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.
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/anti-inflammatory 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.
Inflammation plays a key role in Alzheimer disease, and dissecting the genetics of inflammation may provide an answer to the possible treatment. The next-generation therapy is based on a pharmacogenomics that will reconure new approaches to a drug used on definite people with specific dosage. The translation of pharmacogenomics into clinical practice will allow bold steps to be taken toward personalized medicine. In response to tissue injury elicited by trauma or infection, the inflammatory response sets in as a complex network of molecular and cellular interactions, directed to facilitate a return to physiological homeostasis and tissue repair. The role of an individual's genetic background and predisposition for the extent of an inflammatory response is determined by variability of genes encoding endogenous mediators that constitute the pathways of inflammation. Due to its clinical relevance, in this review, the view on genetics of inflammation will be illustrated through a description of the genetic basis of a specific inflammatory disease, Alzheimer's disease (AD). Several studies report a significantly different distribution, in patients and controls, of proinflammatory genes, alleles of which are under-represented in control subjects and over-represented in patients affected by AD. These studies will permit the detection of a risk profile that will potentially allow both the early identification of individuals susceptible to disease and the possible design or utilization of drug at the right dose for a desired effect - a pharmacogenomic approach for this disease.
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.
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