Pathophysiology of aging, longevity and age-related diseases

Pathophysiology of ageing, longevity and age related diseases
Büerkle et al., Immunity & Ageing 2007

Resume On April 18, 2007, the international conference "Pathophysiology of Aging, longevity and age-related diseases" was held in Palermo, Italy.

In the proposed report, we present basic information about the most important issues discussed. Despite the fact that aging must be considered as the inevitable end point of each individual's life story, the deepening of knowledge about the mechanisms of aging provides the basis for the development of many different strategies to mitigate the symptoms of aging and prolong youth. Thus, a better understanding of the pathophysiology of aging and age-related diseases is necessary to provide each person with a real chance to live a long and disease-free final stage of life.

Cancer

Most cases of cancer develop in patients over the age of 65. The incidence of cancer increases dramatically with aging in both sexes: after 65 years, the incidence of cancer is 12-36 times higher than in the 25-44 age group, and 2-3 times higher than in people aged 45-65 years. It should be noted that 70% of cancer–related deaths occur in men and women aged 65 and older, while 35% of cancer-related deaths in men and 46% in women occur after the age of 75. The relationship between aging and cancer is the same for almost all forms of cancer and is well described by a multi-stage model of carcinogenesis. Therefore, aging itself should not be considered as a determining factor in the development of cancer, but as an indirect marker of the duration of exposure to significant carcinogenic factors [1]. On the other hand, according to the results of a recent revision of views on the relationship between cancer and inflammation, inflammatory cells and cytokines occurring in the tumor zone are highly likely to stimulate the growth and progression of tumors [2]. Moreover, the predisposition to cancer and the severity of the course of the disease may be associated with functional polymorphism of genes encoding inflammatory cytokines [1]. If genetic damage is compared with a match that ignites a fire, then some types of inflammation can provide "flame-supporting fuel" [2]. Thus, the reason for the increase in the incidence of cancer in old age may well be the well-known pro-inflammatory status of the body associated with aging [3].

At the conference, the role of oncogenes in the development of human cancer was highlighted by the authors of works [4, 5] devoted to the study of epithelial tumors of the human thyroid gland that developed from follicular or parafollicular cells. Follicular cell tumors represent a wide range of pathological changes (from benign adenomas to differentiated papillary and follicular carcinomas and undifferentiated anaplastic carcinomas) which makes them a good model for studying the correlation between specific genetic damage and histological phenotype. Follicular adenomas often appear in the presence of mutations in one of the three genes of the ras family: HRAS, KRAS and NRAS. Mutations of the G-stimulating protein (gsp) and thyrotropin receptor (TSH-R) genes trigger the formation of hyperfunctioning benign tumors (toxic nodes and adenomas). Two different types of differentiated thyroid carcinomas differ not only in morphology, but also in behavior; in addition, they are associated with mutations of different oncogenes: papillary carcinoma – with a rearrangement of the RET or TRK genes, and follicular carcinomas – with mutations of one of the three oncogenes of the ras family. The tumor suppressor gene p53 is often associated with anaplastic thyroid cancer. The RET gene is a classic example of a gene whose various mutations can lead to the development of different neoplastic phenotypes. Somatic rearrangements, often caused by chromosomal inversions (180° rotation of the chromosome section), activate the oncogenic potential of the RET gene in human papillary thyroid cancer cells. Such changes occur in the cells of almost 50% of papillary tumors and represent an overlap of the 3' tyrosine kinase domain of the RET gene encoding a protein receptor that is not usually expressed by follicular cells, and the 5' domain of one of the universally expressed genes, resulting in the formation of several types of chimeric RET/PTC genes characteristic of papillary thyroid cancer glands. Such ubiquitously expressed genes perform the activation and dimerization functions necessary for the constitutional activation of RET/PTC proteins. Point mutations of the RET gene of stem cells are the cause of the development of syndromes of familial multiple endocrine neoplasia type 2 (MEN II), represented by (a) familial medullary thyroid cancer, (b) MEN IIA and (c) MEN IIB. A common characteristic of these diseases is the presence of medullary thyroid cancer formed by parafollicular C cells. Point mutations of the RET gene can also occur in somatic cells, which leads to the development of sporadic medullary thyroid cancers and pheochromocytomas. Detailed information about specific mutations of the RET gene underlying the development of malignant tumors of the human thyroid gland greatly facilitates the treatment of these diseases.

