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Objective: Red blood cell distribution width (RDW), is a measurement of the size variation as well as an erythrocyte heterogeneity index (i.e., anysocytosis). used in combination with the mean corpuscular volume for anemia diagnosis. However, it is emerging as an useful predictor biomarker of mortality and morbidity of cardiovascular diseases. However, until now no literature data there are about the RDW role in predicting mortality after aortic valve replacement (AVR). Thus, in this pilot study biological significance of elevated RDW values in early outcome following AVR was evaluated Methods: We enrolled 75 patients (mean age 73.5 ±7.9 years) subjected to AVR and/ or not co temporally to other surgical procedures . Demographics, comorbidities, clinical presentations, and laboratory parameters were collected. The RDW values were considered elevated when more high than 48 fL. Multivariable and univariable examinations were performed in determine associations between preoperative high RDW values and postoperative outcome. Results: Preoperative higher RDW values had a prevalence of 41% (31 patients) in AVR cases studied. These 31 patients were older (76 ± 5.5 years vs 71.6± 8.9 years, p-value=0,02 ), low weight (69.7 vs. 74.1 Kg, p-value= 0,12) with higher platelet levels (p-value 0,005) than the other 44 cases. In addition, they represented the patients that should have likely required renal replacement therapy (13% vs 0%, p-value = 0.026), and prolonged ventilation (16% vs 0%, p-value =0.01). Multivariable adjustment analysis also demonstrated significant associations between higher preoperative RDW values with high BMI values (p-value= 0.05) and renal failure (p-value= 0,06 and p-value=0,02). Conclusions: Increased RDW values seem to be a good predictor biomarker of early outcome after AVR, particularly in patients with high BMI, renal impairment and postoperative prolonged ventilation

Aim. The aim of this paper was to ascertain whether macrophage colony stimulating factor (MCSF) serum levels, measured during the acute phase of coronary syndromes (ACS), are useful to predict short term outcomes. Methods. Seventy-four consecutive patients (mean age: 66±12), admitted to the Intensive Coronary Care Unit of Palermo University Hospital (Italy) affected by ACS were observed; 39 patients showed a non ST elevation (NSTEMI) and 35 showed a ST elevation myocardial infarction (STEMI). During the hospital stay, all patients underwent echocardiography and 84% of patients received coronary angiography. Peripheral venous blood samples were collected for the determination of serum levels of MCSF, C-reactive protein (CRP), fibrinogen, I troponin and complete lipid pattern. Results. There was no significant difference in MCSF concentrations for STEMI versus NSTEMI patients (326.65±143.87 vs 297.15±H0.43 pg/mL, P=NS). Higher levels of MCSF (363.00±147.61 vs 251.00±186.69, P=0.03) and CRP (1.04±0.40 vs 0.97±0.50 mg/L, P=0.03) were found in patients with a worst in hospital stay (recurrence of angina, re-infarction, death) and with a more severe coronary artery disease (330.03±241.51 vs 223.61±128.29 pg/mL, P=0.04 and 1.14±0.50 vs 0.60±0.22 mg/L, P=0.05). Conclusion. MCSF levels are useful in the prediction of short term prognosis in ACS patients

Strong evidence suggests that systemic inflammation and central adiposity contribute to and perpetuate metabolic syndrome. All of these alterations predispose individuals to type 2 diabetes mellitus (T2DM), cardiovascular disease, as well as Alzheimer's disease (AD), all characterized by chronic inflammatory status. On the other hand, extensive abnormalities in insulin and insulin-like growth factor I (IGF-I) and IGF-II signaling mechanisms in brains with AD have been demonstrated, suggesting that AD could be a third form of diabetes. The Src homology domain-containing inositol 5-phosphatase 2 (SHIP2) has an important role in the insulin pathway because its over-expression causes impairment of insulin/IGF-1 signaling. Because some single-nucleotide polymorphisms (SNP) of the gene encoding SHIP2 were significantly associated in T2DM patients with metabolic syndrome and some related conditions, we decided to conduct a case-control study on this gene, analyzing AD and T2DM subjects as cases and young, old, and centenarians as controls. Our results suggest a putative correlation between the the rs144989913 SNP and aging, both successful and unsuccessful, rather than age-related diseases. Because this SNP is an insertion/deletion of 28 bp, it might cause an alteration in SHIP2 expression. It is noteworthy that SHIP2 has been demonstrated to be a potent negative regulator of insulin signaling and insulin sensitivity. Many studies demonstrated the association of the insulin/IGF1 pathway with aging and longevity, so it is tempting to speculate that the found association with SHIP2 and aging might depend on its effect on the insulin/IGF-1 pathway.

The major trait characterizing offspring in centenarians is a reduction in the prevalence of cardiovascular disease. Because a pro-inflammatory genotype seems to contribute significantly to the risk of coronary heart disease, alleles associated with disease susceptibility would not be included in the genetic background favoring longevity, as suggested by our previous studies on inflammatory cytokines. To confirm whether genotypes of inflammatory molecules play an opposite role in atherosclerosis and longevity, we are studying the role of other proinflammatory alleles, such as pyrin and CCR5, in acute myocardial infarction and longevity. The results support the hypothesis that the genetic background favoring cardiovascular diseases is detrimental to longevity. In addition, they suggest that the centenarian genetic background may be useful for investigating genetic key components of age-associated diseases that are characterized by a multifactorial etiology.

