Giuseppina Candore

Role of TGF-β Pathway Polymorphisms in Sporadic Thoracic Aortic Aneurysm: rs900 TGF-β2 Is a Marker of Differential Gender Susceptibility

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-β pathway 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-β isoforms 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.

NF-κB pathway activators as potential ageing biomarkers: targets for new therapeutic strategies

Chronic inflammation is a major biological mechanism underpinning biological ageing process and age-related diseases. Inflammation is also the key response of host defense against pathogens and tissue injury. Current opinion sustains that during evolution the host defense and ageing process have become linked together. Thus, the large array of defense factors and mechanisms linked to the NF-κB system seem to be involved in ageing process. This concept leads us in proposing inductors of NF-κB signaling pathway as potential ageing biomarkers. On the other hand, ageing biomarkers, represented by biological indicators and selected through apposite criteria, should help to characterize biological age and, since age is a major risk factor in many degenerative diseases, could be subsequently used to identify individuals at high risk of developing age-associated diseases or disabilities. In this report, some inflammatory biomarkers will be discussed for a better understanding of the concept of biological ageing, providing ideas on eventual working hypothesis about potential targets for the development of new therapeutic strategies and improving, as consequence, the quality of life of elderly population.

Association between interleukin-10 polymorphisms and Alzheimer's disease: a systematic review and meta-analysis.

UNLABELLED It has been hypothesized that polymorphisms of interleukin (IL)-10 genes affect the risk of developing late onset Alzheimers disease (AD). However, results of different studies are often inconsistent. Our aim was to investigate by meta-analysis the association of the common polymorphisms comprehensively defining the genetic variability of the IL-10 gene with AD risk. Fifteen studies investigating the association between IL-10 polymorphisms (-1082, -819, -592) and AD were found and analyzed. The model-free approach was applied to meta-analyze these case-control genetic association studies. Available data suggested an association between -1082 polymorphism and AD risk with a marginal statistical significance (GG versus AG/AA pooled odds ratio [OR]: 0.82, 95% confidence interval CI: 0.65-1.02) and evidence of a moderate degree of between-study heterogeneity (χ2 = 27.13, d.f. = 13, p = 0.01, I2 = 52%). For the -819 and -592 polymorphisms, we did not find an association with AD, but significant between-study heterogeneity made genotype data pooling unacceptable. Analysis by IL-10 haplotype showed that the -1082G/-819C/-592C haplotype is associated with a lower risk of AD, although with a marginal statistical significance, probably due to the low number of studies included (GCC versus other genotypes: OR: 0.61, 95% CI: 0.32-1.15; I2: 85%). Current findings suggest a possible association between -1082 A > G polymorphism and the risk of developing AD; this effect is more evident in the oldest patients. The high degree of between-study heterogeneity, due to several underpowered studies and to other methodological problems of individual studies underlies the need for further methodologically adequate studies.

Sex, gender and immunosenescence: a key to understand the different lifespan between men and women?

