94 results on '"D'Annibale, Alessandro"'
Search Results
2. BPIFB4 and its longevity-associated haplotype protect from cardiac ischemia in humans and mice.
- Author
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Cattaneo M, Aleksova A, Malovini A, Avolio E, Thomas A, Alvino VV, Kilcooley M, Pieronne-Deperrois M, Ouvrard-Pascaud A, Maciag A, Spinetti G, Kussauer S, Lemcke H, Skorska A, Vasudevan P, Castiglione S, Raucci A, David R, Richard V, Beltrami AP, Madeddu P, and Puca AA
- Subjects
- Aged, Animals, Humans, Mice, Aging genetics, Haplotypes genetics, Ischemia, Coronary Artery Disease, Intercellular Signaling Peptides and Proteins genetics, Longevity genetics
- Abstract
Long-living individuals (LLIs) escape age-related cardiovascular complications until the very last stage of life. Previous studies have shown that a Longevity-Associated Variant (LAV) of the BPI Fold Containing Family B Member 4 (BPIFB4) gene correlates with an extraordinarily prolonged life span. Moreover, delivery of the LAV-BPIFB4 gene exerted therapeutic action in murine models of atherosclerosis, limb ischemia, diabetic cardiomyopathy, and aging. We hypothesize that downregulation of BPIFB4 expression marks the severity of coronary artery disease (CAD) in human subjects, and supplementation of the LAV-BPIFB4 protects the heart from ischemia. In an elderly cohort with acute myocardial infarction (MI), patients with three-vessel CAD were characterized by lower levels of the natural logarithm (Ln) of peripheral blood BPIFB4 (p = 0.0077). The inverse association between Ln BPIFB4 and three-vessel CAD was confirmed by logistic regression adjusting for confounders (Odds Ratio = 0.81, p = 0.0054). Moreover, in infarcted mice, a single administration of LAV-BPIFB4 rescued cardiac function and vascularization. In vitro studies showed that LAV-BPIFB4 protein supplementation exerted chronotropic and inotropic actions on induced pluripotent stem cell (iPSC)-derived cardiomyocytes. In addition, LAV-BPIFB4 inhibited the pro-fibrotic phenotype in human cardiac fibroblasts. These findings provide a strong rationale and proof of concept evidence for treating CAD with the longevity BPIFB4 gene/protein., (© 2023. The Author(s).)
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- 2023
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3. Effects of Human LAV-BPIFB4 Gene Therapy on the Epigenetic Clock and Health of Aged Mice.
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Giuliani ME, Barbi V, Bigossi G, Marcozzi S, Giacconi R, Cardelli M, Piacenza F, Orlando F, Ciaglia E, Cattaneo M, Mongelli A, Gaetano C, Provinciali M, Puca AA, and Malavolta M
- Subjects
- Humans, Mice, Animals, Aged, Mice, Inbred C57BL, Epigenesis, Genetic, Biomarkers, Genetic Therapy, DNA Methylation, Intercellular Signaling Peptides and Proteins genetics, Longevity genetics, Frailty genetics
- Abstract
The homozygous genotype of the Longevity-Associated Variant (LAV) in Bactericidal/Permeability-Increasing Fold-Containing Family B member 4 (BPIFB4) is enriched in long-living individuals of three independent populations and its genetic transfer in C57BL/6J mice showed a delay in frailty progression and improvement of several biomarkers of aging and multiple aspects of health. The C57BL/6J strain is a suitable model for studying therapies aimed at extending healthy aging and longevity due to its relatively short lifespan and the availability of aging biomarkers. Epigenetic clocks based on DNA methylation profiles are reliable molecular biomarkers of aging, while frailty measurement tools are used to evaluate overall health during aging. In this study, we show that the systemic gene transfer of LAV-BPIFB4 in aged C57BL/6J mice was associated with a significant reduction in the epigenetic clock-based biological age, as measured by a three CpG clock method. Furthermore, LAV-BPIFB4 gene transfer resulted in an improvement of the Vitality Score with a reduction in the Frailty Index. These findings further support the use of LAV-BPIFB4 gene therapy to induce beneficial effects on epigenetic mechanisms associated with aging and frailty in aged mice, with potential implications for future therapies to prevent frailty in humans.
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- 2023
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4. Transfer of the longevity-associated variant of BPIFB4 gene rejuvenates immune system and vasculature by a reduction of CD38 + macrophages and NAD + decline.
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Ciaglia E, Lopardo V, Montella F, Carrizzo A, Di Pietro P, Malavolta M, Giacconi R, Orlando F, Cattaneo M, Madeddu P, Vecchione C, and Puca AA
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- Animals, Inflammation, Macrophages, Mice, Mice, Inbred C57BL, NAD, Phosphoproteins genetics, Cardiovascular Diseases therapy, Genetic Therapy, Immune System, Intercellular Signaling Peptides and Proteins genetics, Longevity
- Abstract
As we age, our body experiences chronic, systemic inflammation contributing to the morbidity and mortality of the elderly. The senescent immune system has been described to have a causal role in driving systemic aging and therefore may represent a key therapeutic target to prevent pathological consequences associated with aging and extend a healthy lifespan. Previous studies from our group associated a polymorphic haplotype variant in the BPIFB4 gene (LAV-BPIFB4) with exceptional longevity. Transfer of the LAV-BPIFB4 in preclinical models halted the progression of cardiovascular diseases (CVDs) and frailty by counterbalancing chronic inflammation. In the present study, we aimed to delineate the action of systemic adeno-associated viral vector-mediated LAV-BPIFB4 gene transfer (AAV-LAV-BPIFB4) on the deleterious age-related changes of the immune system and thereby the senescence-associated events occurring in C57BL/6J mice aged 26 months. Our in vivo data showed that 26-months-old mice had a higher frequency of CD45
+ SA-beta Gal+ immune cells in peripheral blood than young (4-months-old) C57BL/6J mice. Notably, AAV-LAV-BPIFB4 gene transfer in aged mice reduced the pool of peripheral immunosenescent cells that were shown to be enriched in the spleen. In addition, the proper tuning of the immune secretory phenotype (IL1βlow , IL6low , IL10high ) associated with a significant reduction in SA-beta Gal-positive area of aorta from AAV-LAV treated mice. At the functional level, the reduction of senescence-associated inflammation ensured sustained NAD+ levels in the plasma of AAV-LAV-BPIFB4 old mice by preventing the NADase CD38 increase in F4/80+ tissue-resident macrophages and Ly6Chigh pro-inflammatory monocytes of the spleen and bone marrow. Finally, to validate the clinical implication of our findings, we showed that Long-living-individuals (LLIs, >95 years), which delay CVDs onset, especially if LAV-carriers, were characterized by high NAD+ levels. In conclusion, the new senotherapeutic action of LAV-BPIFB4 may offer a valuable therapeutic tool to control aging and reduce the burden of its pathophysiological disorders, such as CVDs., (© 2022. The Author(s).)- Published
- 2022
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5. The Longevity-Associated Variant of BPIFB4 Reduces Senescence in Glioma Cells and in Patients' Lymphocytes Favoring Chemotherapy Efficacy.
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Puca AA, Lopardo V, Montella F, Di Pietro P, Cesselli D, Rolle IG, Bulfoni M, Di Sarno V, Iaconetta G, Campiglia P, Vecchione C, Beltrami AP, and Ciaglia E
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- Cell Line, Tumor, Cellular Senescence drug effects, Cellular Senescence immunology, Cytokines metabolism, Glioma drug therapy, Humans, Lymphocytes drug effects, Phenotype, Recombinant Proteins metabolism, Temozolomide pharmacology, Temozolomide therapeutic use, Treatment Outcome, Antineoplastic Agents therapeutic use, Cellular Senescence genetics, Glioma blood, Glioma genetics, Intercellular Signaling Peptides and Proteins genetics, Longevity drug effects, Lymphocytes metabolism, Mutation genetics
- Abstract
Glioblastoma (GBM) is the most common primary brain cancer with the median age at diagnosis around 64 years, thus pointing to aging as an important risk factor. Indeed, aging, by increasing the senescence burden, is configured as a negative prognostic factor for GBM stage. Furthermore, several anti-GBM therapies exist, such as temozolomide (TMZ) and etoposide (ETP), that unfortunately trigger senescence and the secretion of proinflammatory senescence-associated secretory phenotype (SASP) factors that are responsible for the improper burst of (i) tumorigenesis, (ii) cancer metastasis, (iii) immunosuppression, and (iv) tissue dysfunction. Thus, adjuvant therapies that limit senescence are urgently needed. The longevity-associated variant (LAV) of the bactericidal/permeability-increasing fold-containing family B member 4 (BPIFB4) gene previously demonstrated a modulatory activity in restoring age-related immune dysfunction and in balancing the low-grade inflammatory status of elderly people. Based on the above findings, we tested LAV-BPIFB4 senotherapeutic effects on senescent glioblastoma U87-MG cells and on T cells from GBM patients. We interrogated SA-β-gal and HLA-E senescence markers, SASP factors, and proliferation and apoptosis assays. The results highlighted a LAV-BPIFB4 remodeling of the senescent phenotype of GBM cells, enhancement of their sensitivity to temozolomide and a selective reduction of the T cells' senescence from GBM patients. Overall, these findings candidate LAV-BPIFB4 as an adjuvant therapy for GBM.
- Published
- 2022
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6. BPIFB4 Circulating Levels and Its Prognostic Relevance in COVID-19.
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Ciaglia E, Lopardo V, Montella F, Sellitto C, Manzo V, De Bellis E, Iannaccone T, Franci G, Zannella C, Pagliano P, Di Pietro P, Carrizzo A, Vecchione C, Conti V, Filippelli A, and Puca AA
- Subjects
- Aged, 80 and over, Biomarkers blood, Cell Line, Cytokines blood, Cytotoxicity, Immunologic drug effects, Female, Humans, Immunologic Factors immunology, Immunologic Factors pharmacology, Inflammation blood, Inflammation immunology, Italy epidemiology, Male, Prognosis, Recombinant Proteins immunology, Recombinant Proteins pharmacology, SARS-CoV-2 immunology, Severity of Illness Index, COVID-19 diagnosis, COVID-19 epidemiology, COVID-19 immunology, Intercellular Signaling Peptides and Proteins blood, Intercellular Signaling Peptides and Proteins immunology, Longevity immunology
- Abstract
Aging and comorbidities make individuals at greatest risk of COVID-19 serious illness and mortality due to senescence-related events and deleterious inflammation. Long-living individuals (LLIs) are less susceptible to inflammation and develop more resiliency to COVID-19. As demonstrated, LLIs are characterized by high circulating levels of BPIFB4, a protein involved in homeostatic response to inflammatory stimuli. Also, LLIs show enrichment of homozygous genotype for the minor alleles of a 4 missense single-nucleotide polymorphism haplotype (longevity-associated variant [LAV]) in BPIFB4, able to counteract progression of diseases in animal models. Thus, the present study was designed to assess the presence and significance of BPIFB4 level in COVID-19 patients and the potential therapeutic use of LAV-BPIFB4 in fighting COVID-19. BPIFB4 plasma concentration was found significantly higher in LLIs compared to old healthy controls while it significantly decreased in 64 COVID-19 patients. Further, the drop in BPIFB4 values correlated with disease severity. Accordingly to the LAV-BPIFB4 immunomodulatory role, while lysates of SARS-CoV-2-infected cells induced an inflammatory response in healthy peripheral blood mononuclear cells in vitro, the co-treatment with recombinant protein (rh) LAV-BPIFB4 resulted in a protective and self-limiting reaction, culminating in the downregulation of CD69 activating-marker for T cells (both TCD4+ and TCD8+) and in MCP-1 reduction. On the contrary, rhLAV-BPIFB4 induced a rapid increase in IL-18 and IL-1b levels, shown largely protective during the early stages of the virus infection. This evidence, along with the ability of rhLAV-BPIFB4 to counteract the cytotoxicity induced by SARS-CoV-2 lysate in selected target cell lines, corroborates BPIFB4 prognostic value and open new therapeutic possibilities in more vulnerable people., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Gerontological Society of America.)
- Published
- 2021
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7. Special Issue "Centenarians-A Model to Study the Molecular Basis of Lifespan and Healthspan".
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Caruso C and Puca AA
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- Aged, 80 and over, Clinical Trials as Topic, Diet, Epigenesis, Genetic, Health, Humans, Longevity genetics, Probiotics pharmacology, Longevity physiology, Models, Biological
- Abstract
People are living longer, not, as was previously the case, due to reduced child mortality, but because we are postponing the ill-health of old age [...].
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- 2021
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8. High TARC plasma levels confer protection to long living individuals by inducing M2 profile.
- Author
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Montella F, Lopardo V, Vecchione C, Puca AA, and Ciaglia E
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- Adult, Aged, Aged, 80 and over, Chemokine CXCL10 blood, Enzyme-Linked Immunosorbent Assay, Female, Humans, Intercellular Signaling Peptides and Proteins blood, Macrophage Activation, Macrophages classification, Macrophages immunology, Male, Middle Aged, Aging blood, Chemokine CCL17 blood, Longevity, Macrophages metabolism
- Abstract
A way to delay aging and the related low-grade chronic inflammatory state is to study the model of positive physiology such as the Long-Living Individuals (LLIs). Our recent studies have shown higher levels of the host defense BPI Fold-Containing Family B Member 4 (BPIFB4) protein in the LLIs' blood. Notably, BPIFB4 has been shown to influence monocytes typesetting and M2 anti-inflammatory phenotype (CD206+CD163++) macrophages skewing. According to the role of a complex cytokine milieu in guiding the macrophage polarization, here we found that circulating concentrations of thymus and activation regulated chemokine (TARC)/CCL17 and small-inducible cytokine B10 (IP-10)/CXCL10) cytokines, were additionally associated with the LLIs' state. In a differentiation process in vitro, the addition of LLIs' plasma to the cell culture medium, enhanced the ability of monocytes, either from LLIs or controls, to acquire a M2 phenotype. Interestingly, a neutralizing antibody against TARC blunted the M2 skewing effect of the LLIs' plasma. Collectively, these data indicate that exceptional longevity may associate with a peculiar anti-inflammatory myeloid profile responsible for improved reparative processes and reduced inflammatory status mediated in part by TARC and M2 generation., (Copyright © 2020 Elsevier Ltd. All rights reserved.)