Background: We have previously reported the increase of IgD-CD27- (Double Negative, DN) B cell population in the aged. These memory B cells have short telomeres and poor abilities to proliferate in vitro. Here, we investigated whether the low ability of DN B cells to proliferate depends on the expression levels of the CD307d and CD22 inhibitory receptors or whether DN B cells can proliferate and reactivate telomerase by the engagement of both innate and adaptive immune receptors. Methods: Phenotypic analyses were made by using flow cytometry. Quantitative analysis of telomerase activity was made by using a TRAP and a photometric enzyme immunoassay in young, healthy elderly, centenarian offspring (CO), and Alzheimer’s disease patients (AD). Results: We show that CD307d and CD22 expression levels are not related with the different ability of DN to be activated in the young and elderly. Moreover, CpG/α-IgG/α-CD40 (and not CpG or α-IgG/α-CD40) stimulation induces DN B cell proliferation in both young and elderly subjects. Furthermore, DN B cell telomerase activity in young, elderly, CO and AD patients, mirrors the age and health status of the subjects studied. Indeed, young donors show the highest levels of RTA, whereas AD patients the lowest. Healthy elderly and CO show lower levels than young, with a slight increase of activity in CO vs. elderly. Conclusions: Our present data add new information to our knowledge of DN B cells during aging. We demonstrate that the low ability of DN cells to proliferate depends on RTA and not on the expression of inhibitory receptors.

Alzheimer's disease (AD) is a heterogeneous and progressive neurodegenerative disease which in Western society mainly accounts for clinical dementia. Inflammation plays a key role in AD and dissecting the genetics of inflammation may provide an answer to the possible treatment. Hence, the better understanding of different molecular and cellular inflammatory mechanisms is crucial for complete knowledge of AD pathophysiology, and for its prevention and drug therapy. Accordingly, in the present study we evaluated whether the pro-inflammatory polymorphisms of lipopolysaccaride-receptors, +896A/G Toll-Like Receptor (TLR4) and -260C/T CD14, are risk factors for AD. The study included both 626 AD patients (427 women and 199 men; age range: 53-98 years; mean age: 74.88+/-8.44) from Northern Italy and age and gender matched controls. Our results demonstrate that the +896A/G TLR4 single nucleotide polymorphism (SNP) is associated with AD, whereas no association has been observed with -260C/T CD14 SNP. Furthermore, no differences have been observed evaluating the combined presence of +896A+TLR4/-260T+CD14 "high responder"(proinflammatory-profile). However, our results showing the involvement of TLR4 in AD pathophysiology, strengthen the suggestion that systemic inflammation plays a key role in AD. Carriers of high responder SNP, affected by mild cognitive impairment might, be the ideal target for a preventive treatment with biologics as monoclonal antibodies directed against the pro-inflammatory cytokines to decrease the level of systemic inflammation involved in AD pathophysiology.

Anti-aging medicine has become a popular topic in recent years. It considers biological aging a revertible process that physiologically serves no posi tive function. Different technologies in systemic delivery and various strategies that characterize and optimize the performance of systemic delivery have been covered in this book. These technologies are essential for the establishment of a technical platform for interventive biogerontology. As the last chapter of this book, we would like to highlight some directions for future applications of systemic drug delivery in anti-aging medicine. We believe that biological aging and aging-related diseases are strongly associated with genetics/genomics and are pre-programmed. Several interventive approaches such as cellular/tissue reprogramming, microbiota supple mentation, seno-therapeutics and pharmacological targeting will be discussed in this chapter

Background: Degenerative forms of mitral valve diseases (MVDs) are complex pathologies. Thus, it is difficult to make generalizations about MVD pathways or genetic risk factors. However, a key role of metalloproteinases (MMPs) in their pathophysiology is emerging. Thus, we performed a study to assess eventual associations of some functional SNPs in MMP-2 and MMP-9 genes with MVD risk, symptom severity and short- and long-term (4.8 years) complications. Methods: For this purpose, 90 patients and two control groups were genotyped for MMP-2 and MMP-9 gene SNPs, and systemic levels of proatrial natriuretic peptide (ANP), and two enzymes were quantified and correlated to the MMP-2 and MMP-9 SNPs. In addition, associations between these SNPs and symptom severity and short- and long-term complications were evaluated. Results: Interestingly, rs3918242 MMP-9 and rs2285053 MMP-2 SNPs were significantly represented in cases compared to two control groups, and were associated with a higher MVD risk. Cases stratified for New York Heart Association (NYHA) symptoms, and particularly NYHA III+IV, with rs3918242 CT+TT MMP-9 and rs2285053CT+TT genotypes also showed higher severity related to significant higher systemic levels of MMP enzymes and pro-ANP at enrollment and 4.8-year follow-up times. In addition, cases with these genotypes, and particularly NYHAIII+IV, had a very significant percentage of complications, particularly at the 4.8-year follow-up. Surprisingly, 20% of patient controls developed MVD at 4.8- year follow-up and were carriers of these genotypes. Conclusions: The associations observed seem to suggest that the two SNPs might represent useful biomarkers and targets for preventing and monitoring MVDs, leading to a more appropriate management and outcome

