,mtDNA mutation ,Cell Biology ,Phenotype ,Mutation ,Genetics of aging ,Epistasis ,Human mitochondrial DNA haplogroup - Abstract
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.
- Full Text
- View/download PDF
30. Long telomeres and well preserved proliferative vigor in cells from centenarians: A contribution to longevity?
- Author
-
Chiara Mondello, Massimiliano Bonafè, Paolo Sansoni, Sandro Sorbi, Claudio Franceschi, and Silvana Valensin
- Subjects
Gerontology ,Aging ,Geriatrics gerontology ,media_common.quotation_subject ,Longevity ,Biology ,Fibroblasts ,Telomere ,Humans ,Lymphocytes ,Geriatrics and Gerontology ,Cell Division ,media_common ,Aged
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.