Immunological aging

Many health-threatening disorders of the functioning of innate and acquired immunity in the elderly have been described, which caused the appearance of the term "immunological aging". On the other hand, immunological aging is rather a complex process that includes many changes caused by evolution and restructuring of the body, rather than a simple gradual extinction of the functioning of the entire system. Nevertheless, some immunological parameters are often significantly reduced in the elderly and, conversely, the good functioning of the immune system is closely related to the state of health. Recent observations suggest that immunological aging is not accompanied by an inevitable progressive decline in the functioning of the immune system, but rather is the result of restructuring, leading to the suppression of a number of functions, while the effectiveness of other functions does not change or even increases. It is important to note the fact that age-related changes in the immune system are directly or indirectly involved in the development of increased susceptibility of older people to infectious, autoimmune and oncological diseases, as well as reduced immunological reactivity during vaccination. The same applies to the pathogenesis of the most important age-related diseases, such as cardiovascular and neurodegenerative diseases, as well as diabetes and osteoporosis: there is an important immune component in the pathogenesis of all these diseases. In addition, it seems that innate immunity is relatively well preserved in the aging process, compared with a younger and more complex clonotypic immune response, which aging has a stronger effect on [3,6-8].

Aging of clonotypic immunity is mostly the result of changes in the state of T cells. It is believed that chronic antigenic load is the main cause of immunological aging, affecting human life expectancy by reducing the number of naive (not interacting with antigens) T cells and filling the resulting immunological niche with memory T cells and effector T cells that have already encountered antigens [9]. Such a chronic antigenic load affecting the immune system throughout life is the cause of the chronic inflammatory status characteristic of the elderly [3]. A progressive decrease in the number of naive CD4+ and CD8+ T-lymphocytes occurs in parallel with the growth of the population of CD28-T memory cells with an aging phenotype, that is, demonstrating progressive shortening of telomeres and reduced ability to replicate [10]. The second fundamental aspect of immunological aging is the progressive aggravation of the pro-inflammatory status, characterized by an increase in the levels of inflammatory cytokines and inflammatory markers, which are prognostic factors of morbidity and mortality [11, 12]. This chronic pro-inflammatory condition is caused by chronic antigenic load (bacteria, viruses, fungi, toxins, mutated cells), constantly stimulating the mechanisms of innate immunity and, apparently, contributing to the development of typical age-related diseases (atherosclerosis, dementia, osteoporosis, neoplasia), in the development of which immune and autoimmune factors play a significant role [3].