Chronic inflammatory diseases, such as cardiovascular diseases (CVDs), diabetes, Alzheimer’s disease (AD) and cancer, have a disproportionate prevalence with advancing age owing to the continuous growth in the aging population. This condition determines several medical, economic and social problems due to the dramatic increase in the number of affected individuals, who are not autonomous. Thus, research efforts are centred around reducing and/or delaying the onset and progression of these diseases by researching new strategies for early prevention and diagnosis. In this context, understanding the mechanisms involved in the tissue, organ protection and repair are imperative for the development of new preventive treatments. Accordingly, medical research is pursuing new ways of trying to face this imposing challenge, i.e. regenerative medicine with stem cells and progenitors, such as endothelial progenitor cells (EPCs). Since their discovery, EPCs have rapidly caught the attention of researchers for their ability to facilitate vascular repair in different ischemic tissues, by contributing to neovascularization in several tissue injury models. Interest has also heightened dramatically after evidence about their capacity to counteract related CVD endothelium dysfunction. In addition, recent studies, using different animal models of cancer, suggested the importance of bone marrow-derived EPCs (i.e. postnatal vasculogenesis) in tumor vascularization and growth. EPCs are present in the peripheral blood; their levels are increased in response to certain signals/cytokines; and they home into the neovascular bed of malignant tissues. Furthermore, at the clinical level, evidence is emerging that changes in EPC levels might predict the efficacy of anticancer drug combinations, such as anti-angiogenic agents. On the basis of these observations, EPCs have attractive potential diagnostic and therapeutic applications for malignant diseases. Additional recent evidence also suggests the possibility to adopt EPCs as prognostic biomarkers for AD. It has been observed that patients with AD have reduced circulating EPCs, suggesting that an anomalous capacity to regenerate endothelium is associated with AD. In the case of diabetes, numerous groups have detected decreased EPC numbers and functionality in affected patients, confirmed by decreased numbers of colony-forming units, decreased adhesion and migration and decreased tubule formation. In addition, it has been found that strategies based on ix the administration of statins, angiotensin converting enzyme inhibitors, angiotensin receptor blockers and peroxisome-proliferator-activating-receptor-c agonists, up-regulate and enhance both the EPC number and functionality. Emerging evidence also indicates that transplantation of EPCs is beneficial for the recovery of ischemic cerebral injury. EPC-based therapy could open a new avenue for ischemic diseases. Currently, clinical trials for evaluating EPC transfusion in treating ischemic stroke are underway. However, much of the increasing evidence implicating progenitors in these diseases is contrasting. Thus, their real role remains uncertain. This is compounded by the necessity for a standardization of the different methodologies and protocols for characterizing, identifying and defining these cells, or their subsets. This problem represents one of the major consequences of the large heterogeneity that exists in data from the literature. In this monograph, some of these aspects are discussed using research to give clear indications regarding EPC functions and definitions, as well as evidence to support the problem of their characterization. In addition, recent findings on their role as disease biomarkers and exogenous or autologous cell therapy are provided. Certainly, limitations are also stressed. Based on these observations, this monograph, structured in 3 chapters, will describe, in the first chapter, the relevance of translational medicine (TM) as a new research approach to counteract the imposing challenge of age-related diseases. In particular, a considerable emphasis will be given to regenerative medicine (RegMed), a new branch of TM. RegMed can be used to improve health and quality of life, by restoring, maintaining or enhancing tissue and functions of organs. Of the diverse RegMed approaches, a particular focus will be given to stem/progenitor cell-based therapies, their benefits and disadvantages, as well as to the description of types of stem and progenitor cells considered for regenerative cell therapies, such as EPCs as emerging candidates for RegMed applications. To understand the value and potentiality of EPCs in this field, as well as the related limitations, in Chap. 1, the biological features, origins, sources and endogenous functions of EPCs will be reported. In addition, a critique of EPCs, namely relating to their characterization and definition, will be put forward, because they represent the real cause of the extensive heterogeneity of existing data in the literature on this topic, which creates more confusion than comprehension. Chapter 2 outlines the clinical relevance of EPCs as both potential predictors, and diagnostic and prognostic biomarkers of age-related diseases and therapeutic agents, by discussing the advantages, disadvantages and the conflicting data. To conclude, Chap. 3 will propose a potential roadmap for revising the findings obtained to date, reordering them and creating a clear puzzle of the valid data. It can facilitate understanding of important aspects, including firstly defining, isolating and characterizing EPCs by establishing a standardized criteria for EPC research, discrimination of appropriate sub-populations for cell therapy, timing, dosing, priming of cells, and delivery mode for different applications. Furthermore, influencing factors might also be identified with the aim to focus resources and efforts, and the problems linked to the local retention and fate of cells in the therapeutic target zone might be resolved. Finally, an overview of innovative strategies will be reported, which might improve x Preface the efficacy of cell therapy at all levels, including cell priming, bio-nanotechnology, and tissue engineering. They might be used as emerging tools, and, in particular, their combination might produce very advantageous results. Such descriptions and discussions address an extensive audience, including students, health care professionals, biologists, physicians and diverse scientific community. In particular, it will be a valuable resource for clinical scientists, researchers, university professors, health practitioners, gerontologists and geriatricians, students, and for all those who wish to broaden their knowledge in the allied field. Policy makers and agencies involved in implementing preventive policies might also use this monograph as an updated integral resource. All government and private organizations, including libraries at the college level, academic universities, and research institutions might benefit from it as resource for its current references. Palermo, Italy Carmela Rita Balistreri July 2016

“The senescence status of somatic stem/progenitor cells contributes to ageing process”, and “an individual is as old as old are its stem cells”. These quotes represent the concepts, which are actually object of investigations of researchers involved in ageing studies.

Preclinical and clinical studies suggest that specific subsets of cells isolated from the peripheral blood, play an essential role in the imbalance of damage and repair during age-associated diseases, such as metabolic syndrome, diabetes, atherosclerosis, neurodegenerative diseases, osteoporosis and cancer. Endogenous regeneration of the vessel wall involves cells of the vascular wall, inflammatory cells, circulating precursors, and mature endothelial cells, which are capable to restore the endothelium in a concerted interaction. Early detection of such imbalances with specific biomarkers may reduce age-associated diseases and subsequent cardiovascular events. Likewise, new strategies have the potentiality of acting selectively on these cell populations and co-temporally mediate the stimulation of the function and number of those cell populations with regenerative action on the vessel, and inhibit those able to evocate vascular damage. These strategies may be an alternative innovative way with superior and more efficacy biological effects than conventional attempts used for treating actually vascular diseases, characterizing those co-morbidities related to ageing.