Gender and sex are known to be associated with longevity. While males are usually stronger, females live longer. In the Western world, the life expectancy of individual born between 2005 and 2010 is 80.4 for women and 73.4 for men [1]. Potential factors have been examined to explain this disagreement. It is possible distinguish advantage in longevity related to biological traits and factors related to socio-cultural characteristics of the population. Males and females have different behavioral tendencies, social responsibilities and expectation. So, differences in mortality between men and women can be not only a matter of sex that refers to biological differences, but also a matter of “socially constructed sex”, i.e. gender [2,3]. One of the main interaction between gender and longevity is linked to the kind of job. Indeed, in the to-day elderly, professional exposure to stressors was stronger in males rather than in females [4]. Since many classic “old” jobs needed specific physical characteristics, females were often housewives, hence they were commonly more protected. Furthermore, alcoholism, smoking and accidents were the main factors contributing to excess male mortality although it is’nt anymore true in the actual generation [2,3]. On the other hand, it is well known that female mithocondria produce less reactive oxygen species than male ones and that estrogens increase high density lipoproteins and decrease low density ones [5,6]. Thus, both gender and sex might be responsible for the differences in lifespan between males and females [2,3]. However, immune-inflammatory responses play a key role in successful ageing [2]. So, immunosenescence, a complex process in which different immunological functions are impaired, others are remodeled, is believed to be a major contributory factor to the increased frequency of morbidity and mortality among elderly [2,7]. On the other hand, it is still controversial whether age-related changes of immune system are different between men and women. To elucidate the relationship between immunological changes and lifespan, peripheral blood mononuclear cells of 356 healthy Japanese ranging in age from 20 to 90 years were analyzed for the number and percentage of various lymphocytes by using three color flow cytometry [8]. The proliferative and cytokine producing ability of T cells in response to anti-CD3 monoclonal antibody stimulation was also assessed. The results show that an age-related decline is observed in the numbers of T cells, in certain subpopulations of T cells (including CD8+ T cells, CD4+CDRA+ T cells, and CD8+CD28+ T cells), and B cells, and in the proliferative ability of T cells. The rate of decline in these immunological parameters, except for the number of CD8+ T cells, is greater in male than in female. An age-related increase is observed in the number of CD4+ T cells, CD4+CDRO+ T cells, and NK (CD56+CD16+) cells and in the CD4+ T cell/CD8+ T cell ratio. The rate of increase of these immunological parameters is greater in female than in male. The T cell proliferation index (TCPI), which was calculated based on T cell proliferative activity and the number of T cells, shows an age-related decline. The rate of decline in the TCPI is again greater in male than in female. T cell immune score, which was calculated by using 5 T cells parameters, also declines with age, and the rate of decline is greater in male than female. In addition, a trend of age-related decrease was observed in the production of some cytokines, when lymphocytes were cultured in the presence of anti-CD3 monoclonal antibody stimulation. In particular, the rate of decline in IL-6 and IL-10 is greater in male than in female [8]. Because IL-10 acts as an immune-inflammatory suppressor [9], this relatively lesser production can be consistent with the fact that the age-related decline of various immunological parameters is less pronounced in female than in male. The authors conclude that the age-related changes of various immunological parameters is different between men and women, likely due to a lower biological age of women. These findings, indicating a slower rate of decline in these immunological parameters in women than in men, are consistent with the fact that women live longer than men, i.e. in Japan 85.5 years in women and 79.0 in men [8]. It is indeed well known that the strength and the kind of immune responses are different between males and females. Hormonal and genetic influences are the main biological differences to consider when the attention is focused on immunology. While from a gender point of view food intake and variety, exposure to non-microbiological antigens and health care access have to be take into account [2,10]. Steroid hormones, linking to specific receptors, modulate in different manner the immunological cells. Estrogen receptors have been detected not only in classical reproductive tissues, but also in immune cell population, including lymphocytes, monocytes and macrophages [2]. In general, while estrogens action increase the immune response, it falls with progesterone and androgens action [10]. As an example, estradiol activates the mitogen-activated protein kinase (MAPK) pathway that leads to the downstream activation of nuclear factor kappa B (NFkB) signaling pathway. Both, MAPK and NFkB pathways, are involved in enhanced expression of genes involved in immune response and in genes encoding antioxidant enzymes [11]. A sexual dimorphism in the immune response means that females are more resistant to infections but they have higher incidence of autoimmune diseases compared to male [12], but their relevance for life span is negligible [13]. In addition to hormones, the most intuitive genetic factor that can determine difference in the immune response between male and female is the X chromosome, since it is well known that some genes involved in immunity map in this chromosome. However, other important genes are located on autosomes although they are regulated in sex-specific manner. Since X chromosome is present only in one copy in male, every X chromosome random recessive mutation will be expressed. It is not the same for female in which two copies are present at tissue level (“mosaicism”) balancing the mutation [3,10,14-16]. Another cellular process that differs between male and female and that can play a role, is the rate at which telomeres shorten since women have less telomere shortening than do men. However, telomere shortening may be a cause for and/or a consequence of immunosenescence [17]. On the other hand, whereas sexual differences can advantage females, gender differences can damage them. In fact, financial trouble and cultural factors are the cause of a reduced consumption of food for female. Indeed, they are often more prone to the renounce thus they are mainly subjected to malnutrition. Food intake and composition can modulate the immune response trough the lack of micronutrients and vitamins, essential for immune cells. Vitamins affect mast cells function and immunoglobulin, NK and lymphocyte number [18]. The lack of zinc and copper, immunomodulatory micronutrients, can, also, negatively affect the immune response in gender specific manner [19,20]. In term of health care, then, females are underprivileged while males and children have often the priority. Thus, for example, female have less access to antibiotics and chemioterapics [21]. These gender differences might explain why in certain developing countries the female life expectancy is almost similar to male life expectancy [1]. Finally, it is well known that men and women follow different trajectories to reach longevity. The reasons are most likely multifactorial, involving genetic, epigenetic and environmental factors [22]. Several key molecules and regulatory pathways have been identified that may play a role in determining lifespan and new molecular mechanisms that regulate longevity, are waiting for to be uncovered. The detection of potentially involved mechanisms might allow the way to a better identification of anti-aging strategies.