It has been suggested that chronic viral antigenic stimulation may be the cause of modifications of lymphocyte populations characteristic of aging, including clonal expansion of CD8+ T lymphocytes specific to viral antigens, expressing the phenotype of memory cells and in some cases constituting up to a quarter of the entire CD8+ T cell population [13]. In the framework of a recent work [14], the authors evaluated the quantitative ratio of CD8+ T cell populations with different phenotypes in the blood of elderly people of two age groups: from 90 to 100 years old and over 100 years old. The cell phenotype was evaluated using tetramers of antigens of the main histocompatibility complex HLA-A2 HLA-B7 containing epitopes specific to Epstein-Barr virus (EBV) and cytomegalovirus (CMV). The data obtained showed that in elderly people, these viruses induce quantitatively and qualitatively different immune responses mediated by CD8+ T cells. The relative and absolute number of CD8+ cells specific to the three epitopes of the Epstein-Barr virus was small, and these cells were predominantly represented by the CD8+CD28+ phenotype. In cytomegalovirus infection, on the contrary, different levels of CD8+ T cells specific to the two epitopes of the virus were recorded in the blood of different people. In some individuals, populations of these cells that did not express the CD28 molecule were extremely numerous. For a more detailed study of the roles of cytomegalovirus infection and the immune system, scientists recently examined 121 people aged 25 to 100 years, 18 of whom were seronegative, and 118 were seropositive to this cytomegalovirus. The results of the analysis of the obtained data showed that individuals infected with cytomegalovirus were characterized by a more pronounced decrease in the number of naive CD8+ T cells, whereas the decrease in the number of naive CD4+ T cells did not depend on the presence of CMV infection. A decrease in the number of naive CD8+ T lymphocytes was accompanied by a progressive increase in the population of CD8+CD28+ effector cells, especially pronounced in CMV-infected individuals. Age-associated accumulation of cells with the CD4+CD28-phenotype was observed only in infected individuals, whereas in CMV-negative subjects these cells were practically absent. Samples of peripheral blood mononuclear cells were stimulated by combinations of peptides, the fragments of amino acid chains included in which completely covered the sequences of cytomegalovirus pp65 and IE-1 protein molecules. As a result, reacting cells expressing interferon-gamma (IFN-gamma+) appeared in populations of both CD8+ and CD4+ lymphocytes. At the functional level, age-associated accumulation of CMV-specific (IFN-γ+) CD8+ cells was observed in all individuals, whereas the population growth of pp65-specific CD4+ cells occurred only in people over 85 years of age. At the same time, most of the cytomegalovirus-specific CD8+ (IFN-gamma+) cells and 25% of CD4+ (IFN-gamma+) expressed the cytotoxic degranulation marker CD107a (Sansoni et al., article accepted for publication). These data confirm the hypothesis that chronic cytomegalovirus infection underlies pronounced changes in the ratio of lymphocyte subpopulations affecting not only CD8+ but also CD4+ cells and possibly contributes to the development of age-related proinflammatory status accompanying most age-related diseases.

The study of the immune response in healthy elderly people has shown that immunological aging affects not only the reactions of T cells, but also various aspects of innate immunity. Perhaps the most detailed studies of age-related changes in the innate immune system have been devoted to the so-called natural killers (NC). These cells, as well as polymorphonuclear leukocytes and macrophages, are components of innate immunity, and represent the body's main defense system responsible for the spontaneous destruction of tumor and virus-infected cells. Natural killers do not have T-cell receptors and express CD56 and CD16 molecules on their membrane. In addition, they have two alternative mechanisms of cytolysis: direct spontaneous cytotoxicity directed against various tumor cells, and indirect Fc-receptor-mediated cytotoxicity against antibody-coated targets (antibody-dependent cell-mediated cytotoxicity) [15]. A finely balanced complex of signals coming from numerous activating and inhibiting receptors controls their effector functions. These receptors provide the ability of cells to quickly detect potentially dangerous cells in their environment. In the case of a shift in the balance of the signaling complex towards activation, natural killers begin to secrete cytokines and/or release cytotoxic substances contained in cytoplasmic granules. In humans, one of the activating receptors expressed by NK cells, as well as T-gamma-delta cells and CD8-alpha-beta T cells, is the NKG2D molecule. As ligands, this receptor recognizes UL16-binding protein 1 (ULBP1), ULBP2, ULBP3, ULBP4, as well as MICA and MICB chains of MHC I antigen molecules. On the surface of healthy cells, these ligands are absent or contained in insignificant amounts, but their expression can be induced by viral or bacterial infections. Several papers have been devoted to the study of the ability of natural killers in the early stages of the development of the infectious process to regulate the development of acquired immune response reactions through the production of cytokines, usually synthesized by type I T-helpers, or through the activation of dendritic cells. In addition, the joint cultivation of natural killers and antigen-activated T cells showed that in response to the production of IL-2 interleukin by activated T cells, human NK cells begin to secrete interferon-gamma. On the contrary, there is very little evidence of the existence of physical interaction between natural killers and cells that provide reactions of acquired immunity, especially CD4+ cells. Natural killers stimulate acquired immunity through the production of type 1 or type 2 cytokines or chemokines. The secretion of these factors by activated NK cells affects the differentiation of B and T lymphocytes. More and more data obtained by scientists indicates the direct involvement of natural killers in the maturation of dendritic cells. At the same time, the potential role of direct intercellular interaction between natural killers and T-lymphocytes, in particular CD4+ T-lymphocytes, has not been studied to date. There is evidence that activated natural human killers are able to stimulate T-cell receptor-mediated (TCR-dependent) proliferation of resting autologous CD4+ T cells in peripheral blood through a process involving costimulatory molecules of the immunoglobulin superfamilies and tumor necrosis factor (TNF). These data indicate the existence of a previously unknown mechanism of the relationship between the innate and acquired components of immunity [16, 17].