Objective The objective of this study was to evaluate the effectiveness of the Penn classification in predicting in-hospital mortality after surgery in acute type A aortic dissection patients. Methods We evaluated 58 patients (42 men and 16 women; mean age 62.17 ± 10.6 years) who underwent emergency surgery for acute type A aortic dissection between September 2003 and June 2010 in our department. We investigated the correlation between the pre-operative malperfusion and in-hospital outcome after surgery. Results Twenty-eight patients (48%) were Penn class Aa (absence of branch vessel malperfusion or circulatory collapse), 11 (19%) were Penn class Ab (branch vessel malperfusion with ischaemia), 5 (9%) were Penn class Ac (circulatory collapse with or without cardiac involvement) and 14 (24%) were Penn class Abc (both branch vessel malperfusion and circulatory collapse). The number of patients with localized or generalized ischaemia or both, Penn class non-Aa, was 30 (52%). In-hospital mortality was 24%. In-hospital mortality was significantly higher in Penn class Abc and Penn class non-Aa. Intensive unit care stay, hospital ward stay and overall hospital stay was longer in Penn class non-Aa vs Penn class Aa. De Bakey type I dissection and type II diabetes mellitus were associated with in-hospital mortality. Conclusion Preoperative malperfusion is important for the evaluation of patients with acute aortic type A dissection. The Penn classification is a simple and quick method to apply and predict in-hospital mortality and outcomes. Keywords Type A dissection – Stanford classification – DeBakey classification – Penn classification.

Telomeres have been postulated as a universal clock that shortens in parallel with cellular aging. They are specialized DNA-protein structures at the ends of chromosome with remarkable functions--preventing their recognition as double-stranded DNA breaks, protecting their recombination and degradation, and avoiding a DNA damage cellular response. Telomere shortening is currently considered the best aging marker, but is also a predictor for age-related diseases, including cardiovascular diseases. Biological age clearly seems to be a better predictor of vascular risk rather than chronological age. This concept is supported by key assumptions that peripheral blood leukocyte telomere content accurately reflects that of the vascular wall and its decrease is associated with premature vascular disease. Thus, we are analyzing whether the mean of blood leukocyte telomere length might also be a predictor for sporadic thoracic aortic aneurysm (S-TAA). The preliminary results seem to be promising. Shorter telomeres were detected in patients than in controls. Thus, mean of blood leukocyte telomere length could contribute to identify individuals at S-TAA risk.

Coronary artery fistulas are rare anatomic abnormalities of the coronary arteries present in 0.002% of the general population and represent 14% of all anomalies of coronary arteries. Their clinical relevance focuses mainly on the mechanism of "coronary steal phenomenon”, causing myocardial functional ischemia even in the absence of stenosis, hence common symptoms are angina or dyspnea. Small size fistulas are mostly asymptomatic and have excellent prognosis if managed medically with regular follow-up consisting also in echocardiography every 2-5 years. Big-sized and symptomatic fistulas, on the contrary, should undergo invasive closure, either with a transcatheter approach or with surgical ligation, whose results are equivalent at long-term follow-up. However, in some cases, symptoms may not correspond with size. Larger fistulas may be asymptomatic and very small fistulas may cause symptoms like angina in our patient. Here, we are presenting an emblematic and very rare case with a complete literature review. Particularly, very didactic angiography images and then during surgery are shown.

Ageing of human skin may result from both the passage of time (intrinsic ageing) and from cumulative exposure to external influences (extrinsic ageing) such as ultraviolet radiation (UVR) which promotes wrinkle formation and loss of tissue elasticity. Whilst both ageing processes are associated with phenotypic changes in cutaneous cells, we summarize, in this chapter, related mechanisms involved, discuss on potentential treatment until now disposable, and suggest preventive measures.

Toll-like receptors (TLRs) are the principal mediators of rapid microbial recognition: the lipopolysaccharide (LPS) receptor TLR4 seems to have a paradigmatic role. Single nucleotide polymorphisms (SNPs) in the TLR4 gene, such as +896A/G, known to attenuate receptor signaling, have been described. The +896A/G SNP is significantly less frequent in patients with myocardial infarction, Alzheimer's disease or prostate cancer, whereas it is overrepresented in centenarians. To clarify and confirm the biological effects of +896A/G SNP and its role in the pathophysiology of age-related diseases and longevity, we assessed the levels of IL-6, TNF-α, IL-10 and eicosanoids (LTB4 and PGE2) in LPS-stimulated whole blood samples in vitro of 50 young healthy Sicilians, screened for the presence of this SNP. To evaluate the possible influence of SNPs in PTGS2 and 5-Lo genes on eicosanoid production, the enrolled individuals were also genotyped for -765G/C PTGS2 and -1708G/A 5-Lo SNPs. Both pro-inflammatory cytokines and eicosanoids were significantly lower in carriers bearing the TLR4 mutation, whereas the anti-inflammatory IL-10 values were higher. On the basis of data reported herein, some suggestions can be drawn. First, pathogen load, by interacting with the host genotype, determines the type and intensity of inflammatory responses, according to the pro-inflammatory status and tissue injury, implicated in the pathophysiology of major age-related diseases. Second, adequate control of inflammatory response might reduce the risk of these diseases, and, reciprocally, might increase the chance of extended survival in an environment with reduced antigen (that is, pathogen) load.

This review discusses the role of estrogens as pro- or antiinflammatory players in immune-inflammatory responses. In particular, their role in Alzheimer’s disease (AD), an example of immune-inflammatory disease, is discussed briefly. AD is a progressive neurodegenerative disease, which in Western societies accounts for the majority of cases of clinical senile dementia. However, sexual dimorphism of diseases may also depend on factors independent of sex hormones (i.e., a gender effect), as demonstrated by our data on differential longevity in females and males. In fact, differences in mortality between men and women are not only a question of sex that refers to biological differences, but rather a question of ‘‘socially constructed sex,’’ a question of gender (i.e., the characteristics that a society or culture delineates as masculine or feminine). In gender medicine, we conclude that it is important to consider the role played both by hormones, customs, and educational levels regarding the different propensity of males and females to fall ill. So, in programming antiaging strategies, we have also to take these aspects into account