- Published
- 2021
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9. New Insights for BPIFB4 in Cardiovascular Therapy.
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Dossena M, Ferrario A, Lopardo V, Ciaglia E, and Puca AA
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- Adaptive Immunity, Age Factors, Animals, Atherosclerosis immunology, Atherosclerosis prevention & control, Diabetic Cardiomyopathies immunology, Diabetic Cardiomyopathies prevention & control, Frailty immunology, Frailty prevention & control, Gene Expression Regulation, Developmental immunology, Genetic Therapy methods, Humans, Hypertension immunology, Hypertension prevention & control, Immunity, Innate, Intercellular Signaling Peptides and Proteins, Longevity immunology, Mice, Nitric Oxide Synthase Type III genetics, Nitric Oxide Synthase Type III immunology, Phosphoproteins immunology, Protein Isoforms genetics, Protein Isoforms immunology, Risk Factors, Atherosclerosis genetics, Diabetic Cardiomyopathies genetics, Frailty genetics, Hypertension genetics, Immunosenescence genetics, Longevity genetics, Phosphoproteins genetics
- Abstract
Aging is the most relevant risk factor for cardiovascular diseases which are the main cause of mortality in industrialized countries. In this context, there is a progressive loss of cardiovascular homeostasis that translates in illness and death. The study of long living individuals (LLIs), which show compression of morbidity toward the end of their life, is a valuable approach to find the key to delay aging and postpone associate cardiovascular events. A contribution to the age-related decline of cardiovascular system (CVS) comes from the immune system; indeed, it is dysfunctional during aging, a process described as immunosenescence and comprises the combination of several processes overpowering both innate and adaptative immune system. We have recently discovered a longevity-associated variant (LAV) in bactericidal/permeability-increasing fold-containing family B member 4 (BPIFB4), which is a secreted protein able to enhance endothelial function through endothelial nitric oxide synthase (eNOS) activation and capable to protect from hypertension, atherosclerosis, diabetic cardiopathy, frailty, and inflammaging. Here, we sum up the state of the art of the mechanisms involved in the main pathological processes related to CVD (atherosclerosis, aging, diabetic cardiopathy, and frailty) and shed light on the therapeutic effects of LAV-BPIFB4 in these contexts.
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- 2020
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10. Circulating BPIFB4 Levels Associate With and Influence the Abundance of Reparative Monocytes and Macrophages in Long Living Individuals.
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Ciaglia E, Montella F, Lopardo V, Scala P, Ferrario A, Cattaneo M, Carrizzo A, Malovini A, Madeddu P, Vecchione C, and Puca AA
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- Aged, 80 and over, Antibodies, Neutralizing metabolism, Cell Differentiation, Cells, Cultured, Female, Humans, Immunophenotyping, Intercellular Signaling Peptides and Proteins genetics, Intercellular Signaling Peptides and Proteins immunology, Lipopolysaccharide Receptors metabolism, Male, Middle Aged, Polymorphism, Genetic, Th2 Cells immunology, Atherosclerosis genetics, Biomarkers blood, Intercellular Signaling Peptides and Proteins blood, Longevity physiology, Macrophages immunology, Monocytes immunology
- Abstract
Long-Living Individuals (LLIs) delay aging and are less prone to chronic inflammatory reactions. Whether a distinct monocytes and macrophages repertoire is involved in such a characteristic remains unknown. Previous studies from our group have shown high levels of the host defense BPI Fold Containing Family B Member 4 (BPIFB4) protein in the peripheral blood of LLIs. Moreover, a polymorphic variant of the BPIFB4 gene associated with exceptional longevity ( LAV-BPIFB4 ) confers protection from cardiovascular diseases underpinned by low-grade chronic inflammation, such as atherosclerosis. We hypothesize that BPIFB4 may influence monocytes pool and macrophages skewing, shifting the balance toward an anti-inflammatory phenotype. We profiled circulating monocytes in 52 LLIs (median-age 97) and 52 healthy volunteers (median-age 55) using flow cytometry. If the frequency of total monocyte did not change, the intermediate CD14++CD16+ monocytes counts were lower in LLIs compared to control adults. Conversely, non-classical CD14+CD16++ monocyte counts, which are M2 macrophage precursors with an immunomodulatory function, were found significantly associated with the LLIs' state. In a differentiation assay, supplementation of the LLIs' plasma enhanced the capacity of monocytes, either from LLIs or controls, to acquire a paracrine M2 phenotype. A neutralizing antibody against the phosphorylation site (ser 75) of BPIFB4 blunted the M2 skewing effect of the LLIs' plasma. These data indicate that LLIs carry a peculiar anti-inflammatory myeloid profile, which is associated with and possibly sustained by high circulating levels of BPIFB4. Supplementation of recombinant BPIFB4 may represent a novel means to attenuate inflammation-related conditions typical of unhealthy aging., (Copyright © 2020 Ciaglia, Montella, Lopardo, Scala, Ferrario, Cattaneo, Carrizzo, Malovini, Madeddu, Vecchione and Puca.)
- Published
- 2020
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11. Longevity-Associated Variant of BPIFB4 Mitigates Monocyte-Mediated Acquired Immune Response.
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Ciaglia E, Montella F, Maciag A, Scala P, Ferrario A, Banco C, Carrizzo A, Spinelli CC, Cattaneo M, De Candia P, Vecchione C, Villa F, and Puca AA
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- Adult, Aged, Aged, 80 and over, Cells, Cultured, Humans, Intercellular Signaling Peptides and Proteins, Interleukin-1beta physiology, Middle Aged, Monocytes metabolism, Tumor Necrosis Factor-alpha physiology, Adaptive Immunity, Longevity physiology, Monocytes physiology, Phosphoproteins physiology
- Abstract
One of the basis of exceptional longevity is the maintaining of the balance between inflammatory and anti-inflammatory networks. The monocyte-macrophages activation plays a major role in tuning the immune responses, by oscillating between patrolling-protective to inflammatory status. Longevity-associated variant (LAV) of bactericidal/permeability-increasing fold-containing family B member 4 (BPIFB4) activates calcium, PKC-alpha, and eNOS, rescuing endothelial dysfunction in aged mice and inducing revascularization. The BPIFB4's increment in serum of healthy long-living individuals (LLIs) compared to nonhealthy ones, its therapeutic potential in improving vascular homeostasis, which depends on immune system, together with its expression in bone marrow myeloid cells, suggests that LAV-BPIFB4 may improve immune regulation. Here we show that human monocytes exposed to LAV-BPIFB4 protein increased co-stimulatory molecules in resting state and reduced pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) after activating stimuli. Accordingly, a low percentage of CD69+ activated lymphocytes are found among LAV-BPIFB4-treated peripheral blood mononuclear cells (PBMCs). Moreover, human monocyte-derived dendritic cells (DCs) generated in presence of LAV-BPIFB4 secreted higher anti-(IL-10 and TGF-β) and lower pro-inflammatory (TNF-α and IL-1β) cytokines. Accordingly, LLIs' plasma showed higher levels of circulating IL-10 and of neutralizing IL-1 receptor antagonist (IL-1RA) compared to controls. Thus, LAV-BPIFB4 effects on myeloid compartment could represent one example of a genetic predisposition carried by LLIs to protect from immunological dysfunctions., (© The Author(s) 2019. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2019
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12. A Model of Evolutionary Selection: The Cardiovascular Protective Function of the Longevity Associated Variant of BPIFB4.
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Villa F, Carrizzo A, Ferrario A, Maciag A, Cattaneo M, Spinelli CC, Montella F, Damato A, Ciaglia E, and Puca AA
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- Evolution, Molecular, Humans, Intercellular Signaling Peptides and Proteins, Cardiovascular Diseases genetics, Longevity genetics, Phosphoproteins genetics, Polymorphism, Single Nucleotide, Selection, Genetic
- Abstract
Evolutionary forces select genetic variants that allow adaptation to environmental stresses. The genomes of centenarian populations could recapitulate the evolutionary adaptation model and reveal the secrets of disease resistance shown by these individuals. Indeed, longevity phenotype is supposed to have a genetic background able to survive or escape to age-related diseases. Among these, cardiovascular diseases (CVDs) are the most lethal and their major risk factor is aging and the associated frailty status. One example of genetic evolution revealed by the study of centenarians genome is the four missense Single Nucleotide Polymorphisms (SNPs) haplotype in bactericidal/permeability-increasing fold-containing family B, member 4 (BPIFB4) locus that is enriched in long living individuals: the longevity associated variant (LAV). Indeed, LAV-BPIFB4 is able to improve endothelial function and revascularization through the increase of endothelial nitric oxide synthase (eNOS) dependent nitric oxide production. This review recapitulates the beneficial effects of LAV-BPIFB4 and its therapeutic potential for the treatment of CVDs.
- Published
- 2018
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13. The expression of the BPIFB4 and CXCR4 associates with sustained health in long-living individuals from Cilento-Italy.
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Spinetti G, Sangalli E, Specchia C, Villa F, Spinelli C, Pipolo R, Carrizzo A, Greco S, Voellenkle C, Vecchione C, Madeddu P, Martelli F, and Puca AA
- Subjects
- Adrenomedullin genetics, Aged, 80 and over, Cell Movement physiology, Female, Glucose Transporter Type 1 genetics, Health Status, Humans, Intercellular Signaling Peptides and Proteins, Italy, Leukocytes, Mononuclear cytology, Leukocytes, Mononuclear metabolism, Male, Vascular Endothelial Growth Factor A genetics, Aging genetics, Longevity genetics, Phosphoproteins genetics, Receptors, CXCR4 genetics
- Abstract
The study of the health status in long-living individuals (LLIs) may help identifying health-span and life-span determinants. BPI-Fold-Containing-Family-B-Member-4 (BPIFB4) protein is higher in healthy vs. non-healthy (frail) LLIs serum and its longevity-associated variant forced expression improves cardiovascular outcomes in ischemia mice models. Thus, we tested the association of BPIFB4 and ischemia-responding HIF-1α pathway components (i.e. CXCR4 , AK3, ALDO-C, ADM , VEGF-A , GLUT-1 and miR-210) with human life-span and health-span by analyzing mRNA expression in circulating mononuclear cells (MNCs) of LLIs (N=14 healthy; N=31 frail) and young controls (N=63). ALDO-C, ADM , VEGF-A and GLUT-1 significantly decreased and miR-210 increased in LLIs vs., Controls: Only VEGF-A and GLUT-1 showed further significant reduction in healthy-LLIs vs. frail-LLIs comparison. While BPIFB4 and CXCR4 were similar between LLIs and controls, BPIFB4 was significantly higher and CXCR4 lower in healthy- versus frail-LLIs. On a new set of LLIs (N=7 healthy and N=5 non-healthy) we assessed a potentially correlated function with low CXCR4 expression. Healthy donors' MNCs showed efficient migration ability toward CXCR4 ligand SDF-1α/CXCL12 and high percentage of migrated CXCR4
pos cells which inversely correlated with CXCR4 RNA expression. In conclusion, BPIFB4 and CXCR4 expression classify LLIs health status that correlates with maintained MNCs migration.- Published
- 2017
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14. No or only population-specific effect of PON1 on human longevity: a comprehensive meta-analysis.
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Caliebe A, Kleindorp R, Blanché H, Christiansen L, Puca AA, Rea IM, Slagboom E, Flachsbart F, Christensen K, Rimbach G, Schreiber S, and Nebel A
- Subjects
- Apolipoprotein E4 blood, Europe, Humans, United States, Aryldialkylphosphatase genetics, Longevity genetics
- Abstract
Paraoxonase 1 (PON1) has been suggested as a plausible candidate gene for human longevity due to its modulation of cardiovascular disease risk, by preventing oxidation of atherogenic low-density lipoprotein. The role of the PON1 192 Q/R polymorphism has been analyzed for association with survival at old age in several populations, albeit with controversial results. To reconcile the conflicting evidence, we performed a large association study with two samples of 2357 Germans and 1025 French, respectively. We combined our results with those from seven previous studies in the largest and most comprehensive meta-analysis on PON1 192 Q/R and longevity to-date, to include a total of 9580 individuals. No significant association of PON1 192 Q/R with longevity was observed, for either R allele or carriership. This finding relied on very large sample sizes, is supported by different analysis methods and is therefore considered very robust. Moreover, we have investigated a potential interaction of PON1 192 Q/R with APOE epsilon4 using data from four populations. Whereas a significant result was found in the German sample, this could not be confirmed in the other examined groups. Our large-scale meta-analysis provided no evidence that the PON1 192 Q/R polymorphism is associated with longevity, but this does not exclude the possibility of population-specific effects due to the influence of, and interaction between, different genetic and/or environmental factors (e.g. diet)., (2010 Elsevier Ireland Ltd. All rights reserved.)
- Published
- 2010
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15. Association of the FOXO3A locus with extreme longevity in a southern Italian centenarian study.