The results of a quantitative analysis of cells expressing the phenotype of natural killers carried out in 1987 showed that the number of circulating NK cells in the peripheral blood of healthy individuals over 70 years of age is higher than in young people and middle-aged people [18]. The growth of the NK cell population in the peripheral blood of elderly people clearly correlates with age and a decrease in the number of T-lymphocytes, which supports the theory that an increase in the number of natural killers compensates for a decrease in their cytolytic activity. The cytolytic activity of peripheral blood lymphocytes is approximately proportional to the relative content of NK cells in the blood sample. However, it turned out that after incubation with K562 cells, the cytolytic activity of natural killers is the same for both young people and exceptionally healthy elderly individuals selected according to the SENIEUR protocol, despite the twice higher content of effector cells in the blood of the latter [18]. In any case, isolated or cloned NK cells of elderly people showed reduced cytolytic activity per cell. These results confirm the data according to which, after binding to the CD16+ target cell, the cell of an elderly donor exhibits, on average, two times lower cytolytic activity than the cell of a young person [19]. However, natural killers of elderly people do not differ significantly from cells of young individuals either in their ability to bind to the target, or in intracellular content, or in the distribution and utilization of perforin. Therefore, it is obvious that some other factors are responsible for the decrease in the cytolytic activity of natural killers in the elderly. In fact, the ability of NK cells to transform a receptor-mediated signal into an effector response associated with the ability to synthesize secondary messengers after stimulation by K562 cells decreases significantly with age. The main biochemical defect underlying this phenomenon appears to be an age-associated slowdown in PIP2 hydrolysis and a decrease in the rate of IP3 formation after stimulation of natural killer cells by K562 [20]. Since the density of surface receptors involved in recognition and adhesion, as well as the ability of NK cells to form complexes with target cells, practically does not change with age, it can be assumed that a violation of signal transmission in these cells occurs at stages remote from the moment of receptor binding.

An increasing amount of data obtained by scientists suggests that the immune, endocrine and nervous systems are strongly interconnected and interact with each other through circulating cytokines, hormones and neurotransmitters. Many hormones and trace elements have an important effect on the homeostasis of the immune system and the maintenance of a constant composition of the body. The decrease in the amount of adipose tissue associated with aging, as well as muscle and bone mass, in combination with an increased risk of malnutrition and deficiency of vitamins and trace elements are among the main factors causing the development of painful conditions and a decrease in the resistance of older people to infectious diseases. A pronounced relationship was revealed between the amount and cytolytic activity of natural killers and the content of vitamin D in blood serum, which corresponds to data according to which the intake of vitamin D by elderly people has a pronounced effect on the activity of NK cells, increasing the level of interferon-alpha in the blood. Anthropometric parameters used to estimate the volume of fat and muscle tissue also correlate with the number and activity of natural killers, and indicators of adipose tissue volume correlate with the level of vitamin D in blood serum [21]. Another important result is the identification of a strong correlation between the number of NK cells and the concentration of zinc in the blood serum, which is necessary for the implementation of many homeostatic reactions of the body, including oxidative stress, and many body functions, including effective immune reactions [22]. In addition, taking zinc aspartate led to an increase in the concentration of zinc ions in the blood of people with an initially low content of this element in the blood serum and stimulated the cytolytic activity of their natural killers [Mariani, unpublished observations], which indicates a softening of the pro-inflammatory status (characterized by high levels of pro-inflammatory cytokines and possibly chemokines) [23] and the development of more balanced immune responses mediated by type 1 and type 2 T-helpers. Due to the pronounced relationship between the degree of deficiency of trace elements and vitamins and immunodeficiency in the elderly (increased risk of infectious diseases, as evidenced by the high level of non-response to influenza vaccine among malnourished elderly people) these results indicate the paramount importance of assessing the quality of nutrition in the clinical study of the health status of elderly people [24].