Association between genetic variations in the insulin/insulin-like growth factor (Igf-1) signaling pathway and longevity: a systematic review and meta-analysis.

Some studies have shown that polymorphisms in the insulin growth factor-1 (IGF-1) signaling pathway genes could influence human longevity. However, the results of different studies are often inconsistent. Our aim was to investigate by systematic review and meta-analysis the association of the common polymorphisms defining the genetic variability of the IGF-1 signaling pathway associated with human longevity. Eleven studies investigating the association between the polymorphisms in the IGF-1 signaling pathway genes (IGF-1, IGF-1 receptor (IGF-1R), Forkhead box O3A (FOXO3A) and Silent mating type Information Regulation 1 (SIRT1) and longevity were found and analyzed. The modelfree approach was applied to meta-analyze these studies. No association was reported between the single nucleotide polymorphisms (SNPs) of IGF-1 and longevity in the only available study. The meta-analysis of available data from four studies, showed a significant association with the IGF-1R polymorphism rs2229765, suggesting that subjects with the Abearing genotype have a greater chance of longevity. Concerning the five studies on FOXO3A SNPs, for the rs2764264 a significant association with longevity was observed for C allele when only males were included in the analysis. Statistically significant results were obtained for other SNPs as well, i.e. rs2802292 (G allele), rs9400239 and rs479744 (T and A alleles, respectively). For rs9400239 the association was observed in long lived males with a lower odds ratio than in centenarians, while in rs479744 a significant association was highlighted in centenarians. Concerning SIRT1, no association between the SNPs under study and longevity was observed in the only available report. Current findings suggest that both IGF-1R and FOXO3A polymorphisms could be associated with longevity. The high degree of between-study heterogeneity and the low number of available studies underline the need for further methodologically adequate analyses to confirm this evidence.

Pro-Inflammatory Genetic Markers of Atherosclerosis

Atherosclerosis (AS) is a chronic, progressive, multifactorial disease mostly affecting large and medium-sized elastic and muscular arteries. It has formerly been considered a bland lipid storage disease. Currently, multiple independent pathways of evidence suggest this pathological condition is a peculiar form of inflammation, triggered by cholesterol-rich lipoproteins and influenced both by environmental and genetic factors. The Human Genome Project opened up the opportunity to dissect complex human traits and to understand basic pathways of multifactorial diseases such as AS. Population-based association studies have emerged as powerful tools for examining genes with a role in common multifactorial diseases that have a strong environmental component. These association studies often estimate the risk of developing a certain disease in carriers and non-carriers of a particular genetic polymorphism. Dissecting out the influence of pro-inflammatory genes within the complex pathophysiology of AS and its complications will help to provide a more complete risk assessment and complement known classical cardiovascular risk factors. The detection of a risk profile will potentially allow both the early identification of individuals susceptible to disease and the possible discovery of potential targets for drug or lifestyle modification; i.e. it will open the door to personalized medicine.

Can the TLR-4-Mediated Signaling Pathway Be “A Key Inflammatory Promoter for Sporadic TAA”?

Thoracic aorta shows with advancing age various changes and a progressive deterioration in structure and function. As a result, vascular remodeling (VR) and medial degeneration (MD) occur as pathological entities responsible principally for the sporadic TAA onset. Little is known about their genetic, molecular, and cellular mechanisms. Recent evidence is proposing the strong role of a chronic immune/inflammatory process in their evocation and progression. Thus, we evaluated the potential role of Toll like receptor- (TLR-) 4-mediated signaling pathway and its polymorphisms in sporadic TAA. Genetic, immunohistochemical, and biochemical analyses were assessed. Interestingly, the rs4986790 TLR4 polymorphism confers a higher susceptibility for sporadic TAA (OR = 14.4, P = 0.0008) and it represents, together with rs1799752 ACE, rs3918242 MMP-9, and rs2285053 MMP-2 SNPs, an independent sporadic TAA risk factor. In consistency with these data, a significant association was observed between their combined risk genotype and sporadic TAA. Cases bearing this risk genotype showed higher systemic inflammatory mediator levels, significant inflammatory/immune infiltrate, a typical MD phenotype, lower telomere length, and positive correlations with histopatological abnormalities, hypertension, smoking, and ageing. Thus, TLR4 pathway should seem to have a key role in sporadic TAA. It might represent a potential useful tool for preventing and monitoring sporadic TAA and developing personalized treatments.