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Anselmi CV, Malovini A, Roncarati R, Novelli V, Villa F, Condorelli G, Bellazzi R, and Puca AA
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- Adolescent, Adult, Age Distribution, Aged, 80 and over, Case-Control Studies, Female, Forkhead Box Protein O3, Haplotypes, Humans, Italy, Linkage Disequilibrium genetics, Male, Meta-Analysis as Topic, Middle Aged, Population Dynamics, Forkhead Transcription Factors genetics, Longevity genetics
- Abstract
A number of potential candidate genes in a variety of biological pathways have been associated with longevity in model organisms. Many of these genes have human homologs and thus have the potential to provide insights into human longevity. Recently, several studies suggested that FOXO3A functions as a key bridge for various signaling pathways that influence aging and longevity. Interestingly, Willcox and colleagues identified several variants that displayed significant genotype-gender interaction in male human longevity. In particular, a nested case-control study was performed in an ethnic Japanese population in Hawaii, and five candidate longevity genes were chosen based on links to the insulin-insulin-like growth factor-1 (IGF-1) signaling pathway. In the Willcox study, the investigated genetic variations (rs2802292, rs2764264, and rs13217795) within the FOXO3A gene were significantly associated with longevity in male centenarians. We validated the association of FOXO3A polymorphisms with extreme longevity in males from the Southern Italian Centenarian Study. Particularly, rs2802288, a proxy of rs2802292, showed the best allelic association--minor allele frequency (MAF) = 0.49; p = 0.003; odds ratio (OR) = 1.51; 95% confidence interval (CI), 1.15-1.98). Furthermore, we undertook a meta-analysis to explore the significance of rs2802292 association with longevity by combining the association results of the current study and the findings coming from the Willcox et al. investigation. Our data point to a key role of FOXO3A in human longevity and confirm the feasibility of the identification of such genes with centenarian-controls studies. Moreover, we hypothesize the susceptibility to the longevity phenotype may well be the result of complex interactions involving genes and environmental factors but also gender.
- Published
- 2009
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16. Lack of replication of genetic associations with human longevity.
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Novelli V, Viviani Anselmi C, Roncarati R, Guffanti G, Malovini A, Piluso G, and Puca AA
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- Adolescent, Adult, Aged, 80 and over, Apolipoproteins E genetics, Case-Control Studies, Child, Child, Preschool, Female, Gene Frequency, Genotype, Humans, Infant, Infant, Newborn, Male, Phenotype, Reproducibility of Results, Sample Size, United States, White People genetics, Longevity genetics, Polymorphism, Single Nucleotide
- Abstract
The exceptional longevity of centenarians is due in part to inherited genetic factors, as deduced from data that show that first degree relatives of centenarians live longer and have reduced overall mortality. In recent years, a number of groups have performed genetic association studies on long-living individuals (LLI) and young controls to identify alleles that are either positively or negatively selected in the centenarian population as consequence of a demographic pressure. Many of the reported studies have shown genetic loci associated with longevity. Of these, with the exception of APOE, none have been convincingly reproduced. We validated our populations by typing the APOE locus. In addition, we used 749 American Caucasian LLI, organized in two independent tiers and 355 American Caucasian controls in the attempt to replicate previously published findings. We tested Klotho (KL)-VS variant (rs952706), Cholesteryl Ester Transfer Protein (CETP) I405V (rs5882), Paraoxonase 1 (PON1) Q192R (rs662), Apolipoprotein C-III (APOC3) -641C/A (rs2542052), Microsomal Transfer Protein (MTP) -493G/T (rs2866164) and apolipoprotein E (APOE) epsilon2 and epsilon4 isoforms, (rs7412 and rs429358) haplotypes respectively. Our results show that, at present, except for APOE, none of the selected genes show association with longevity if carefully tested in a large cohort of LLI and their controls, pointing to the need of larger populations for case-control studies in extreme longevity.
- Published
- 2008
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17. Lipid metabolism and diet: possible mechanisms of slow aging.
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Puca AA, Chatgilialoglu C, and Ferreri C
- Subjects
- Animals, Caloric Restriction, Diet, Humans, Life Expectancy, Aging genetics, Heat-Shock Proteins physiology, Lipid Metabolism, Lipids physiology, Longevity genetics
- Abstract
The ability to survive to an extremely old age is a consequence of complex interactions among genes, environment, lifestyle and luck. In the last two centuries, life expectancy in western countries has doubled, increasing from 40 to 81 years (79 for males and 82 for females). The candidate factors to determine such mortality reduction are reduced exposure to infections and the subsequent reduction in inflammatory responses, and to some extent, improvement in diet and nutrition. Among the people born at the beginning of the previous century, a small portion of individuals (1 in 10,000 born) have reached 100 years, surviving approximately 20 years more than the general population. The successful longevity of these individuals shows a familial component, possibly genetic, as underlined by the centenarian sibling's increased chance of reaching 100 years of age compared to the general population. Genetic studies on long living individuals have led to the discovery of potential genetic causes of extreme longevity. These discoveries have highlighted the role of lipid metabolism as a potential key player in the ability to survive to extreme old age. Additional studies on the longevity phenotype have confirmed the role of lipids and lipid-associated cell activities in the predisposition to longevity, from lower eukaryotes to humans. The main focus of this review is the appreciation of demographic survival data and changes in recent diet with the above mentioned genetic and phenotypic biomarkers of longevity, in order to elucidate hypotheses on mechanisms of slow aging and disease resistance.
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- 2008
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18. Genetic Signatures of Centenarians
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Villa, Francesco, Ferrario, Anna, Puca, Annibale Alessandro, and Caruso, Calogero, editor
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- 2019
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19. Old, Nonagenarians, and Centenarians in Cilento, Italy and the Association of Lifespan with the Level of Some Physicochemical Elements in Tap Drinking Water
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Silvana Mirella Aliberti, Richard H. W. Funk, Elena Ciaglia, Joseph Gonnella, Aldo Giudice, Carmine Vecchione, Annibale Alessandro Puca, and Mario Capunzo
- Subjects
longevity ,old population ,centenarians ,physicochemical elements ,tap drinking water ,healthy living ,Nutrition. Foods and food supply ,TX341-641 - Abstract
Longevity, as a complex life-history trait, shares an ontogenetic relationship with other quantitative traits, such as epigenetic and environmental factors. Therefore, it is important to identify environmental factors that may modify the epigenome to establish healthy aging. This study explored the association between tap drinking water and longevity in Cilento, Italy, to understand whether trace elements in local drinking water may have an influence on old, nonagenarian, and centenarian people and promote their health and longevity. Data on population and water sources were collected through the National Demographic Statistics, the Cilento Municipal Archives, and the Cilento Integrated Water Service. Ordinary least squares (OLS) regression and a geographically weight regression (GWR) model were used to study the spatial relationship between the explanatory and outcome variables of longevity. The results of the study showed that the prevalence of longevity is concentrated in the central, northern and southeastern areas of the territory and that some trace elements present in tap water may contribute to local longevity in Cilento. Specifically, all Cilento municipalities had alkaline tap water, and the municipalities with the highest longevity concentrations had higher alkalinity levels than the other municipalities, soft to medium-hard water hardness, an amount of total dissolved solids equivalent to the level of excellent water, lower amounts of sodium, adequate iron concentration, and adequate dietary intake of manganese per day.
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- 2023
- Full Text
- View/download PDF
20. Circulating BPIFB4 Levels Associate With and Influence the Abundance of Reparative Monocytes and Macrophages in Long Living Individuals
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Elena Ciaglia, Francesco Montella, Valentina Lopardo, Pasqualina Scala, Anna Ferrario, Monica Cattaneo, Albino Carrizzo, Alberto Malovini, Paolo Madeddu, Carmine Vecchione, and Annibale Alessandro Puca
- Subjects
longevity ,patrolling-monocytes ,plasma ,M2 macrophages ,FACS ,immunity ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Long-Living Individuals (LLIs) delay aging and are less prone to chronic inflammatory reactions. Whether a distinct monocytes and macrophages repertoire is involved in such a characteristic remains unknown. Previous studies from our group have shown high levels of the host defense BPI Fold Containing Family B Member 4 (BPIFB4) protein in the peripheral blood of LLIs. Moreover, a polymorphic variant of the BPIFB4 gene associated with exceptional longevity (LAV-BPIFB4) confers protection from cardiovascular diseases underpinned by low-grade chronic inflammation, such as atherosclerosis. We hypothesize that BPIFB4 may influence monocytes pool and macrophages skewing, shifting the balance toward an anti-inflammatory phenotype. We profiled circulating monocytes in 52 LLIs (median-age 97) and 52 healthy volunteers (median-age 55) using flow cytometry. If the frequency of total monocyte did not change, the intermediate CD14++CD16+ monocytes counts were lower in LLIs compared to control adults. Conversely, non-classical CD14+CD16++ monocyte counts, which are M2 macrophage precursors with an immunomodulatory function, were found significantly associated with the LLIs' state. In a differentiation assay, supplementation of the LLIs' plasma enhanced the capacity of monocytes, either from LLIs or controls, to acquire a paracrine M2 phenotype. A neutralizing antibody against the phosphorylation site (ser 75) of BPIFB4 blunted the M2 skewing effect of the LLIs' plasma. These data indicate that LLIs carry a peculiar anti-inflammatory myeloid profile, which is associated with and possibly sustained by high circulating levels of BPIFB4. Supplementation of recombinant BPIFB4 may represent a novel means to attenuate inflammation-related conditions typical of unhealthy aging.
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- 2020
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21. The Longevity-Associated Variant of BPIFB4 Reduces Senescence in Glioma Cells and in Patients’ Lymphocytes Favoring Chemotherapy Efficacy
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Annibale Alessandro Puca, Valentina Lopardo, Francesco Montella, Paola Di Pietro, Daniela Cesselli, Irene Giulia Rolle, Michela Bulfoni, Veronica Di Sarno, Giorgio Iaconetta, Pietro Campiglia, Carmine Vecchione, Antonio Paolo Beltrami, and Elena Ciaglia
- Subjects
senescence ,glioma ,longevity ,PBMCs ,chemotherapy ,Cytology ,QH573-671 - Abstract
Glioblastoma (GBM) is the most common primary brain cancer with the median age at diagnosis around 64 years, thus pointing to aging as an important risk factor. Indeed, aging, by increasing the senescence burden, is configured as a negative prognostic factor for GBM stage. Furthermore, several anti-GBM therapies exist, such as temozolomide (TMZ) and etoposide (ETP), that unfortunately trigger senescence and the secretion of proinflammatory senescence-associated secretory phenotype (SASP) factors that are responsible for the improper burst of (i) tumorigenesis, (ii) cancer metastasis, (iii) immunosuppression, and (iv) tissue dysfunction. Thus, adjuvant therapies that limit senescence are urgently needed. The longevity-associated variant (LAV) of the bactericidal/permeability-increasing fold-containing family B member 4 (BPIFB4) gene previously demonstrated a modulatory activity in restoring age-related immune dysfunction and in balancing the low-grade inflammatory status of elderly people. Based on the above findings, we tested LAV-BPIFB4 senotherapeutic effects on senescent glioblastoma U87-MG cells and on T cells from GBM patients. We interrogated SA-β-gal and HLA-E senescence markers, SASP factors, and proliferation and apoptosis assays. The results highlighted a LAV-BPIFB4 remodeling of the senescent phenotype of GBM cells, enhancement of their sensitivity to temozolomide and a selective reduction of the T cells’ senescence from GBM patients. Overall, these findings candidate LAV-BPIFB4 as an adjuvant therapy for GBM.
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- 2022
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22. Old, Nonagenarians, and Centenarians in Cilento, Italy and the Association of Lifespan with the Level of Some Physicochemical Elements in Tap Drinking Water
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Silvana Mirella Aliberti, Richard H. W. Funk, Elena Ciaglia, Joseph Gonnella, Aldo Giudice, Carmine Vecchione, Annibale Alessandro Puca, and Mario Capunzo
- Subjects
longevity ,old population ,centenarians ,physicochemical elements ,tap drinking water ,healthy living ,Cilento region ,Nutrition and Dietetics ,Food Science - Abstract
Longevity, as a complex life-history trait, shares an ontogenetic relationship with other quantitative traits, such as epigenetic and environmental factors. Therefore, it is important to identify environmental factors that may modify the epigenome to establish healthy aging. This study explored the association between tap drinking water and longevity in Cilento, Italy, to understand whether trace elements in local drinking water may have an influence on old, nonagenarian, and centenarian people and promote their health and longevity. Data on population and water sources were collected through the National Demographic Statistics, the Cilento Municipal Archives, and the Cilento Integrated Water Service. Ordinary least squares (OLS) regression and a geographically weight regression (GWR) model were used to study the spatial relationship between the explanatory and outcome variables of longevity. The results of the study showed that the prevalence of longevity is concentrated in the central, northern and southeastern areas of the territory and that some trace elements present in tap water may contribute to local longevity in Cilento. Specifically, all Cilento municipalities had alkaline tap water, and the municipalities with the highest longevity concentrations had higher alkalinity levels than the other municipalities, soft to medium-hard water hardness, an amount of total dissolved solids equivalent to the level of excellent water, lower amounts of sodium, adequate iron concentration, and adequate dietary intake of manganese per day.