Acute myocardial infarction (AMI) in young adult presents a typical pattern of risk factors, clinical, angiographic and prognostic characteristics. In the last years we demonstrated that hemorheological profile is altered in these patients in a persistent way and independently of the number of risk factors and of the extent of coronary lesions. Thus, the hyperviscosity syndrome following AMI could be considered an intrinsic characteristic of these patients. Consequently it is possible to hypothesise the presence of a genetic background at the origin of this predisposition. If this background is able to influence the risk of ischemic heart disease, this should be particularly evident in young subjects. Since inflammatory mechanisms play a central role in mediating all phases of atherosclerosis, genes encoding for inflammatory or anti-inflammatory molecules are candidates for the risk of developing atherosclerosis. As atherosclerosis is the first cause of mortality in Western countries and if pro-inflammatory genotypes contribute to risk of coronary heart disease, alleles associated to disease susceptibility should not be included in the genetic background favouring longevity: People genetically predisposed to a weak inflammatory activity have fewer chances to develop cardiovascular disease and, therefore, have better chance for a long-life. According to this hypothesis, we studied in our population of young patients with AMI, the distribution of some polymorphisms influencing a inflammation and found an higher prevalence of pro-inflammatory polymorphisms (SNP A2080G of pyrin gene, SNP Gly670Arg of PECAM gene, C1019T of Cx 37 gene, SNP G1059C of PCR gene) and a lower prevalence of anti-inflammatory polymorphisms (Asp299Gly of TLR4 gene, SNP -1082 G/A of IL10 gene, CCR5Δ32). Results of these studies show that early myocardial infarction could be associated with a genetic predisposition to an intense inflammatory response, associated also to an hyperviscosity syndrome.

Prostate cancer (PCa) is the most common malignant neoplasm in older men in Western countries. The number of affected older men is increasing. Therefore, strategies for prevention of prostate cancer are crucial. To this purpose it is essential to know the mechanisms involved in development and progression of this malignancy. Recently, an increasing body of genetic and epidemiological studies proposed new hypotheses for prostate carcinogenesis. It has been suggested that genetic factors as well as exposure to environmental factors such as infectious agents, dietary carcinogens, and hormonal imbalances participate in PCa development. Besides, chronic inflammation plays a key role in PCa. Taking into consideration this complex scenario, in the present study we evaluated whether CCR5Delta32 deletion of CCR5 gene might be associated with PCa susceptibility. For the control group we used centenarians, since they represent a disease-free human model. These preliminary results suggest that the CCR5Delta32 anti-inflammatory variant might be a resistance factor for the development of PCa.

The CC chemokine receptor 5 (CCR5) is a member of CC-chemokine receptor family. CCR5 has the characteristic structure of a seven transmembrane G protein-coupled receptor (GPCR), which regulates trafficking and effector functions of memory/effector Th1 cells, macrophages, NK cells, and immature dendritic cells. CCR5 and its ligands are important molecules in viral pathogenesis. CCR5 represents the co-receptor for macrophage (M) and dual (T cell and M)-tropic immunodeficiency viruses. Recent evidence has also demonstrated the role of CCR5 in a variety of human diseases, ranging from infectious and inflammatory diseases to cancer. In this article, we describe the involvement of CCR5 in two age-related diseases, atherosclerosis and Alzheimer's disease, suggesting a possible role of chemokine system on these diseases' pathophysiology. Finally, we review the data on the probable association between CCR5Delta32 deletion and cardiovascular diseases and Alzheimer's disease.

In response to tissue injury elicited by trauma or infection, the inflammatory response, as a complex network of molecular and cellular interactions, sets an answer directed to facilitate a return to physiological homeostasis and tissue repair. The role of the genetic background and the subsequent predisposition toward the extent of the inflammatory response is determined by gene variability encoding endogenous mediators involved in the inflammatory pathway. Due to its clinical relevance, the genetics of inflammation in aging will be studied using an inflammatory disease like atherosclerosis as an example. Several studies have reported a significant difference in distribution, between patients and controls, of genes involved in inflammation. So, the proinflammatory alleles are underrepresented in control subjects and overrepresented in patients affected by atherosclerosis. These studies will allow building a risk profile that potentially enables the early identification of individuals susceptible to disease and the possible design or use of drug at the right dose for a desired effect, that is, a pharmacogenomic approach for this disease.

Sporadic thoracic aortic aneurysms (TAA) and dissections are one of the major causes of morbidity and mortality worldwide, especially in those older than 65 years. The presentation of TAA is varied and often silent. Thus, sporadic TAA detection is often fortuitous, with identification occurring during a routine physical examination or during an unrelated medical evaluation. Once suspected, confirmation by imaging clinical approaches is needed to allow the choose of the unique treatments for TAA, namely the surgery procedures, including elective surgery or endovascular repair before the onset of catastrophic and fatal complications, such as dissection or rupture. At present, there are no biomarkers available to identify TAAs before visible symptoms. However, recent progresses in understanding of molecular and cellular mechanisms involved in the patho-physiology of sporadic TAA are suggesting different molecular pathways and their genetic variants as potential biomarkers, which might be applied into TAA clinical practice in the near future. Here, we report literature evidence on some disease pathways and their genetic variants on TAA susceptibility and compliances, and their translation as promising TAA preventive and prognostic biomarkers and targets for new personalized therapeutic treatments.

Advanced knowledge in the field of stem cell biology and their ability to provide a cue for counteracting several diseases are leading numerous researchers to focus their attention on “regenerative medicine” as possible solutions for cardiovascular diseases (CVDs). However, the lack of consistent evidence in this arena has hampered the clinical application. The same condition affects the research on endothelial progenitor cells (EPCs), creating more confusion than comprehension. In this review, this aspect is discussed with particular emphasis. In particular, we describe biology and physiology of EPCs, outline their clinical relevance as both new predictive, diagnostic, and prognostic CVD biomarkers and therapeutic agents, discuss advantages, disadvantages, and conflicting data about their use as possible solutions for vascular impairment and clinical applications, and finally underline a very crucial aspect of EPCs “characterization and definition,” which seems to be the real cause of large heterogeneity existing in literature data on this topic.