Nutraceutical Properties of Extra-Virgin Olive Oil: A Natural Remedy for Age-Related Disease?

The health benefits of the Mediterranean diet can be largely ascribed to the nutraceutical properties of extra-virgin olive oil (EVOO). Mono-unsaturated fatty acids and various phenolic compounds, such as oleocanthal, oleuropein, hydroxytyrosol, and tyrosol, are the main nutraceutical substances of EVOO. These substances have been suggested to have the ability to modulate aging-associated processes. In experimental models, it has been shown that EVOO with high concentrations of polyphenols has anti-inflammatory and anti-oxidant properties. Indeed, it was observed that hydroxytyrosol and oleocanthal inhibit the cyclooxygenases (COX-1 and -2) responsible for prostaglandin production; oleuropein is a radical scavenger that blocks the oxidation of low-density lipoproteins. Due to the relevance of olive oil in the economy of Sicily, our group has been funded to assess the nutraceutical properties of different kinds of olive oil. Indeed, the aim of the study is to evaluate effects of EVOOs, with low and high polyphenols content, on immuno-inflammatory and oxidative stress responses in young and old people. A further objective of our group is to evaluate effects of EVOO, with low and high polyphenol content, on the expression of genes encoding proteins that take part in the insulin/insulin-like growth factor-1 signaling pathway involved in longevity. The results of the study will be useful for producing olive oil enriched in nutraceutical properties that may be likely helpful in the prevention of age-related diseases.

Prostate cancer: from the pathophysiologic implications of some genetic risk factors to translation in personalized cancer treatments

Several pathologies affect human prostate, such as prostate cancer (PC), which is the most common non-skin malignant cancer in Western male populations. A complex interaction between genetic and environmental factors (i.e. infectious agents, dietary carcinogens) and hormonal imbalances has been reported to have a fundamental role in PC pathophysiology by evoking chronic inflammation. Thus, chronic inflammation drives prostate carcinogenesis and neoplastic progression. No adequate biomarkers exist until now to guide PC prognosis and treatment. Accordingly, the research has particularly focused its attention on genetic variants in genes, codifying molecules of signaling innate immune/inflammatory and steroid metabolism pathways, which are able to modify the PC genetic susceptibility and clinical disease outcome. Single-nucleotide polymorphisms (SNPs) may operate in combination to create a ‘risk profile’. Combinations of several inflammatory and sex steroid hormone pathway SNPs are found in PC patients. Thus, their combinations might be used as promising biomarkers in a pre- and post-treatment clinical PC setting. Indeed, their identification may hold promise for the realization of a personalized PC medicine. Many of these aspects are summarized in this report through the elucidation of literature data and the results of our studies.

Centenarian offspring: a model for understanding longevity.

A main objective of current medical research is to improve the life quality of elderly people as priority of the continuous increase of ageing population. This phenomenon implies several medical, economic and social problems because of dramatic increase in number of non autonomous individuals affected by various pathologies. Accordingly, the research interest is focused on understanding the biological mechanisms involved in determining the positive ageing phenotype, i.e. the centenarian phenotype. In achieving this goal the choice of an appropriate study models is fundamental. Centenarians have been used as an optimal model for successful ageing. However, this model shows several limitations, i.e. the selection of appropriate controls and the use itself of the centenarians as a suitable model for healthy ageing. Thus, the interest has been centered on centenarian offspring, healthy elderly people. They may represent a model for understanding exceptional longevity for the following reasons: they exhibit a protective genetic background, cardiovascular and immunological profile, as well as a reduced rate of cognitive decline than age-matched people without centenarian relatives. Several of these aspects are summarized in this review based on the literature and the results of our studies.