- Published
- 2022
23. Transfer of a human gene variant associated with exceptional longevity improves cardiac function in obese type 2 diabetic mice through induction of the <scp>SDF</scp> ‐1/ <scp>CXCR4</scp> signalling pathway
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Gaia Spinetti, Stephen J. Paisey, Ashton Faulkner, Zexu Dang, Elena Ciaglia, Aishah Alenzi, Annibale Alessandro Puca, Carmine Vecchione, Antonio D'Amato, Elisa Avolio, Albino Carrizzo, Nicoletta Finato, Paolo Madeddu, Anna Maciag, Yue Gu, Celeste Cervellin, Anita C Thomas, and Antonio Paolo Beltrami
- Subjects
Cardiac function curve ,Receptors, CXCR4 ,medicine.medical_specialty ,Cardiomyopathy ,Bristol Heart Institute ,Longevity ,Mice, Obese ,030204 cardiovascular system & hematology ,Diabetes Mellitus, Experimental ,Mice ,03 medical and health sciences ,Gene therapy ,0302 clinical medicine ,longevity ,Internal medicine ,Diabetes mellitus ,Diabetic cardiomyopathy ,medicine ,Animals ,Humans ,Obesity ,Endothelial dysfunction ,Heart Failure ,BPIFB4 ,Diabetes ,diabetes ,business.industry ,Myocardium ,Phosphoproteins ,medicine.disease ,gene therapy ,Db/db Mouse ,Endocrinology ,Diabetes Mellitus, Type 2 ,Heart failure ,Cardiovascular agent ,Intercellular Signaling Peptides and Proteins ,Cardiology and Cardiovascular Medicine ,business ,cardiomyopathy ,Signal Transduction - Abstract
Aims: Homozygosity for a 4-missense single-nucleotide-polymorphism-haplotype of the human BPIFB4 gene is enriched in long-living individuals. Delivery of this Longevity Associated Variant (LAV) improved revascularisation and reduced endothelial dysfunction and atherosclerosis in mice through a mechanism involving the stromal cell-derived factor-1 (SDF-1). Here, we investigated if delivery of the LAV-BPIFB4 gene may attenuate the progression of diabetic cardiomyopathy. Methods and Results: Compared with age-matched lean controls, diabetic db/db mice showed altered echocardiographic indices of diastolic and systolic function and histological evidence of microvascular rarefaction, lipid accumulation, and fibrosis in the myocardium. All these alterations, as well as endothelial dysfunction, were prevented by systemic LAV-BPIFB4 gene therapy using an adeno-associated viral vector serotype 9 (AAV9). In contrast, AAV9-wild type (WT)-BPIFB4 exerted no benefit. Interestingly, the LAV-BPIFB4-treated mice showed increased SDF-1 levels in peripheral blood and myocardium and upregulation of cardiac myosin heavy chain isoform alpha, a contractile protein that was reduced in diabetic hearts. SDF-1 upregulation was instrumental to LAV-BPIFB4-induced benefit as both haemodynamic and structural improvements were inhibited by an orally active antagonist of the SDF-1 CXCR4 receptor. Conclusions: In mice with type-2 diabetes, LAV-BPIFB4 gene therapy promotes an advantageous remodelling of the heart, allowing it to better withstand diabetes-induced stress. These results support the viability of transferring healthy characteristics of longevity to attenuate diabetic cardiac disease.
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- 2020
24. Transfer of the longevity-associated variant of BPIFB4 gene rejuvenates immune system and vasculature by a reduction of CD38+ macrophages and NAD+ decline
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Elena Ciaglia, Valentina Lopardo, Francesco Montella, Albino Carrizzo, Paola Di Pietro, Marco Malavolta, Robertina Giacconi, Fiorenza Orlando, Monica Cattaneo, Paolo Madeddu, Carmine Vecchione, and Annibale Alessandro Puca
- Subjects
Inflammation ,Cancer Research ,QH573-671 ,Macrophages ,Immunology ,Longevity ,Cell Biology ,Genetic Therapy ,Inflammatory diseases ,Senescence ,NAD ,Phosphoproteins ,Article ,Mice, Inbred C57BL ,Cellular and Molecular Neuroscience ,Mice ,Cardiovascular Diseases ,Immune System ,Animals ,Intercellular Signaling Peptides and Proteins ,Cytology ,Immunological disorders - Abstract
As we age, our body experiences chronic, systemic inflammation contributing to the morbidity and mortality of the elderly. The senescent immune system has been described to have a causal role in driving systemic aging and therefore may represent a key therapeutic target to prevent pathological consequences associated with aging and extend a healthy lifespan. Previous studies from our group associated a polymorphic haplotype variant in the BPIFB4 gene (LAV-BPIFB4) with exceptional longevity. Transfer of the LAV-BPIFB4 in preclinical models halted the progression of cardiovascular diseases (CVDs) and frailty by counterbalancing chronic inflammation. In the present study, we aimed to delineate the action of systemic adeno-associated viral vector-mediated LAV-BPIFB4 gene transfer (AAV-LAV-BPIFB4) on the deleterious age-related changes of the immune system and thereby the senescence-associated events occurring in C57BL/6J mice aged 26 months. Our in vivo data showed that 26-months-old mice had a higher frequency of CD45+SA-beta Gal+immune cells in peripheral blood than young (4-months-old) C57BL/6J mice. Notably, AAV-LAV-BPIFB4 gene transfer in aged mice reduced the pool of peripheral immunosenescent cells that were shown to be enriched in the spleen. In addition, the proper tuning of the immune secretory phenotype (IL1βlow, IL6low, IL10high) associated with a significant reduction in SA-beta Gal-positive area of aorta from AAV-LAV treated mice. At the functional level, the reduction of senescence-associated inflammation ensured sustained NAD+levels in the plasma of AAV-LAV-BPIFB4 old mice by preventing the NADase CD38 increase in F4/80+ tissue-resident macrophages and Ly6Chighpro-inflammatory monocytes of the spleen and bone marrow. Finally, to validate the clinical implication of our findings, we showed that Long-living-individuals (LLIs, >95 years), which delay CVDs onset, especially if LAV-carriers, were characterized by high NAD+levels. In conclusion, the new senotherapeutic action of LAV-BPIFB4 may offer a valuable therapeutic tool to control aging and reduce the burden of its pathophysiological disorders, such as CVDs.
- Published
- 2022
25. Old, Nonagenarians, and Centenarians in Cilento, Italy and the Association of Lifespan with the Level of Some Physicochemical Elements in Tap Drinking Water.
- Author
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Aliberti, Silvana Mirella, Funk, Richard H. W., Ciaglia, Elena, Gonnella, Joseph, Giudice, Aldo, Vecchione, Carmine, Puca, Annibale Alessandro, and Capunzo, Mario
- Abstract
Longevity, as a complex life-history trait, shares an ontogenetic relationship with other quantitative traits, such as epigenetic and environmental factors. Therefore, it is important to identify environmental factors that may modify the epigenome to establish healthy aging. This study explored the association between tap drinking water and longevity in Cilento, Italy, to understand whether trace elements in local drinking water may have an influence on old, nonagenarian, and centenarian people and promote their health and longevity. Data on population and water sources were collected through the National Demographic Statistics, the Cilento Municipal Archives, and the Cilento Integrated Water Service. Ordinary least squares (OLS) regression and a geographically weight regression (GWR) model were used to study the spatial relationship between the explanatory and outcome variables of longevity. The results of the study showed that the prevalence of longevity is concentrated in the central, northern and southeastern areas of the territory and that some trace elements present in tap water may contribute to local longevity in Cilento. Specifically, all Cilento municipalities had alkaline tap water, and the municipalities with the highest longevity concentrations had higher alkalinity levels than the other municipalities, soft to medium-hard water hardness, an amount of total dissolved solids equivalent to the level of excellent water, lower amounts of sodium, adequate iron concentration, and adequate dietary intake of manganese per day. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
26. Modulation of soluble receptor for advanced glycation end products isoforms and advanced glycation end products in long-living individuals
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Anna Maciag, Gaia Spinetti, Francesco Scavello, Angela Raucci, Stefania Castiglione, Fabrizio Veglia, Calogero C. Tedesco, Annibale Alessandro Puca, and Elena Sangalli
- Subjects
cardiovascular risk ,secretory esRAGE ,0301 basic medicine ,Gene isoform ,medicine.medical_specialty ,Clinical Biochemistry ,Receptor for Advanced Glycation End Products ,030204 cardiovascular system & hematology ,RAGE (receptor) ,03 medical and health sciences ,0302 clinical medicine ,longevity ,Glycation ,Internal medicine ,Drug Discovery ,medicine ,Receptor ,business.industry ,aging ,Biochemistry (medical) ,Chronological age ,030104 developmental biology ,Endocrinology ,Disease risk ,biomarker ,Biomarker (medicine) ,soluble cleaved RAGE ,business - Abstract
Lay abstract Aging is the major risk factor for disease development. Long-living individuals (LLIs) are subjects older than 90 years that represent an invaluable model to study mechanisms underpinning longevity and healthy aging. Circulating levels of soluble receptor for advanced glycation end products (sRAGE) change with aging and can forecast the cardiovascular risk, which is reduced in centenarians. sRAGE is composed of two isoforms, the cleaved RAGE (cRAGE) and the secretory RAGE (esRAGE), that are known to inhibit the oxidative stress and inflammatory activities of their ligands such the advanced glycation end products (AGEs). In this study, we measured the plasmatic levels of both sRAGE isoforms and AGEs in LLIs (90–105 years) and control subjects (11–89 years). We found that cRAGE decreases with age in controls and LLIs. esRAGE increases in LLIs and AGEs increase in controls with age but decrease in LLIs. AGEs/esRAGE ratio and cRAGE were able to discriminate controls from LLIs. Hence, LLIs are characterized by a lower AGEs/sRAGE ratio, due to esRAGE increase and AGEs reduction that may explain their reduced cardiovascular and metabolic risk. Besides, circulating cRAGE could be considered a reliable marker of chronological age, while esRAGE a protective factor associated with longevity.
- Published
- 2021
27. LAV-BPIFB4 associates with reduced frailty in humans and its transfer prevents frailty progression in old mice
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Antonio D'Amato, Marco Malavolta, Anna Ferrario, Francesco Villa, Francesca Iannone, Paolo Madeddu, Francesco De Rango, Annibale Alessandro Puca, Mauro Provinciali, Elena Ciaglia, Giuseppe Passarino, Albino Carrizzo, Andrea Basso, Serena Dato, Carmine Vecchione, Giuseppina Rose, Anna Maciag, and Fiorenza Orlando
- Subjects
Longevity-Associated Variant-LAV ,Male ,Genotype ,Aging ,BPIFB4 ,Frailty ,Survival ,Longevity ,Population ,Mice, Transgenic ,frailty ,survival ,Mice ,medicine ,Animals ,Humans ,Endothelial dysfunction ,education ,Inverse correlation ,Gene ,Aged ,Aged, 80 and over ,education.field_of_study ,business.industry ,Haplotype ,aging ,Correction ,Cell Biology ,Phosphoproteins ,medicine.disease ,Specific Pathogen-Free Organisms ,Mice, Inbred C57BL ,Gene Expression Regulation ,Genetic marker ,Cohort ,Immunology ,Intercellular Signaling Peptides and Proteins ,Female ,Risk of death ,business ,longevity-associated variant-lav ,Research Paper - Abstract
BACKGROUND:There is an increasing concern about age-related frailty because of the growing number of elderly people in the general population. The Longevity-Associated Variant (LAV) of the human BPIFB4 gene was found to correct endothelial dysfunction, one of the mechanisms underlying frailty, in aging mice whereas the RV-BPIFB4 variant induced opposite effects. Thus, we newly hypothesize that, besides being associated with life expectancy, BPIFB4 polymorphisms can predict frailty.Aim and Results: Here we investigated if the BPIFB4 haplotypes, LAV, wild-type (WT) and RV, differentially associate with frailty in a cohort of 237 elderly subjects from Calabria region in Southern Italy. Moreover, we studied the effect of systemic adeno-associated viral vector-mediated LAV-BPIFB4 gene transfer on the progression of frailty in aging mice. We found an inverse correlation of the homozygous LAV-BPIFB4 haplotype with frailty in elderly subjects. Conversely, carriers of the RV-BPIFB4 haplotype showed an increase in the frailty status and risk of death. Moreover, in old mice, LAV-BPIFB4 gene transfer delayed frailty progression.CONCLUSIONS:These data indicate that specific BPIFB4 haplotypes could represent useful genetic markers of frailty. In addition, horizontal transfer of a healthy gene variant can attenuate frailty in aging organisms.
- Published
- 2019
28. Special Issue 'Centenarians-A Model to Study the Molecular Basis of Lifespan and Healthspan'
- Author
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Calogero Caruso, Annibale Alessandro Puca, Caruso C., and Puca A.A.
- Subjects
Gerontology ,Longevity ,MEDLINE ,Probiotic ,Models, Biological ,Catalysis ,Epigenesis, Genetic ,Inorganic Chemistry ,lcsh:Chemistry ,Medicine ,Humans ,Physical and Theoretical Chemistry ,Molecular Biology ,lcsh:QH301-705.5 ,Spectroscopy ,Settore MED/04 - Patologia Generale ,Aged, 80 and over ,Clinical Trials as Topic ,business.industry ,Probiotics ,Organic Chemistry ,General Medicine ,Computer Science Applications ,Diet ,Child mortality ,Editorial ,n/a ,lcsh:Biology (General) ,lcsh:QD1-999 ,Health ,business ,Human - Abstract
People are living longer, not, as was previously the case, due to reduced child mortality, but because we are postponing the ill-health of old age [...]