In this article we discuss relevant data on aging, longevity, and gender with particular focus on inflammation gene polymorphisms which could affect an individual's chance to reach the extreme limit of human life. The present review is not an extensive revision of the literature, but rather an expert opinion based on selected data from the authors' laboratories. In 2000-2005 in the more developed regions, the life expectancy at birth is 71.9 years for men (78.3 in Japan) and 79.3 years for women (86.3 in Japan). Indeed, gender accounts for important differences in the prevalence of a variety of age-related diseases. Considering people of far-advanced age, demographic data document a clear-cut prevalence of females compared to males, suggesting that sex-specific mortality rates follow different trajectories during aging. In Italy this female/male ratio is relatively lower (about 5/1; F/M ratios are usually 5-6:1 in other developed countries), but significant differences have been observed between Italian regions in the distribution of centenarians by gender - from two women per man in the South to more than eight in certain regions in the North. Thus, a complex interaction of environmental, historical, and genetic factors, differently characterizing the various parts of Italy, likely plays an important role in determining the gender-specific probability of achieving longevity. This can be due to gender-specific cultural and anthropological characteristics of Italian society in the last 100 years. Age-related immunoinflammatory factors increase during proinflammatory status, and the frequency of pro/antiinflammatory gene variants also show gender differences. There is some suggestion that people genetically predisposed to weak inflammatory activity may be at reduced chance of developing coronary heart disease (CHD) and, therefore, may achieve longer lifespan if they avoid serious life-threatening infectious disease thoroughout life. Thus, the pathogen burden, by interacting with host genotype, could determine the type and intensity of the immune-inflammatory response responsible for both proinflammatory status and CHD. These findings point to a strong relationship between the genetics of inflammation, successful aging, and the control of cardiovascular disease, but seem to suggest that the evidence for men is much stronger. The importance of these studies lies in the fact that half of the population (males) lives approximately 10% shorter lives than the other half (females). Understanding the different strategies that men and women seem to follow to achieve longevity may help us to comprehend better the basic phenomenon of aging and allow us to search for safe ways to increase male lifespan.

The total burden of infection at various sites may affect the progression of atherosclerosis, the risk being modulated by host genotype. The role of lipopolysaccaride receptor TLR4 is paradigmatic. It initiates the innate immune response against gram-negative bacteria; and TLR4 polymorphisms, as ASP299GLY, suggested to attenuate receptor signaling, have been described. We demonstrated that TLR4 ASP299GLY polymorphism shows a significantly lower frequency in patients affected by myocardial infarction compared to controls, whereas centenarians show a higher frequency. Thus, people genetically predisposed to developing weak inflammatory activity, seem to have fewer chances of developing cardiovascular diseases (CVD) and, subsequently, live longer if they do not become affected by serious infectious diseases. These results are in agreement with our other data demonstrating how genetic background may exert the opposite effect with respect to inflammatory components in CVD and longevity. In the present report, to validate this hypothesis, the levels of interleukin (IL)-6, a pro-inflammatory cytokine involved in atherosclerosis and longevity, were determined by an enzyme-linked immuno-sorbent assay (ELISA) in supernatants from a whole blood assay after stimulation with subliminal doses of lipopolysaccaride (LPS) from Escherichia coli (E. coli). The samples, genotyped for the ASP299GLY polymorphism, were challenged with LPS for 4, 24, and 48 h. What we found was that Il-6 values were significantly lower in carriers bearing TLR4 mutation. Therefore, the pathogen burden, by interacting with host genotype, determines the type and intensity of the immune-inflammatory responses accountable for pro-inflammatory status, CVD, and unsuccessful aging. On the other hand, our present data seem to explain the inconclusive results obtained in case-control studies taking into account the role of functional IL-6 polymorphisms in successful and unsuccessful aging. In fact, IL6 levels seem to depend, in addition, on IL-6 polymorphisms and on innate immunity gene polymorphisms as well.

Genetic factors play a relevant role in the attainment of longevity because they are involved in cell maintenance systems, including the immune system. In fact, longevity may be correlated with optimal functioning of clonotypic and natural immunity. The aging of the immune system, known as immunosenescence, is the consequence of the continuous attrition caused by chronic antigenic overload. The antigenic load results in the progressive generation of inflammatory responses involved in age-related diseases. Most of the parameters influencing immunosenescence appear to be under genetic control, and immunosenescence fits with the basic assumptions of evolutionary theories of aging, such as antagonistic pleiotropy. In fact, by neutralizing infectious agents the immune system plays a beneficial role until reproduction and parenting. However, by determining chronic inflammation, it can be detrimental later in life, a period largely unforeseen by evolution. In particular, the data coming from the long-lived male population under study show that genetic polymorphisms responsible for a low inflammatory response might result in an increased chance of long lifespan in an environment with a reduced pathogen burden. Such a modern and healthy environment also permits a lower grade of survivable atherogenic inflammatory response.

The genetics of the interaction between host and microbes plays an essential role in the survival of the individual and attainment of longevity. The activation of toll-like receptor (TLR)4 plays a key role in natural and clonotypic immune responses. We evaluated whether TLR4 genotype is a component of genetic background protective versus rickettsiosis and whether this background influences longevity. We genotyped for +896A/G TLR4 polymorphism 78 patients affected by Boutonneuse fever, 78 age-matched controls and 78 advanced age individuals from Sicily. The +869G allele, that attenuates receptor signalling, was significantly overrepresented in patients in comparison with age-matched controls. By analyzing data according to gender, this allele was significantly higher in female patients when compared to advanced age women. Pro-inflammatory responses are programmed to resist fatal infections. So, it is not surprising that the genetic background of people that survive to an advanced age may be protective against infections. However, this seems to occur in women but not in men. In a previous study, the +896G TLR4 allele was overrepresented in advanced age men and underrepresented in men affected by myocardial infarction. Thus, previous and present results tend to agree with the suggestion that men and women may follow different trajectories to reach longevity. For men it might be more important to control atherogenesis, whereas for women it might be more important to control infectious diseases.