Age-related inflammatory diseases

The individual rate of aging of the whole organism or any organ system may vary depending on genetic characteristics, the history of the course of the disease, random factors, etc. The immune system is no exception. Disorders of homeostasis and functioning of the immune system (especially the main immune cells – CD4+ lymphocytes) are the basis or at least one of the causes of the development of Alzheimer's disease and rheumatoid arthritis. These diseases relate to conditions that accelerate aging (reduce life expectancy) of a person. The question arises: is the aging of CD4+ cells accelerated in people suffering from these diseases? The main tasks of CD4+ lymphocytes are the production of a large number of different cytokines and periodic proliferation, which ensures the formation of clones of effector cells and memory cells. It is known that CD4+ lymphocytes of patients with rheumatoid arthritis, as well as cells of healthy elderly people, are characterized by signs of aging, including relatively short telomeres, a decrease in the number of CD28 molecules expressed on the surface, a decrease in the frequency of proliferation, etc. To study the probability of accelerated aging of CD4+ lymphocytes in patients with Alzheimer's disease and rheumatoid arthritis, scientists used a new flow-cytometric technique for assessing the frequency of cell proliferation. This technique is based on labeling cells with carboxyfluorescein-succinimide ether and a complex mathematical analysis of the data obtained, which allows to determine the number of proliferating lymphocytes with a high degree of accuracy, as well as to evaluate the dynamic parameters of proliferation, including the timing of the cell cycle, in particular the transition time from phase G0 to phase G1. The obtained results showed that CD4+ cells of patients with rheumatoid arthritis (especially young ones) do not differ from cells of healthy elderly people in these parameters, thereby confirming the assumption of their premature aging. At least one of these parameters (the duration of the G0–G1 transition) correlates with the level of CD28 expression on the surface of lymphocytes, which, in turn, depends on the regulatory activity of the proinflammatory cytokine – tumor necrosis factor. There is also a Klotho gene (the protein product of which is sometimes called the "aging hormone") containing a regulatory sequence presumably reacting to the tumor necrosis factor. His study showed that both the transcriptional activity of the gene itself and the content of the Klotho protein in the cell are significantly reduced in CD4+ cells of patients with rheumatoid arthritis, regardless of their age, and do not differ from similar parameters of cells of healthy elderly people. As expected, the enzymatic activity of beta-glucuronidase attributed to the Klotho protein (presumably involved in the hydrolysis of steroid glucuronides) is reduced in CD4+ lymphocytes of patients with rheumatoid arthritis and healthy elderly people, which may be one of the factors causing the proinflammatory status characteristic of both groups [25, 26]. Using the same methodology to study CD4+ cells of patients with Alzheimer's disease revealed a quasi-opposite pattern. The values of the dynamic parameters of proliferation, including the timing of the cell cycle and the G0–G1 transition, of lymphocytes of typical elderly patients with Alzheimer's disease corresponded to similar indicators obtained when studying cells of healthy young people. Obviously, this feature is due to the effect of beta-amyloid peptide on cells. An interesting fact is that CD4+ cells of patients with Alzheimer's disease show a more pronounced reaction to beta-amyloid than cells of healthy people. Perhaps one of the factors causing this phenomenon are genetic differences, such as different variants of histocompatibility complex genes. In short, the data obtained indicate that rheumatoid arthritis is the cause of accelerated aging of CD4+ lymphocytes, whereas Alzheimer's disease does not affect the aging of these cells, which, however, show deviations from normal functions [Witkowski, unpublished observations].