- Published
- 2021
29. BPIFB4 Circulating Levels and Its Prognostic Relevance in COVID-19
- Author
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Elena Ciaglia, Valeria Conti, Carla Zannella, Pasquale Pagliano, Paola Di Pietro, Valentina Manzo, Amelia Filippelli, Emanuela De Bellis, Albino Carrizzo, Gianluigi Franci, Carmine Vecchione, Annibale Alessandro Puca, Carmine Sellitto, Francesco Montella, Valentina Lopardo, and Teresa Iannaccone
- Subjects
Cytotoxicity, Immunologic ,Male ,Aging ,THE JOURNAL OF GERONTOLOGY: Biological Sciences ,Immunity function ,Cytotoxicity ,Longevity ,Inflammation ,Peripheral blood mononuclear cell ,Severity of Illness Index ,Cell Line ,AcademicSubjects/MED00280 ,Plasma ,Downregulation and upregulation ,Immunologic ,Severity of illness ,SARS-CoV-2 ,Aged, 80 and over ,Biomarkers ,Cytokines ,Female ,Humans ,Immunologic Factors ,Italy ,Prognosis ,Recombinant Proteins ,COVID-19 ,Intercellular Signaling Peptides and Proteins ,80 and over ,Medicine ,Aged ,business.industry ,CD69 ,Haplotype ,Covid19 ,Cell culture ,Immunology ,AcademicSubjects/SCI00960 ,Geriatrics and Gerontology ,medicine.symptom ,business ,Homeostasis - Abstract
Aging and comorbidities make individuals at greatest risk of COVID-19 serious illness and mortality due to senescence-related events and deleterious inflammation. Long-living individuals (LLIs) are less susceptible to inflammation and develop more resiliency to COVID-19. As demonstrated, LLIs are characterized by high circulating levels of BPIFB4, a protein involved in homeostatic response to inflammatory stimuli. Also, LLIs show enrichment of homozygous genotype for the minor alleles of a 4 missense single-nucleotide polymorphism haplotype (longevity-associated variant [LAV]) in BPIFB4, able to counteract progression of diseases in animal models. Thus, the present study was designed to assess the presence and significance of BPIFB4 level in COVID-19 patients and the potential therapeutic use of LAV-BPIFB4 in fighting COVID-19. BPIFB4 plasma concentration was found significantly higher in LLIs compared to old healthy controls while it significantly decreased in 64 COVID-19 patients. Further, the drop in BPIFB4 values correlated with disease severity. Accordingly to the LAV-BPIFB4 immunomodulatory role, while lysates of SARS-CoV-2-infected cells induced an inflammatory response in healthy peripheral blood mononuclear cells in vitro, the co-treatment with recombinant protein (rh) LAV-BPIFB4 resulted in a protective and self-limiting reaction, culminating in the downregulation of CD69 activating-marker for T cells (both TCD4+ and TCD8+) and in MCP-1 reduction. On the contrary, rhLAV-BPIFB4 induced a rapid increase in IL-18 and IL-1b levels, shown largely protective during the early stages of the virus infection. This evidence, along with the ability of rhLAV-BPIFB4 to counteract the cytotoxicity induced by SARS-CoV-2 lysate in selected target cell lines, corroborates BPIFB4 prognostic value and open new therapeutic possibilities in more vulnerable people.
- Published
- 2021
30. Rescue of cardiac function in obese type-2 diabetic mice by transfer of a human longevity gene
- Author
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Annibale Alessandro Puca, Elisa Avolio, Carmine Vecchione, Paolo Madeddu, Zexu Dang, Anna Maciag, Anna Ferrario, Elena Ciaglia, Antonio D'Amato, Gaia Spinetti, Ashton Faulkner, Yue Gu, Anita C Thomas, Antonio Paolo Beltrami, and Albino Carrizzo
- Subjects
Cardiac function curve ,medicine.medical_specialty ,business.industry ,Genetic enhancement ,media_common.quotation_subject ,Longevity ,medicine.disease ,gene therapy ,cardiac diseases ,Cell therapy ,Cardiac Myosins ,Endocrinology ,Basic Science ,Diabetes mellitus ,Internal medicine ,Diabetic cardiomyopathy ,Heart failure ,medicine ,cell therapy ,Cardiology and Cardiovascular Medicine ,business ,media_common - Abstract
Background Healthy longevity is the result of the interaction between favourable environment and unique genetic makeup. We showed that horizontal transfer of a longevity-associated gene variant (LAV-BPIFB4) improves endothelial function and accelerates the recovery from ischemia. Purpose To determine if the benefit of LAV-BPIFB4 gene therapy can be extended to diabetic cardiomyopathy. Methods and results We confirmed that human diabetic patients with heart failure (n=13) show a decreased cardiac expression of BPIFB4 compared with healthy subjects (n=10). Obese db/db mice received a systemic injection of adeno-associated viral vector (AAV9)-LAV-BPIFB4, AAV9-wild type (WT)-BPIFB4 (both 100 μL at 1×1012 GC/mL) or vehicle before the onset of cardiomyopathy, and were euthanised four weeks later for histological, metabolic and transcriptional analyses. Echocardiographic evaluation (n=8/group), performed at baseline and after gene therapy, showed that LAV-BPIFB4 treatment, despite not resolving hyperglycaemia, improved left ventricular function compared with the other groups. Histological analyses of the hearts (n=5 to 10/group) revealed that LAV-BPIFB4 reduced myocardial fibrosis and increased angiogenesis compared with vehicle and WT-hearts; moreover, LAV increased the expression of the alpha-isoform of the cardiac myosin heavy chain, which is associated with a superior cardiomyocyte contractility. Interestingly, LAV-BPIFB4 treatment induced an increase in cardiac SDF1 expression compared with WT and vehicle, despite the mechanism linking the two events is still unknown. The oral administration of the CXCR4 antagonist AMD-070, given at 2 mg/kg/day for four weeks, abolished several of the beneficial effects exerted by the LAV-BPIFB4 therapy in the obese diabetic mice, as assessed by echocardiography and histology (n=7/group). At the molecular level, next-generation RNA sequencing (n=3 to 4 /group) showed 8 genes were differentially expressed by LAV-BPIFB4-hearts compared with vehicle-hearts. These genes are associated with mitochondrial and metabolic functions. Among them, changes in the UCP3, HMGCS2, CS, ATPB and TOMM20 expression were also validated at the protein level by western blotting. Lipidomics using ultrahigh-performance liquid chromatography-mass spectrometry (n=6 or 7/group) showed 63 metabolites differentially expressed by LAV-BPIFB4- compared with vehicle-hearts, with only 3 (two cardiolipins and one glycerophospholipid) returning close to the non-diabetic phenotype following LAV-BPIFB4 treatment. Conclusions This study newly shows the possibility of transferring the benefit of salutary polymorphic gene variants to protect the cardiovascular system from metabolic pressure. Rather than combating pathogenic mechanisms, the strategy activates alternative pathways overriding disease risk factors. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): British Heart Foundation project grant “Longevity-associated BPIFB4 gene therapy for treatment of ischemic disease”
- Published
- 2020
31. Murine transfer of a human gene variant associated with exceptional longevity displays senolytic effects both in immune compartment and endothelium of aged mice
- Author
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M Malavolta, Elena Ciaglia, Annibale Alessandro Puca, Francesco Montella, Valentina Lopardo, Carmine Vecchione, and Albino Carrizzo
- Subjects
Endothelium ,business.industry ,media_common.quotation_subject ,Genetic variants ,Longevity ,Compartment (chemistry) ,Cell biology ,Immune system ,medicine.anatomical_structure ,Medicine ,Cardiology and Cardiovascular Medicine ,Senolytic ,business ,media_common - Abstract
The persistence and accumulation of senescent cells has been shown to potentially play a role in the pathophysiology of age-related cardiovascular diseases. Indeed with time, a decline in immune efficacy, termed immunesenescence, and a deleterious secretory phenotype of senescent cells (SASP) generate that inflammatory background mainly mediating the elderly cardiovascular phenotype. Long Living Individuals (LLI) which delay aging, represent a model of positive biology and an exceptional resource to study and find a way to improve general public health. Previous studies from our group have shown that a human gene associated with exceptional longevity (LAV-BPIFB4) was able to block the atherosclerotic process in ApoE−/− mice by conferring the animals with a pro-resolving M2 macrophages profile. Furthermore, LAV-BPIFB4 promotes the recruitment of hematopoietic stem cells, reparative vascularization and frailty reduction. Here we sought to underpinn the role of LAV-BPIFB4 in counteracting the age-related remodeling of the immune responses. The effects of systemic adeno-associated viral vector-mediated LAV-BPIFB4 gene transfer on the immune dynamics in old mice have been investigated by an extensive flow cytometric approach in lymphoid tissues (bone marrow, spleen and peripheral blood). C57BL/6J mice were assigned to two age-matched experimental groups: a treatment group (AAV-LAV-BPIFB4; N=6 mice, aged 18–23 months and a control group (AAV-GFP; N=6 mice, aged 18–23 months. 30th and 60th day since the beginning of the infection, SA-beta Gal substrate has been used to identify CD45+ senescent cells in freshly isolated PBMC, splenocytes, bone marrow (BM)-derived cells. As expected, we monitored an increase in SA-betaGal activity in blood. This increase is most significant in CD11b+ myeloid cells, whithout affecting neither CD3+T neither NK1.1+Natural Killer (NK) cell compartment. Notably 30 days AAV-LAV-BPIFB4 infection and to a more the 60 days-treatment, resulted in a significant decrease in senescent pool of peripheral immune cells and a concomitant enrichment of senescent cells in spleen. Concomitantly, aorta from AAV-LAV treated mice showed significant reduction in SA-beta Gal positive area. Furthermore a LAV-BPIFB4 induction of pro-resolving M2 macrophages compared to control group was documented in the main haemocateretic organ. As consequence the senolytic effect of LAV-BPIFB4 gene-therapy well correlated with the rescue of proliferative index of splenocytes upon PHA stimulation, and their functional protective response to lipopolysaccharide (LPS) in term of IL-6 and TNF-alpha secretion. The restoration of a protective and balanced immune response finally reflected the reduction of senescent phenopype acquired by mouse aortic endothelial cells during the aging process in vivo. A better underpinning of the senolytic action of LAV-BPIFB4 may offer a valuable therapeutic tool to reverse aging phenotype causing most of cardiac diseases Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Cariplo Foundation (n.2016-0874) to AAP and CV
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- 2020
32. The longevity-associated variant of BPIFB4 improves a CXCR4-mediated striatum–microglia crosstalk preventing disease progression in a mouse model of Huntington’s disease
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Alberto Auricchio, Francesco Montella, Annibale Alessandro Puca, Alba Di Pardo, Valentina Lopardo, Enrico Amico, Anna Maciag, Vittorio Maglione, Albino Carrizzo, Monica Cattaneo, Elena Ciaglia, Carmine Vecchione, Antonio D'Amato, Francesco Villa, Giuseppe Pepe, Federico Marracino, Anna Ferrario, Michele Madonna, Di Pardo, A., Ciaglia, E., Cattaneo, M., Maciag, A., Montella, F., Lopardo, V., Ferrario, A., Villa, F., Madonna, M., Amico, E., Carrizzo, A., Damato, A., Pepe, G., Marracino, F., Auricchio, A., Vecchione, C., Maglione, V., and Puca, A. A.
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0301 basic medicine ,Cancer Research ,Benzylamines ,Cellular homeostasis ,Cyclams ,0302 clinical medicine ,Cell Line, Transformed ,Microglia ,Cell Death ,lcsh:Cytology ,Cell Polarity ,Huntington's disease ,Polyglutamine tract ,Cell biology ,medicine.anatomical_structure ,Huntington Disease ,Disease Progression ,Intercellular Signaling Peptides and Proteins ,Proteasome Endopeptidase Complex ,Receptors, CXCR4 ,Cell Survival ,Immunology ,Longevity ,Biology ,Motor Activity ,Neuroprotection ,Article ,Cell Line ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Immune system ,medicine ,Huntingtin Protein ,Animals ,lcsh:QH573-671 ,Neuroinflammation ,Cell Proliferation ,Inflammation ,Genetic Variation ,Cell Biology ,medicine.disease ,Phosphoproteins ,Corpus Striatum ,Disease Models, Animal ,030104 developmental biology ,Gene Ontology ,Gene Expression Regulation ,030217 neurology & neurosurgery - Abstract
The longevity-associated variant (LAV) of the bactericidal/permeability-increasing fold-containing family B member 4 (BPIFB4) has been found significantly enriched in long-living individuals. Neuroinflammation is a key player in Huntington’s disease (HD), a neurodegenerative disorder caused by neural death due to expanded CAG repeats encoding a long polyglutamine tract in the huntingtin protein (Htt). Herein, we showed that striatal-derived cell lines with expanded Htt (STHdh Q111/111) expressed and secreted lower levels of BPIFB4, when compared with Htt expressing cells (STHdh Q7/7), which correlated with a defective stress response to proteasome inhibition. Overexpression of LAV-BPIFB4 in STHdh Q111/111 cells was able to rescue both the BPIFB4 secretory profile and the proliferative/survival response. According to a well-established immunomodulatory role of LAV-BPIFB4, conditioned media from LAV-BPIFB4-overexpressing STHdh Q111/111 cells were able to educate Immortalized Human Microglia—SV40 microglial cells. While STHdh Q111/111 dying cells were ineffective to induce a CD163 + IL-10high pro-resolving microglia compared to normal STHdh Q7/7, LAV-BPIFB4 transduction promptly restored the central immune control through a mechanism involving the stromal cell-derived factor-1. In line with the in vitro results, adeno-associated viral-mediated administration of LAV-BPIFB4 exerted a CXCR4-dependent neuroprotective action in vivo in the R6/2 HD mouse model by preventing important hallmarks of the disease including motor dysfunction, body weight loss, and mutant huntingtin protein aggregation. In this view, LAV-BPIFB4, due to its pleiotropic ability in both immune compartment and cellular homeostasis, may represent a candidate for developing new treatment for HD.