Epidemiological data suggest that some genetic determinants of Alzheimer's disease (AD) might reside in those polymorphisms for the immune system genes that regulate immune inflammatory responses, such as the major histocompatibility complex (MHC). Therefore, MHC polymorphisms have been the focus of a large number of AD association studies. Class Ia, Ib (hemochromatosis gene (HFE)), class II and class III (complement, tumour necrosis factor and heat shock proteins) alleles have been studied. Nearly every positive result has been followed by several studies that have failed to replicate it or that have contradicted it. Several factors, including methodological biases, might explain these discordant results. However, the discordant results obtained with the same alleles in the various populations might also indicate linkage with another nearby locus, different in the diverse populations. In fact, the non-random assortment of alleles at neighbouring loci, i.e. ancestral haplotypes (AH), has been claimed to be maintained as the result of directional selection, i.e. molecular cooperation during the immune response. Thus, AH studies might contribute to explaining why discordant results are obtained with the same alleles in different populations. Hence, it has been suggested that the overall chance of a subject to develop AD might be profoundly affected by a 'susceptibility profile' reflecting the combined influence of inheriting multiple high-risk alleles. Discordant results may be due to other genetic factors not determined in these MHC studies and multivariate analysis in large patient cohorts considering both MHC and non-MHC genes are therefore necessary.

AGE6. Skin Ageing: Focus on the Role of Inflammatory Genetic Factors in Cutaneous Neoplasia C. M. Gambino1, F. Crapanzano1, G. Accardi1, A. Aiello1, C. Virruso1, G. Pistone1, M. R. Bongiorno1, D. Lio1, C. R. Balistreri1, G. Candore1 1University of Palermo, Palermo, Italy Background: Skin aging is a complex process that involves intrinsic and exogenous causes. Photo-oxidative damage caused by UV is the leading cause of extrinsic aging of the skin, known as photo-ageing. UV damages can be linked mostly to overproduction of ROS that induces a complex molecular cascade able to accelerate physiological aging, determining a typical dermal/epidermal inflammation with an increased risk of getting skin cancer. The skin response is strongly influenced by individual genetic background. Thus, polymorphisms in candidate inflammatory genes might play a role in photo-ageing and skin cancer. Methods: A total of 30 Sicilian subjects (12 females and 18 males; age range, 65–90 years) were enrolled. From histo-pathological data, 12 subjects showed skin cancer. Their blood samples have been used to obtain DNA samples and have been genotyped for TLR4 (+896 A/G; rs.4986790), TLR4 (+1196 C/T, rs.4986791), MMP2 (-1306 C/T, rs.243865) and MMP9 (-1562 C/T, rs.3918242) using a RFLP-PCR. Results: Allelic and genotypic frequencies of the SNPs analysed were evaluated by gene count. No significant differences in frequencies of these SNPs among cases and controls were observed. Conclusions: Our results are preliminary, so it is certainly necessary to increase the sample size of our study. In fact, the possible role of these SNPs in skin-ageing related neoplasia might open new perspectives for their analysis and prevention. However, it is imperative to underline the concept that functional effects of each SNP depend on the presence of one or different environmental causes (UV radiation, smoking, etc.).

T2DM is today considered as world-wide health problem, with complications responsible of an enhanced mortality and morbidity. Thus, new strategies for its prevention and therapy are necessary. For this reason, the research interest has focused its attention on TLR4 and its polymorphisms, particularly the rs4986790. However, no conclusive findings have been reported until now about the role of this polymorphism in development of T2DM and its complications, even if a recent meta-analysis showed its T2DM association in Caucasians. In this study, we sought to evaluate the weight of rs4986790 polymorphism in the risk of the major T2DM complications, including 367 T2DM patients complicated for the 55.6%. Patients with A/A and A/G TLR4 genotypes showed significant differences in complication’s prevalence. In particular, AG carriers had higher risk prevalence for neuropathy (P=0.026), lower limb arteriopathy (P=0.013), and the major cardiovascular pathologies (P=0.017). Their cumulative risk was significant (P=0.01), with a threefold risk to develop neuropathy, lower limb arteriopathy, and major cardiovascular events in AG cases compared to AA cases. The adjusted OR for the confounding variables was 3.788 (95% CI: 1.642–8.741). Thus, the rs4986790 polymorphism may be an indicative of prevalence of complications in T2DM patients.

A large variability in occurrence, complications, and age/gender manifestations characterizes individual susceptibility of sporadic thoracic aortic aneurysms (TAA), even in subjects with the same risk factor profiles. The reasons are poorly understood. On the other hand, TAA pathophysiology mechanisms remain unclear than those involved in abdominal aorta aneurysms. However, recent evidence is suggesting a crucial role of biological ageing in inter-individual risk variation of cardiovascular diseases, including sporadic TAA. Biological age rather than chronological age is a better predictor of vascular risk. Relevant assumptions support this concept. In confirming this evidence and our preliminary data, the mean of blood leukocyte telomere length, through use of terminal restriction fragment assay and in blood samples from sporadic TAA patients and controls, was examined. Telomerase activity was also analyzed in two groups. In addition, we verified the weight of genetic inflammatory variants and the major TAA risk factors in telomere/telomerase impairment. Aorta histopathological abnormalities and systemic inflammatory mediators were ultimately correlated with telomere/telomerase impairment. Data obtained demonstrated shorter telomeres and a reduced telomerase activity in TAA patients significantly associated with a genetic inflammatory risk profile, age, gender, smoking, hypertension, a histopathological phenotype, and higher levels of systemic inflammatory mediators than controls. In conclusion, telomere and telomerase activity’s detection might be used as predictor biomarkers of sporadic TAA. Their impairment also suggests a strong role of vascular ageing in sporadic TAA, evocated by both environmental and genetic inflammatory factors.