Repairing DNA damage

50 years ago, when the free radical theory of aging was first proposed, the damaging effect of reactive oxygen species (ROS) was actively studied and recognized as the most important factor in the aging process. However, the theory of expendable soma that appeared 20 years later (or the theory of disposable soma) redirected the attention of specialists to the potential role of mechanisms that neutralize the damaging effects of ROS to maintain cell viability and repair damage, the effectiveness of which is due to both genetic characteristics and environmental factors. In this context, poly is of particular interest(ADP-ribosyl)ionization is a posttranslational modification of protein molecules caused by DNA damage. Poly(ADP-ribosyl)ionization catalyzes the poly enzyme(ADP-ribose)polymerase-1 (PARP-1), the substrate of which is NAD+ [27]. Activation of PARP-1 triggered by DNA chain breaks is functionally associated with DNA damage repair mechanisms and is a survival factor for cells under conditions of low and medium genotoxic stress. More than 10 years ago, a positive correlation was described between the ability of mononuclear blood cells to poly(ADP-ribosyl)and the functioning and life expectancy of various representatives of the mammalian class [28]. The results of the subsequent comparative analysis of purified recombinant molecules of human and rat PARP-1 showed that this correlation is partly explained by differences in the genetic sequence encoding this enzyme that arose during evolution [29]. This observation is in perfect agreement with the recently published results of studying various lines of knockout mice with defects in genes that ensure DNA repair by removing nucleotides. These results demonstrate the exceptional importance of DNA repair for the functioning of mechanisms that ensure the longevity of the organism. For a more detailed study of the role of DNA repair and poly(ADP-ribosyl)Scientists working under the leadership of Bürkle have recently developed an improved method for the quantitative analysis of the formation of cross-links and breaks of DNA chains in living cells using the automated method of alkaline DNA unwinding under the control of fluorescence (automated fluorescence-detected alkaline DNA-unwinding (FADU) assay). They also developed a new method for monitoring the formation of poly(ADP-ribose) in living cells using liquid cytometry, taking as a basis the approach used for cells with impaired membrane permeability (permeabilized cells) [30].

Longevity

The improvement of the quality of social conditions, medical care and quality of life caused an improvement in the health of the population as a whole and, consequently, a decrease in morbidity and mortality, which led to an increase in average life expectancy. In the 70s, a gradual decrease in mortality (by 1-2% per year) of individuals over 80 was observed in all industrialized countries, which led to an increase in the number of people over 100 years of age by about 20 times. These centenarians make up a group of people who have received benefits as a result of delaying the onset of diseases that are a common cause of death for much younger people [31]. Data on the genetics of human longevity, mainly obtained during studies involving people who have crossed the 100-year mark, indicate the following: individuals aged 100 years and older, as well as long-lived siblings are the optimal choice when studying the patterns of human longevity, since they have an extreme phenotype, that is, qualities, which allowed them to avoid death in infancy, death from infectious diseases before the beginning of the era of antibiotics, as well as death as a result of age-related complex diseases. The model of a 100-year-old individual is not just an addition to well-studied model organisms. Studies involving humans have revealed the characteristics of aging and longevity (geographical and sexual differences, the role of antigenic load and inflammation, the role of mtDNA variants), not disclosed in the study of aging processes in animal models. All phenotypic features of centenarians of two age groups (90-100 years and over 100 years) they correspond to the hypothesis according to which the essence of the aging process consists in the "restructuring" or progressive adaptation of the long-lived organism to external and internal damaging agents affecting it for several decades, for the most part not provided for by evolution. Such an adaptation process, which can be considered a Darwinian process occurring at the somatic level under the influence of evolutionary pressure, can explain why the same gene polymorphism can have different (beneficial or harmful to health) effects at different age periods. Demographic data indicate that longevity is provided by various combinations of genes, the environment and random factors, and their influence can differ quantitatively and qualitatively depending on the geographical area, as well as that population-specific genetic factors play a role in the phenotype of longevity. Combined and integrated use of new high-performance strategies based on the use of powerful computers will significantly accelerate the identification of new genes that ensure human longevity [32-36, 3].