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- 2020
33. Multi-Omics Analysis of Diabetic Heart Disease in the db/db Model Reveals Potential Targets for Treatment by a Longevity-Associated Gene
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Paolo Madeddu, Zexu Dang, Thomas E Batstone, Annibale Alessandro Puca, Anita C Thomas, Elisa Avolio, Gavin R. Lloyd, Lukáš Najdekr, Carmine Vecchione, Andris Jankevics, Ralf J. M. Weber, Warwick B. Dunn, Gaia Spinetti, and Ashton Faulkner
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0301 basic medicine ,medicine.medical_specialty ,Bristol Heart Institute ,Cardiomyopathy ,Type 2 diabetes ,type-2 diabetes ,030204 cardiovascular system & hematology ,Biology ,Transcriptome ,03 medical and health sciences ,0302 clinical medicine ,longevity ,Diabetes mellitus ,Diabetic cardiomyopathy ,Internal medicine ,medicine ,Metabolome ,lcsh:QH301-705.5 ,BPIFB4 ,Lipid metabolism ,General Medicine ,medicine.disease ,Phenotype ,gene therapy ,030104 developmental biology ,Endocrinology ,cardiomyopathy ,lcsh:Biology (General) - Abstract
Characterisation of animal models of diabetic cardiomyopathy may help unravel new molecular targets for therapy. Long-living individuals are protected from the adverse influence of diabetes on the heart, and the transfer of a longevity-associated variant (LAV) of the human BPIFB4 gene protects cardiac function in the db/db mouse model. This study aimed to determine the effect of LAV-BPIFB4 therapy on the metabolic phenotype (ultra-high-performance liquid chromatography-mass spectrometry, UHPLC-MS) and cardiac transcriptome (next-generation RNAseq) in db/db mice. UHPLC-MS showed that 493 cardiac metabolites were differentially modulated in diabetic compared with non-diabetic mice, mainly related to lipid metabolism. Moreover, only 3 out of 63 metabolites influenced by LAV-BPIFB4 therapy in diabetic hearts showed a reversion from the diabetic towards the non-diabetic phenotype. RNAseq showed 60 genes were differentially expressed in hearts of diabetic and non-diabetic mice. The contrast between LAV-BPIFB4- and vehicle-treated diabetic hearts revealed eight genes differentially expressed, mainly associated with mitochondrial and metabolic function. Bioinformatic analysis indicated that LAV-BPIFB4 re-programmed the heart transcriptome and metabolome rather than reverting it to a non-diabetic phenotype. Beside illustrating global metabolic and expressional changes in diabetic heart, our findings pinpoint subtle changes in mitochondrial-related proteins and lipid metabolism that could contribute to LAV-BPIFB4-induced cardio-protection in a murine model of type-2 diabetes.
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- 2020
34. Taste receptor polymorphisms and longevity: a systematic review and meta-analysis
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Anna Aiello, Danilo Di Bona, Anna Maciag, Giulia Accardi, Calogero Caruso, Giuseppina Candore, Alberto Malovini, Annibale Alessandro Puca, Mattia Emanuela Ligotti, Anna Ferrario, Di Bona D., Malovini A., Accardi G., Aiello A., Candore G., Ferrario A., Ligotti M.E., Maciag A., Puca A.A., and Caruso C.
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Aging ,Genotype ,media_common.quotation_subject ,Population ,Longevity ,Review ,Biology ,Polymorphism, Single Nucleotide ,Receptors, G-Protein-Coupled ,03 medical and health sciences ,0302 clinical medicine ,Taste receptor ,Genetic variation ,Humans ,Meta-analysi ,education ,030304 developmental biology ,media_common ,Immune-inflammatory responses ,Settore MED/04 - Patologia Generale ,0303 health sciences ,education.field_of_study ,Meta-analysis ,Taste receptors ,TAS2R38 ,Evolutionary biology ,Taste ,Immune-inflammatory response ,Geriatrics and Gerontology ,Bitter taste receptors ,030217 neurology & neurosurgery - Abstract
Bitter taste receptors (TAS2R) are involved in a variety of non-tasting physiological processes, including immune-inflammatory ones. Therefore, their genetic variations might influence various traits. In particular, in different populations of South Italy (Calabria, Cilento, and Sardinia), polymorphisms of TAS2R16 and TAS238 have been analysed in association with longevity with inconsistent results. A meta-analytic approach to quantitatively synthesize the possible effect of the previous variants and, possibly, to reconcile the inconsistencies has been used in the present paper. TAS2R38 variants in the Cilento population were also analysed for their possible association with longevity and the obtained data have been included in the relative meta-analysis. In population from Cilento no association was found between TAS2R38 and longevity, and no association was observed as well, performing the meta-analysis with data of the other studies. Concerning TAS2R16 gene, instead, the genotype associated with longevity in the Calabria population maintained its significance in the meta-analysis with data from Cilento population, that, alone, were not significant in the previously published study. In conclusion, our results suggest that TAS2R16 genotype variant is associated with longevity in South Italy.
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- 2020
35. Molecular therapies delaying cardiovascular aging: disease- or health-oriented approaches
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Maurizio C. Capogrossi, Sunayana Begum Syed, Paolo Madeddu, Reggio Lorde, Alessandra Magenta, and Annibale Alessandro Puca
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Senescence ,lcsh:Diseases of the circulatory (Cardiovascular) system ,media_common.quotation_subject ,epigenetics ,genetics ,vascular regeneration ,Bristol Heart Institute ,Druggability ,Review ,Disease ,Bioinformatics ,Regenerative medicine ,lcsh:Physiology ,Medicine ,Epigenetics ,media_common ,lcsh:QP1-981 ,business.industry ,Regeneration (biology) ,Longevity ,Review article ,lcsh:RC666-701 ,business - Abstract
Regenerative medicine is a new therapeutic modality that aims to mend tissue damage by encouraging the reconstitution of physiological integrity. It represents an advancement over conventional therapies that allow reducing the damage but result in disease chronicization. Age-related decline in spontaneous capacity of repair, especially in organs like the heart that have very limited proliferative capacity, contributes in reducing the benefit of conventional therapy. ncRNAs are emerging as key epigenetic regulators of cardiovascular regeneration. Inhibition or replacement of miRNAs may offer reparative solutions to cardiovascular disease. The first part of this review article is devoted to illustrating novel therapies emerging from research on miRNAs. In the second part, we develop new therapeutic concepts emerging from genetics of longevity. Prolonged survival, as in supercentenarians, denotes an exceptional capacity to repair and cope with risk factors and diseases. These characteristics are shared with offspring, suggesting that the regenerative phenotype is heritable. New evidence indicates that genetic traits responsible for prolongation of health span in humans can be passed to and benefit the outcomes of animal models of cardiovascular disease. Genetic studies have also focused on determinants of accelerated senescence and related druggable targets. Evolutionary genetics assessing the genetic basis of adaptation and comparing successful and unsuccessful genetic changes in response to selection within populations represent a powerful basis to develop novel therapies aiming to prolong cardiovascular and whole organism health.
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- 2020
36. Four Genome-Wide Association Studies Identify New Extreme Longevity Variants
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Francesco Villa, Anastasia Gurinovich, Gil Atzmon, Annibale Alessandro Puca, Thomas T. Perls, Harold Bae, Aldi T. Kraja, Stacy L. Andersen, Paola Sebastiani, Nir Barzilai, Danny Ben-Avraham, and Alberto Malovini
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Male ,0301 basic medicine ,Genetic variants ,Aging ,media_common.quotation_subject ,Longevity ,Genetic profiles ,Healthy aging ,Human longevity ,Genome-wide association study ,Disease ,Bioinformatics ,Polymorphism, Single Nucleotide ,03 medical and health sciences ,Genetic variation ,Humans ,Medicine ,media_common ,Aged, 80 and over ,Health span ,business.industry ,Genetic Variation ,Phenotype ,030104 developmental biology ,The Journal of Gerontology: Biological Sciences ,Extreme longevity tracking ,Cohort ,Female ,Geriatrics and Gerontology ,business ,Genome-Wide Association Study ,Demography - Abstract
The search for the genetic determinants of extreme human longevity has been challenged by the phenotype's rarity and its nonspecific definition by investigators. To address these issues, we established a consortium of four studies of extreme longevity that contributed 2,070 individuals who survived to the oldest one percentile of survival for the 1900 U.S. birth year cohort. We conducted various analyses to discover longevity-associated variants (LAV) and characterized those LAVs that differentiate survival to extreme age at death (eSAVs) from those LAVs that become more frequent in centenarians because of mortality selection (eg, survival to younger years). The analyses identified new rare variants in chromosomes 4 and 7 associated with extreme survival and with reduced risk for cardiovascular disease and Alzheimer's disease. The results confirm the importance of studying truly rare survival to discover those combinations of common and rare variants associated with extreme longevity and longer health span.
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- 2017
37. Taste receptors, innate immunity and longevity: the case of TAS2R16 gene
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Anna Maciag, Giulia Accardi, Francesco Villa, Annibale Alessandro Puca, Giuseppina Candore, Calogero Caruso, Mattia Emanuela Ligotti, Riccardo Bellazzi, Anna Aiello, Alberto Malovini, Malovini, Alberto, Accardi, Giulia, Aiello, Anna, Bellazzi, Riccardo, Candore, Giuseppina, Caruso, Calogero, Ligotti, Mattia Emanuela, Maciag, Anna, Villa, Francesco, and Puca, Annibale A
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0301 basic medicine ,lcsh:Immunologic diseases. Allergy ,Candidate gene ,Aging ,media_common.quotation_subject ,Population ,Immunology ,Longevity ,Short Report ,Case control study ,Genome-wide association study ,Biology ,lcsh:Geriatrics ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,stomatognathic system ,Taste receptor ,GWAS ,Receptor ,education ,Bitter taste receptor ,media_common ,Settore MED/04 - Patologia Generale ,Genetics ,Innate immunity ,education.field_of_study ,Innate immune system ,lcsh:RC952-954.6 ,030104 developmental biology ,Bitter taste receptors ,TAS2R16 gene ,lcsh:RC581-607 ,030215 immunology - Abstract
Background Innate immunity utilizes components of sensory signal transduction such as bitter and sweet taste receptors. In fact, empirical evidence has shown bitter and sweet taste receptors to be an integral component of antimicrobial immune response in upper respiratory tract infections. Since an efficient immune response plays a key role in the attainment of longevity, it is not surprising that the rs978739 polymorphism of the bitter taste receptor TAS2R16 gene has been shown to be associated with longevity in a population of 941 individuals ranging in age from 20 to 106 years from Calabria (Italy). There are many possible candidate genes for human longevity, however of the many genes tested, only APOE and FOXO3 survived to association in replication studies. So, it is necessary to validate in other studies genes proposed to be associated with longevity. Thus, we analysed the association of the quoted polymorphism in a population of long lived individuals (LLIs) and controls from another Italian population from Cilento. Methods The analysis has been performed on data previously obtained with genome-wide association study on a population of LLIs (age range 90–109 years) and young controls (age range 18–45 years) from Cilento (Italy). Results Statistical power calculations showed that the analysed cohort represented by 410 LLIs and 553 young controls was sufficiently powered to replicate the association between rs978739 and the longevity phenotype according to the effect size and frequencies described in the previous paper, under a dominant and additive genetic model. However, no evidence of association between rs978739 and the longevity phenotype was observed according to the additive or dominant model. Conclusion There are several reasons for the failure of the confirmation of a previous study. However, the differences between the two studies in terms of environment of the population adopted and of the criteria of inclusion have made difficult the replication of the findings.
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- 2019
38. Varying Effects of APOE Alleles on Extreme Longevity in European Ethnicities
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Stacy L. Andersen, Annibale Alessandro Puca, Paola Sebastiani, Nir Barzilai, Gil Atzmon, and Anastasia Gurinovich
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Apolipoprotein E ,Male ,Aging ,Bioinformatics ,media_common.quotation_subject ,Genetic genealogy ,Longevity ,Ethnic group ,Supplement Articles ,White People ,Odds ,Danish ,Apolipoproteins E ,Human genetics ,Ethnicity ,Medicine ,Humans ,Allele ,Alleles ,media_common ,Aged, 80 and over ,business.industry ,Odds ratio ,language.human_language ,Europe ,language ,Female ,APOE ,Geriatrics and Gerontology ,business ,Demography - Abstract
APOE is a well-studied gene with multiple effects on aging and longevity. The gene has three alleles: e2, e3, and e4, whose frequencies vary by ethnicity. While the e2 is associated with healthy cognitive aging, the e4 allele is associated with Alzheimer’s disease and early mortality and therefore its prevalence among people with extreme longevity (EL) is low. Using the PopCluster algorithm, we identified several ethnically different clusters in which the effect of the e2 and e4 alleles on EL changed substantially. For example, PopCluster discovered a large group of 1,309 subjects enriched of Southern Italian genetic ancestry with weaker protective effect of e2 (odds ratio [OR] = 1.27, p = .14) and weaker damaging effect of e4 (OR = 0.82, p = .31) on the phenotype of EL compared to other European ethnicities. Further analysis of this cluster suggests that the odds for EL in carriers of the e4 allele with Southern Italian genetic ancestry differ depending on whether they live in the United States (OR = 0.29, p = .009) or Italy (OR = 1.21, p = .38). PopCluster also found clusters enriched of subjects with Danish ancestry with varying effect of e2 on EL. The country of residence (Denmark or United States) appears to change the odds for EL in the e2 carriers.
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- 2019
39. Longevity-Associated Variant of BPIFB4 Mitigates Monocyte-Mediated Acquired Immune Response
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Elena Ciaglia, Paola de Candia, Chiara Carmela Spinelli, Pasqualina Scala, Monica Cattaneo, Francesco Villa, Annibale Alessandro Puca, Francesco Montella, Anna Ferrario, Anna Maciag, Carmine Vecchione, Albino Carrizzo, Carlotta Banco, Ciaglia, E., Montella, F., Maciag, A., Scala, P., Ferrario, A., Banco, C., Carrizzo, A., Spinelli, C. C., Cattaneo, M., De Candia, P., Vecchione, C., Villa, F., and Puca, A. A.