Thoracic aorta shows various changes with advancing age and a progressive deterioration in structure and function. As a result, vascular remodeling (VR) and medial degeneration (MD) occur. VR and MD are typical entities of sporadic thoracic aortic aneurysm (TAA), actually considered a common and serious health risk and a pathology by unclear mechanisms. Increased activity of the coagulation system, inflammation, activation of extracellular matrix remodeling and endothelial dysfunction pathways have been recently evidenced to have a key role in its onset. Thus, polymorphisms of the coagulation system [fibrinogen (rs1800790); Factor II ( rs1799963); Factor V (rs6025); Factor VII (rs121964926); tPA ( rs2020918); PAI-1 (rs1799768); TAFI (rs2146881)], inflammation [TLR4 (rs4986790); CCR5 (rs333)], extra-cellular matrix remodeling [MMP9 (rs3918242); MMP2 (rs243865)], endothelium dysfunction [eNOs (rs 1799983); ACE (rs1799752)] were analyzed. Methods: A total of 161 TAA individuals (127 men and 34 women; mean age: 63±10.7) and 128 controls (61 men and 67 women; mean age: 61.08±5.83 years) from Western Sicily were enrolled. Their DNA samples were genotyped for the selected polymorphisms. Results: Inconsistent associations of coagulation polymorphisms with TAA were observed while analysing preliminary data. More relevant results might be obtained when analysing their combined genotypes. Interestingly, we observed that the rs4986790 TLR4 polymorphism confers a higher susceptibility for sporadic TAA and it represents together with rs1799752 ACE, rs3918242 MMP-9 and rs2285053 MMP-2 SNPs, an independent sporadic TAA risk factor. Their combined risk genotype was also associated with TAA. Conclusions: Results obtained seem to suggest a new perspective for the diagnosis and prevention of sporadic TAA, utilizing genetic profiles as possible risk biomarkers.

Aging has a striking impact on the heart and the vascular system, particularly on the large elastic arteries (i.e., aorta), resulting in a multitude of changes at different structural and functional levels. As result, medial degeneration (MD) occurs. A characteristic example of MD is sporadic thoracic aortic aneurysm (S-TAA), whose patho-physiological mechanisms remain unclear. In this study, typical MD morphological phenotypes were researched in S-TAA cases and control aorta specimens by histopathological and immunohistochemical analyses. Three phenotypes (I, II, and III) were detected, but mainly the phenotype III was observed. Elevated cystic MD, plurifocal medial apoptosis, and increased metalloproteinase-9 amount characterize it. In addition, it was significantly correlated with the severity of elastic fragmentation, hypertension, and smoking, and particularly with advancing age. Thus, phenotype III might represent the typical MD phenotype associated with S-TAA in old people that have a major risk of aorta rupture and dissection independently on aneurysm diameter. This might permit the assumption that phenotype III with its typical histological abnormalities is an optimal biomarker of rupture and/or dissection in aged individuals and is useful both for applying different surgical approaches and providing appropriate surgical indications

OBJECTIVE: Association between aortic aneurysm wall and risk of rupture or dissection. METHODS: Aortic specimens were obtained from 73 patients (51 men and 22 women, whose median age 61.7± 10.7 years) undergoing surgical repair of thoracic ascending aneurysm (TAA). Histopathological and immunohistochemical analyses were performed using adequate tissue specimens, appropriate techniques and criteria. Furthermore, genetic risk factors were also investigated. RESULTS: We identified three phenotypes of TAAs with different quality of aortic wall at the time of operation: phenotype I (normal wall); phenotype II (moderate wall thickness); phenotype III (thin and weak wall). No significant differences were detected in term of demographic and clinical data, co-morbidity conditions and pharmacological treatments. In contrast, significant statistical differences were observed by comparing abnormalities of extracellular matrix components among three phenotypes (fibrosis p

Thoracic aortic aneurysm (TAA) is a progressive disorder involving gradual dilation of ascending and/or descending thoracic aorta with dissection or rupture as complications. It occurs as sporadic or defined syndromes/familial forms.Genetic, molecular and cellular mechanims of sporadic TAA forms are poorly characterized and known. Thus, our interest has been focused on investigating the role of genetic variants of transforming growth factor-β(TGF-β) pathways in TAA risk. On the other hand, no data on the role of genetic variants of TGF-βpathway in sporadic TAA exist until now. In addition, other cytokines, including IL-10, orchestrate TAA pathophysiology. Their balance determines the ultimate fate of the aortic wall as healing atherosclerosis or aneurysm formation. Thus, in this paper it was analyzed the role of ten polymorphisms of genes encoding TGF-βisoforms and receptors, and IL-10 in sporadic TAA. Our study included cases affected by sporadic TAA and two control groups. The most relevant finding obtained allows us to propose that rs900 TGF-β2 SNP is associated with sporadic TAA in women. This might open new perspectives for the analysis of sporadic TAA susceptibility factors and prevention.

Ageing is a systemic condition leading to a gradual loss of molecular and cellular fidelity. A feature of ageing is immunosenescence, consisting in several modifications that increase morbidity and mortality in elderly. Environment, genetic background, immune system, and intestinal microbiota play a fundamental role in immunosenescence. The development of a chronic, low-grade, inflammatory status, known as “inflamm-ageing,” is a typical aspect of immunosenescence mostly due to the pro-inflammatory cytokine production linked to the chronic antigenic load. Nutrition can act on ageing, immunity, and health in general. Unbalanced diet with an insufficient intake of micro- and macronutrient and vitamins is a major nutritional problem among elderly, resulting in a dramatic change in gut microbiota. Calorie restriction and long-term adherence to Mediterranean diet could prevent or manage age-related diseases and immunosenescence.