It is widely believed that the existence of more or less centenarians is mainly due to the mortality rate between the ages of 80 and 100 years. In fact, the low mortality rate in this age group suggests that more people will survive the centenary. Therefore, to determine the longevity of a population, demographers use the mortality rate at the age of 80-100 years, and not the relative number of centenarians (100 years and older) in the population. Sardinia (the second largest Italian island), which is home to a large number of centenarians, attracts great interest, especially the geographical area in which male mortality after 80 years is lower than anywhere else in the region and throughout Italy [37, 38]. This zone covers several municipalities in the center of the island and extends to the south of Nuoro province, where male mortality from cardiovascular diseases and cancer is especially low [39]. The study of populations genetically isolated due to cultural and historical reasons, origin and demographic parameters is considered the optimal method for analyzing and mapping interrelated multifactorial traits [40]. The situation observed in Sardinia attracted the attention of researchers to the larger Italian island, Sicily. First, they wanted to identify geographical zones homogeneous with respect to low mortality of men and women over 80 years of age, and to study the region-specific causes of mortality of older people. Secondly, to compare Sicily and Sardinia in order to identify analogies and find the reasons for such longevity. The scientists chose time periods from 1981 to 1990 and from 1991 to 2001 as reference periods. According to the 2001 census, at that time Sicily was divided into 390, and Sardinia into 377 municipalities. The 386 and 363 municipalities selected for the study, respectively, had similar characteristics from a geographical point of view at the time of the beginning of the municipal analysis (1981). According to generally accepted epidemiological rules, municipalities carried out the calculation of standardized mortality rates (SPS) of people over 80 years of age (for total mortality and mortality due to certain causes). When creating geographical maps, the researchers used nuclear functions (kernel density estimators) of nonparametric density estimation. The nuclear density functions are the average values of the ATP calculated as a spatial moving average for several municipalities bordering the municipality in question. The obtained results testified to the existence of an area in Sicily, which is characterized by male (but not female) longevity to the same extent as the famous region of Sardinia (Fig. 1).

Mortality in the municipalities of Sicily – among men (left) and women (right) over 80 years for the period from 1994 to 2001
Mortality rates are indicated by colors from blue (lowest) to red (highest).
Mortality among women in the "blue" zones is higher than the average for Italy.

Both areas under consideration are sparsely populated, occupy a small area and do not have polluted areas. Thus, the authors concluded that longevity is typical for men living in small towns in ecologically clean areas and, most likely, is due to certain working conditions and lifestyle, including limited alcohol and tobacco use, as well as nutrition according to the principles of the so-called "Mediterranean diet". Accordingly, both regions (both in Sicily and Sardinia) are characterized by low mortality from cancer and cardiovascular diseases [Caselli & Lipsi, unpublished observations]. Apparently, longevity is less characteristic for women due to slightly different living and working conditions, as well as a lower level of education, which results in less access to disease prevention and medical facilities. The reason that longevity is typical for residents of small settlements has been known for quite a long time – this is the best state of health of elderly people who have strong social support from the family, which is especially typical for families with adult daughters.

Final comments

In conclusion, it should be noted that aging should be considered as an inevitable stage in the life of each individual, but the emergence of new information about the mechanisms of aging allows us to work out various strategies to slow down the aging process. Thus, a better understanding of the pathophysiology of aging and associated diseases is necessary to ensure that all people have a real chance to live a long and disease-free final stage of life.

For the list of references to the article, see a separate file.

Translated by Evgenia Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru

18.01.2010