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Adult ,Aging ,Myeloid ,Immune regulation ,Cells ,medicine.medical_treatment ,Interleukin-1beta ,Longevity ,Inflammation ,Myeloid cells ,Aged ,Aged, 80 and over ,Cells, Cultured ,Humans ,Middle Aged ,Monocytes ,Phosphoproteins ,Tumor Necrosis Factor-alpha ,Adaptive Immunity ,Monocyte ,Immune system ,80 and over ,medicine ,Intercellular Signaling Peptides and Protein ,Cultured ,business.industry ,Acquired immune system ,Myeloid cell ,Interleukin 10 ,medicine.anatomical_structure ,Cytokine ,Phosphoprotein ,Immunology ,Intercellular Signaling Peptides and Proteins ,Tumor necrosis factor alpha ,Geriatrics and Gerontology ,medicine.symptom ,business ,Human - Abstract
One of the basis of exceptional longevity is the maintaining of the balance between inflammatory and anti-inflammatory networks. The monocyte-macrophages activation plays a major role in tuning the immune responses, by oscillating between patrolling-protective to inflammatory status. Longevity-associated variant (LAV) of bactericidal/permeability-increasing fold-containing family B member 4 (BPIFB4) activates calcium, PKC-alpha, and eNOS, rescuing endothelial dysfunction in aged mice and inducing revascularization. The BPIFB4’s increment in serum of healthy long-living individuals (LLIs) compared to nonhealthy ones, its therapeutic potential in improving vascular homeostasis, which depends on immune system, together with its expression in bone marrow myeloid cells, suggests that LAV-BPIFB4 may improve immune regulation. Here we show that human monocytes exposed to LAV-BPIFB4 protein increased co-stimulatory molecules in resting state and reduced pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) after activating stimuli. Accordingly, a low percentage of CD69+ activated lymphocytes are found among LAV-BPIFB4-treated peripheral blood mononuclear cells (PBMCs). Moreover, human monocyte-derived dendritic cells (DCs) generated in presence of LAV-BPIFB4 secreted higher anti-(IL-10 and TGF-β) and lower pro-inflammatory (TNF-α and IL-1β) cytokines. Accordingly, LLIs’ plasma showed higher levels of circulating IL-10 and of neutralizing IL-1 receptor antagonist (IL-1RA) compared to controls. Thus, LAV-BPIFB4 effects on myeloid compartment could represent one example of a genetic predisposition carried by LLIs to protect from immunological dysfunctions.
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- 2019
40. Genetic signatures of centenarians: Implications for achieving successful aging
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Giulia Accardi, Anna Aiello, Calogero Caruso, Elena Ciaglia, Annibale Alessandro Puca, Monica Cattaneo, Caruso C., Aiello A., Accardi G., Ciaglia E., Cattaneo M., and Puca A.
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Male ,Aging ,media_common.quotation_subject ,Successful aging ,Population ,Longevity ,Context (language use) ,Biology ,centenarian ,03 medical and health sciences ,0302 clinical medicine ,Drug Discovery ,Cardiovascular diseases ,Centenarians ,Genetics ,Immune-inflammatory responses ,Humans ,Allele ,education ,Alleles ,030304 developmental biology ,media_common ,Aged, 80 and over ,Pharmacology ,0303 health sciences ,education.field_of_study ,Cardiovascular disease ,Phenotype ,immune-inflammatory response ,Trait ,Life expectancy ,Female ,successful aging ,Centenarian ,genetic ,030217 neurology & neurosurgery ,Demography - Abstract
The extraordinary rise in the old population in the Western world underscores the importance of studies on aging and longevity to decrease the medical, economic and social problems associated with the increased number of non-autonomous individuals affected by invalidating pathologies. Centenarians have reached the extreme limits of the human life span. They are the best example of extreme longevity, representing selected individuals in which the appearance of major age-related diseases has been consistently delayed or avoided. There is growing evidence that the genetic component of longevity becomes higher with survival at the age of over 90 years. For centenaries, it reaches up to 33% for women and 48% for men. Therefore, exceptional longevity is a complex, hereditable trait that runs across generations. Longevity should correlate either with the presence of protective alleles or the absence of detrimental alleles. The aim of this review is to discuss the possible attainment of successful aging in the context of the lessons learned from centenarian genetics.
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- 2019
41. P746Protective role of the longevity associated variant of BPIFB4 in chronic ischemia
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Daniela Cesselli, Annibale Alessandro Puca, N Finato, S. Sponga, Ugolino Livi, Francesco Villa, Michela Bulfoni, Celeste Cervellin, Paolo Madeddu, Claudia Veneziano, Angela Caragnano, and Antonio Paolo Beltrami
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Angiogenesis ,business.industry ,media_common.quotation_subject ,Longevity ,Ischemia ,Heterozygote advantage ,medicine.disease ,medicine.disease_cause ,Bioinformatics ,Transplantation ,Heart failure ,medicine ,Myocardial infarction ,Cardiology and Cardiovascular Medicine ,business ,Oxidative stress ,media_common - Abstract
Background A rare Longevity Associated Variant (LAV) of the gene BPIFB4, whose protein product can be secreted, is recessively associated with extreme longevity, positively impacting the cardiovascular system and promoting therapeutic angiogenesis in an hindlimb ischemia model. Aim Aim of this work is to verify if LAV-BPIFB4 may temper the phenotype of chronic ischemia in humans, thus suggesting its therapeutic potential. Methods and results 39 hearts explanted from patients affected by end-stage ischemic heart disease were studied. Of these, 7 were homozygous for BPIFB4-LAV. Homozygous and non-homozygous patients did not differ in sex, age and in the prevalence of comorbidities or risk factors. However, the time elapsed from myocardial infarction to transplantation was significantly longer for LAV homozygous with respect to LAV heterozygous patients (159±95 vs 58±27 months, p=0.045). Histologically, while BPIFB4 levels did not differ in accordance with the genotype, the fraction of Tunel+and 53BP1+apoptotic and senescent myocytes was significantly lower in homozygous patients (1.2±0.4% vs 23.8±21.7%, p=0.026 and 31.5±6.7% vs 44.4±6.1%, p=0.031, respectively). Significantly lower levels of lipoperoxides and higher levels of Parkin were observed in homozygous hearts too. Next, we directly tested the role of BPIFB4 on PDGFRb+ NG2+Tbx18+cardiac pericytes/mural cells (PM) cultured from normal atria (PMnorm, n=10) and from ischemic failing hearts (PMfail, n=7). BPIFB4 gene transcript was significantly more expressed in PMnorm than PMfail. Silencing BPIFB4 expression in PMnorm significantly increased the proportion of senescent gH2AX+Ki67-cells (3.6±2.9% vs 13.6±9.5%, p=0.049). Conversely, addition of recombinant LAV BPIFB4 protein to PMfail cultures significantly reduced the rate of senescent cells (21.1±9.4% vs 6.0±4.8%, p=0.03), an effect that was not observed with the administration of WT BPIFB4. PMfail cultures exposed to LAV BPIFB4 significantly reversed alterations observed with pathology, such as the accumulation of both lipofuscins and of very elongated and interconnected mitochondria in the cell cytoplasm, as well as elevated mitochondrial superoxide anion levels. Finally, a larger fraction of PMnorm cells showed, with respect to PMfail, the nuclear translocation of vitamin D receptor (74.6±6.1% vs 50.1±14.4, p=0.04), coupled with a significant upregulation of its, longevity associated, target gene Klotho. Importantly, LAV BPIFB4 significantly increased the fraction of PMfail with vitamin D receptor nuclear localization (55.8±17.6% vs 85.1±8.2%, p=0.005). Conclusion LAV BPIFB4 could attenuate the progression of ischemic heart disease to heart failure. Part of its protective effect may be due to its ability to reduce mitochondrial oxidative stress and to revert the senescent phenotype of cardiac derived cells. Acknowledgement/Funding CARIPLO foundation
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- 2019
42. Genetics of exceptional longevity: possible role of GM allotypes
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Annibale Alessandro Puca, Calogero Caruso, Janardan P. Pandey, Caruso, Calogero, Pandey, Janardan P, and Puca, Annibale A
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0301 basic medicine ,lcsh:Immunologic diseases. Allergy ,medicine.medical_specialty ,Aging ,media_common.quotation_subject ,Immunology ,Longevity ,Genome-wide association study ,Clinical nutrition ,Biology ,lcsh:Geriatrics ,Case control studies ,03 medical and health sciences ,GM allotypes ,GWAS ,Immune response ,0302 clinical medicine ,medicine ,Case control studie ,media_common ,Genetics ,GM allotype ,Settore MED/04 - Patologia Generale ,Geriatrics gerontology ,Public health ,lcsh:RC952-954.6 ,030104 developmental biology ,Commentary ,Gm Allotypes ,lcsh:RC581-607 ,030215 immunology - Abstract
NOT REQUESTED FOR COMMENTARIES
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- 2018
43. High TARC plasma levels confer protection to long living individuals by inducing M2 profile
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Elena Ciaglia, Annibale Alessandro Puca, Carmine Vecchione, Francesco Montella, and Valentina Lopardo
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Adult ,Male ,0301 basic medicine ,Aging ,Chemokine ,Myeloid ,medicine.medical_treatment ,FACS ,Longevity ,Immunology ,Macrophage polarization ,Enzyme-Linked Immunosorbent Assay ,Biology ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,medicine ,M2 macrophages ,Humans ,Immunology and Allergy ,CXCL10 ,CCL17 ,Molecular Biology ,TARC ,Aged ,Aged, 80 and over ,Macrophages ,Hematology ,Macrophage Activation ,Middle Aged ,Plasma profile ,Chemokine CXCL10 ,030104 developmental biology ,medicine.anatomical_structure ,Cytokine ,Cell culture ,030220 oncology & carcinogenesis ,biology.protein ,Intercellular Signaling Peptides and Proteins ,Female ,Chemokine CCL17 ,CD163 - Abstract
A way to delay aging and the related low-grade chronic inflammatory state is to study the model of positive physiology such as the Long-Living Individuals (LLIs). Our recent studies have shown higher levels of the host defense BPI Fold-Containing Family B Member 4 (BPIFB4) protein in the LLIs' blood. Notably, BPIFB4 has been shown to influence monocytes typesetting and M2 anti-inflammatory phenotype (CD206+CD163++) macrophages skewing. According to the role of a complex cytokine milieu in guiding the macrophage polarization, here we found that circulating concentrations of thymus and activation regulated chemokine (TARC)/CCL17 and small-inducible cytokine B10 (IP-10)/CXCL10) cytokines, were additionally associated with the LLIs' state. In a differentiation process in vitro, the addition of LLIs' plasma to the cell culture medium, enhanced the ability of monocytes, either from LLIs or controls, to acquire a M2 phenotype. Interestingly, a neutralizing antibody against TARC blunted the M2 skewing effect of the LLIs' plasma. Collectively, these data indicate that exceptional longevity may associate with a peculiar anti-inflammatory myeloid profile responsible for improved reparative processes and reduced inflammatory status mediated in part by TARC and M2 generation.
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- 2021
44. Centenarians as a model to discover genetic and epigenetic signatures of healthy ageing
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Francesco Villa, Calogero Caruso, Giulia Accardi, Chiara Carmela Spinelli, Annibale Alessandro Puca, Puca, Annibale Alessandro, Spinelli, Chiara, Accardi, Giulia, Villa, Francesco, and Caruso, Calogero
- Subjects
Ageing ,Diet ,Epigenetics ,Genetics ,Longevity ,Stochasticity ,Aging ,Developmental Biology ,0301 basic medicine ,Male ,media_common.quotation_subject ,Biology ,Models, Biological ,Epigenesis, Genetic ,03 medical and health sciences ,Genetic ,Humans ,media_common ,Settore MED/04 - Patologia Generale ,Aged, 80 and over ,Genetic variants ,Epigenetic ,030104 developmental biology ,Evolutionary biology ,Developmental plasticity ,Chromatin modification ,Successful ageing ,Female ,Healthy ageing - Abstract
Centenarians are a model of successful ageing. The data favours the theory that, in order to live to 100, it is mandatory to inherit the right genetic variants from parents or acquire epigenetic variants through the environment. Therefore, the study of epigenetic signatures of healthy ageing is becoming an important aspect to identify the role of chromatin modification in ageing and understand how manage this fine-tuning system. So, according to the concept of developmental plasticity, establishment of a longevity phenotype requires a combination of stochastic and non-stochastic events that modulate the genetic substrate and leads to a different outcome. It can be concluded that centenarians have a more powerful “engine” shaped by evolution, and that the environment, through epigenetic system, is a component influencing outcome.
- Published
- 2017
45. New Insights for BPIFB4 in Cardiovascular Therapy
- Author
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Elena Ciaglia, Marta Dossena, Anna Ferrario, Valentina Lopardo, and Annibale Alessandro Puca
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0301 basic medicine ,Diabetic Cardiomyopathies ,Review ,Adaptive Immunity ,030204 cardiovascular system & hematology ,Bioinformatics ,lcsh:Chemistry ,Mice ,0302 clinical medicine ,cardiovascular disease ,Risk Factors ,Enos ,Protein Isoforms ,Medicine ,lcsh:QH301-705.5 ,Spectroscopy ,Frailty ,biology ,BPIFB4 ,Age Factors ,Gene Expression Regulation, Developmental ,General Medicine ,Immunosenescence ,Computer Science Applications ,Aging ,Cardiovascular disease ,Hypertension ,Compression of morbidity ,Intercellular Signaling Peptides and Proteins ,Nitric Oxide Synthase Type III ,Longevity ,Context (language use) ,Dysfunctional family ,Catalysis ,Inorganic Chemistry ,03 medical and health sciences ,Immune system ,Animals ,Humans ,Physical and Theoretical Chemistry ,Risk factor ,Molecular Biology ,Pathological ,business.industry ,aging ,Organic Chemistry ,Genetic Therapy ,Atherosclerosis ,Phosphoproteins ,biology.organism_classification ,Immunity, Innate ,030104 developmental biology ,lcsh:Biology (General) ,lcsh:QD1-999 ,business - Abstract
Aging is the most relevant risk factor for cardiovascular diseases which are the main cause of mortality in industrialized countries. In this context, there is a progressive loss of cardiovascular homeostasis that translates in illness and death. The study of long living individuals (LLIs), which show compression of morbidity toward the end of their life, is a valuable approach to find the key to delay aging and postpone associate cardiovascular events. A contribution to the age-related decline of cardiovascular system (CVS) comes from the immune system; indeed, it is dysfunctional during aging, a process described as immunosenescence and comprises the combination of several processes overpowering both innate and adaptative immune system. We have recently discovered a longevity-associated variant (LAV) in bactericidal/permeability-increasing fold-containing family B member 4 (BPIFB4), which is a secreted protein able to enhance endothelial function through endothelial nitric oxide synthase (eNOS) activation and capable to protect from hypertension, atherosclerosis, diabetic cardiopathy, frailty, and inflammaging. Here, we sum up the state of the art of the mechanisms involved in the main pathological processes related to CVD (atherosclerosis, aging, diabetic cardiopathy, and frailty) and shed light on the therapeutic effects of LAV-BPIFB4 in these contexts.
- Published
- 2020
46. APOE Alleles and Extreme Human Longevity
- Author
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Takashi Sasaki, Francesco Villa, Paola Sebastiani, Gil Atzmon, Harold Bae, Nir Barzilai, Kaare Christensen, Marianne Nygaard, Yasumichi Arai, Thomas T. Perls, Lene Christiansen, Nobuyoshi Hirose, Annibale Alessandro Puca, Anastasia Gurinovich, Stacy L. Andersen, and Benjamin Sweigart
- Subjects
0301 basic medicine ,Aging ,Genotype ,media_common.quotation_subject ,Population ,Survival distribution ,DNA/genetics ,Odds ,Healthy Aging ,03 medical and health sciences ,0302 clinical medicine ,Apolipoproteins E ,Genetic model ,Medicine ,Humans ,Allele ,education ,Extreme human longevity ,Alleles ,Genetic association ,media_common ,Aged, 80 and over ,education.field_of_study ,Polymorphism, Genetic ,business.industry ,Longevity ,DNA ,Healthy Aging/genetics ,030104 developmental biology ,The Journal of Gerontology: Biological Sciences ,Female ,Geriatrics and Gerontology ,Centenarian ,business ,Apolipoproteins E/genetics ,APOE ,030217 neurology & neurosurgery ,Demography - Abstract
We assembled a collection of 28,297 participants from seven studies of longevity and healthy aging comprising New England Centenarian, Long Life Family, Longevity Gene Population, Southern Italian Centenarian, Japanese Centenarian, the Danish Longevity, and the Health and Retirement Studies to investigate the association between the APOE alleles ϵ 2 ϵ 3 and ϵ 4 and extreme human longevity and age at death. By using three different genetic models and two definitions of extreme longevity based on either a threshold model or age at death, we show that ϵ 4 is associated with a substantially decreased odds for extreme longevity, and increased risk for death that persists even beyond ages reached by less than 1% of the population. We also show that carrying the ϵ 2 ϵ 2 or ϵ 2 ϵ 3 genotype is associated with significantly increased odds to reach extreme longevity, with decreased risk for death compared with carrying the genotype ϵ 3 ϵ 3 but with only a modest reduction in risk for death beyond an age reached by less than 1% of the population.
- Published
- 2018
47. Association of immunoglobulin GM allotypes with longevity in long-living individuals from Southern Italy
- Author
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Giulia Accardi, Annibale Alessandro Puca, Anna Ferrario, Anna Maciag, Caterina Maria Gambino, Janardan P. Pandey, Calogero Caruso, Anna Aiello, Giuseppina Candore, Aryan M. Namboodiri, Puca, Annibale A, Ferrario, Anna, Maciag, Anna, Accardi, Giulia, Aiello, Anna, Gambino, Caterina Maria, Candore, Giuseppina, Caruso, Calogero, Namboodiri, Aryan M, and Pandey, Janardan P
- Subjects
0301 basic medicine ,lcsh:Immunologic diseases. Allergy ,Aging ,Immunoglobulin Allotypes ,media_common.quotation_subject ,Longevity ,Immunology ,Locus (genetics) ,Biology ,lcsh:Geriatrics ,03 medical and health sciences ,0302 clinical medicine ,Genotype ,GM allotypes ,HMCV ,HSV-1 ,Immune response ,Allele ,Allele frequency ,media_common ,Genetics ,GM allotype ,Settore MED/04 - Patologia Generale ,Research ,Allotype ,lcsh:RC952-954.6 ,030104 developmental biology ,biology.protein ,Antibody ,lcsh:RC581-607 ,030215 immunology - Abstract
Background The aim of this study was to analyse the role of GM allotypes, i.e. the hereditary antigenic determinants expressed on immunoglobulin polypeptide chains, in the attainment of longevity. The role played by immunoglobulin allotypes in the control of immune responses is well known as well as the role of an efficient immune response in longevity achievement. So, it is conceivable that particular GM allotypes may contribute to the generation of an efficient immune response that supports successful ageing, hence longevity. Methods In order to show if GM allotypes play a role in the achievement of longevity, we typed the DNA of 95 Long-living individuals (LLIs) and 96 young control individuals (YCs) from South Italy for GM3/17 and GM23+/− alleles. Results To demonstrate the role of GM allotypes in the attainment of longevity we compared genotype and allele frequencies of GM allotypes between LLIs and YCs. A global chi-square test (3 × 2) shows that the distribution of genotypes at the GM 3/17 locus is highly significantly different in LLIs from that observed in YCs (p
- Published
- 2018
48. Effects of FOXO3 Polymorphisms on Survival to Extreme Longevity in Four Centenarian Studies
- Author
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Gil Atzmon, Stacy L. Andersen, Annibale Alessandro Puca, Anastasia Gurinovich, Alberto Malovini, Thomas T. Perls, Francesco Villa, Harold Bae, Nir Barzilai, and Paola Sebastiani
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0301 basic medicine ,Male ,Aging ,Percentile ,Genotype ,media_common.quotation_subject ,Longevity ,Single-nucleotide polymorphism ,Single-nucleotide polymorphisms ,Hippocampus ,Polymorphism, Single Nucleotide ,03 medical and health sciences ,Polymorphism (computer science) ,Medicine ,Humans ,Extreme longevity ,Survival analysis ,Alleles ,Genetic Association Studies ,Genetic association ,media_common ,Aged, 80 and over ,business.industry ,Forkhead Box Protein O3 ,Homozygote ,Survival Analysis ,030104 developmental biology ,Case-Control Studies ,Expression quantitative trait loci ,The Journal of Gerontology: Biological Sciences ,Female ,Geriatrics and Gerontology ,Centenarian ,business ,Demography - Abstract
Previous studies note specific FOXO3 single-nucleotide polymorphisms (SNPs) associated with human longevity. However, it is not clear if these SNPs influence mortality risk beyond the oldest 1 percentile of survival. Using data from four longevity studies (total n = 8,266, age range 96-119 years for cases), we tested gene-wide association between 107 SNPs and survival to at least the oldest 1 percentile of survival for the 1900 birth cohort (≥96, white males; ≥100 white females). This analysis replicated 17 previously published variants, several of which are significant expression quantitative trait loci of FOXO3; rs6911407 and rs2253310 have the most significant effect on FOXO3 expressions in brain tissue. We then performed a survival analysis to determine if any of these 107 SNPs impact upon mortality risk beyond the oldest 1 percentile. While none of the 17 published variants was significantly associated with mortality risk beyond this extreme age, an uncommon homozygote genotype of rs9384680 exhibited the strongest association with mortality risk (p = 2.68E-04) in only 11 females, a heretofore unreported association. These analyses replicate the previous association of common variants of FOXO3 with older age but these common variants do not modify risk for mortality at ages beyond the oldest 1 percentile age of survival.
- Published
- 2017
49. Limitations and risks of meta-analyses of longevity studies
- Author
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Mette Soerensen, Thomas T. Perls, Harold Bae, Annibale Alessandro Puca, Anastasia Gurinovich, and Paola Sebastiani
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0301 basic medicine ,Male ,Aging ,media_common.quotation_subject ,Longevity ,Ethnic Groups/genetics ,Biology ,Article ,03 medical and health sciences ,Sex Factors ,Ethnicity ,Humans ,Association (psychology) ,Genetic association ,media_common ,Aged, 80 and over ,Odds-ratios ,Confounding ,Genetic Variation ,Longevity/genetics ,Odds ratio ,Human longevity ,Meta-analysis ,Developmental Biology ,030104 developmental biology ,Genetic epidemiology ,Female ,Demography - Abstract
Searching for genetic determinants of human longevity has been challenged by the rarity of data sets with large numbers of individuals who have reached extreme old age, inconsistent definitions of the phenotype, and the difficulty of defining appropriate controls. Meta-analysis - a statistical method to summarize results from different studies - has become a common tool in genetic epidemiology to accrue large sample sizes for powerful genetic association studies. In conducting a meta-analysis of studies of human longevity however, particular attention must be made to the definition of cases and controls (including their health status) and on the effect of possible confounders such as sex and ethnicity upon the genetic effect to be estimated. We will show examples of how a meta-analysis can inflate the false negative rates of genetic association studies or it can bias estimates of the association between a genetic variant and extreme longevity. Searching for genetic determinants of human longevity has been challenged by the rarity of data sets with large numbers of individuals who have reached extreme old age, inconsistent definitions of the phenotype, and the difficulty of defining appropriate controls. Meta-analysis - a statistical method to summarize results from different studies - has become a common tool in genetic epidemiology to accrue large sample sizes for powerful genetic association studies. In conducting a meta-analysis of studies of human longevity however, particular attention must be made to the definition of cases and controls (including their health status) and on the effect of possible confounders such as sex and ethnicity upon the genetic effect to be estimated. We will show examples of how a meta-analysis can inflate the false negative rates of genetic association studies or it can bias estimates of the association between a genetic variant and extreme longevity.
- Published
- 2017
50. The expression of the BPIFB4 and CXCR4 associates with sustained health in long-living individuals from Cilento-Italy
- Author
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Annibale Alessandro Puca, Fabio Martelli, Rita Pipolo, Chiara Carmela Spinelli, Gaia Spinetti, Simona Greco, Paolo Madeddu, Claudia Specchia, Albino Carrizzo, Christine Voellenkle, Carmine Vecchione, Elena Sangalli, and Francesco Villa
- Subjects
Male ,Vascular Endothelial Growth Factor A ,0301 basic medicine ,Receptors, CXCR4 ,Aging ,medicine.medical_specialty ,Health Status ,Mrna expression ,Longevity ,Cell motion ,030204 cardiovascular system & hematology ,Biology ,HIF-1α targets ,Peripheral blood mononuclear cell ,CXCR4 ,Adrenomedullin ,03 medical and health sciences ,0302 clinical medicine ,Cell Movement ,Internal medicine ,medicine ,Humans ,Aged, 80 and over ,Glucose Transporter Type 1 ,mononuclear cell migration ,BPIFB4 ,HIF-1ɑ ,Cell Biology ,Phosphoproteins ,Long-living individuals ,030104 developmental biology ,Rna expression ,Endocrinology ,long-living individuals ,Italy ,Mononuclear cell migration ,Immunology ,Leukocytes, Mononuclear ,targets ,Intercellular Signaling Peptides and Proteins ,Female ,Cardiovascular outcomes ,Research Paper - Abstract
The study of the health status in long-living individuals (LLIs) may help identifying health-span and life-span determinants. BPI-Fold-Containing-Family-B-Member-4 (BPIFB4) protein is higher in healthy vs. non-healthy (frail) LLIs serum and its longevity-associated variant forced expression improves cardiovascular outcomes in ischemia mice models. Thus, we tested the association of BPIFB4 and ischemia-responding HIF-1α pathway components (i.e. CXCR4, AK3, ALDO-C, ADM, VEGF-A, GLUT-1 and miR-210) with human life-span and healthspan by analyzing mRNA expression in circulating mononuclear cells (MNCs) of LLIs (N=14 healthy; N=31 frail) and young controls (N=63). ALDO-C, ADM, VEGF-A and GLUT-1 significantly decreased and miR-210 increased in LLIs vs. controls. Only VEGF-A and GLUT-1 showed further significant reduction in healthy-LLIs vs. frail-LLIs comparison. While BPIFB4 and CXCR4 were similar between LLIs and controls, BPIFB4 was significantly higher and CXCR4 lower in healthyversus frail-LLIs. On a new set of LLIs (N=7 healthy and N=5 non-healthy) we assessed a potentially correlated function with low CXCR4 expression. Healthy donors' MNCs showed efficient migration ability toward CXCR4 ligand SDF-1α/CXCL12 and high percentage of migrated CXCR4pos cells which inversely correlated with CXCR4 RNA expression. In conclusion, BPIFB4 and CXCR4 expression classify LLIs health status that correlates with maintained MNCs migration.
- Published
- 2017
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