Molecular determinants of human longevity.

Aging can be considered the product of an interaction between genetic, environmental, and lifestyle factors, which in turn influence longevity that varies between and within species. Given the high complexity of the phenomenon, several theories have been proposed providing an insight in the role of genetic and environmental factors in the process of aging. The "disposable soma theory", the most attractive theory, as well as other evolutionary theories state that aging is not only under genetic control and can also be considered a result of the failure of homeostasis. Therefore, although most studies agree that genetics influence longevity in humans, the magnitude of this effect is debated. A study on children of nonagenarians indicated a strong relationship between genetic influences and longevity, as did a study that compared the life span of adopted children with those of their adoptive and biological parents. Nonetheless, studies on twins reared together and twins reared apart indicated a small genetic influence on longevity. In fact, in one study, genetic factors explained no more than 30% of the variance in longevity, and in another study, this variance was even less. However, these studies did not analyze the oldest survivors, nor did they compare the longer-living with the shorter-living subjects. In fact, a strong relationship between genetics and longevity was demonstrated when centenarians were included, suggesting that genetic control of longevity is greatest in the oldest adults. A recent study demonstrated that the siblings of centenarians are three to four times more likely to survive to the 10th decade of life, compared with siblings of noncentenarians. Furthermore, immediate ancestors of Jeanne Calment from France, who died at the age of 123 years, were shown to be 10 times more likely to reach age 80 years than the ancestral cohort. These studies support the concept that longevity is a familial trait likely to be inherited and points to extreme age as the phenotype for an initial approach in identifying chromosomal regions that harbor longevity-assurance genes. Therefore, although the debate of the importance on genetics in determining the reaching of extreme longevity is open, it is mandatory to study the role of genetic determinants of longevity in humans, and several studies have been focused on healthy centenarians. In fact, these exceptionally long-living individuals represent a model-not discussed-of successful aging, having escaped the major age-associated diseases, and with most of them maintaining good cognitive and functional status. When age is plotted against the log of mortality rate, it gives a straight line as the mortality rate increases exponentially with age. However, the log of mortality rate falls below the expected at the ages of 95-100 years, indicating that mortality rate is no longer increasing exponentially in this age group. Although the mortality rate from cancers increases by approximately 10% per decade, it actually decreases after the age of 90 years. Thus, those individuals who have achieved an age of 90 years or older seem to be biologically unique; they have escaped disease-related mortality and get the biological make-up for successful aging. Interestingly, because the ratio of women to men at age 100 is 5 to 1, the female phenotype contributes to longevity independent of other genetic characteristics. Thus, based on biological distinctions, differences in mortality pattern, and the marked decrease in cancer, centenarians are likely to possess the strongest genetic determinants of longevity. The identification of gene variants involved in aging and longevity presents an interesting challenge. The discovery of genetic variations that explain even 5%-10% of the variation in survival to extreme old age could yield important clues about the cellular and biochemical mechanisms that affect the aging process and susceptibility to age-associated diseases. Candidate gene approaches, in which a gene is chosen based on function and the presumption that alteration in its function may affect the phenotype, have met with some success. Nonetheless, the definition of longevity and its associated intermediate phenotypes is still being debated. Furthermore, in the absence of detailed genealogies and prospective data, it is not possible to know definitively which individuals are or will be long-lived, and which are or will not be long-lived. Finally, individuals who died at early ages in accidents or war, or even from diseases resulting from environmental or other genetic factors, may still have harbored longevity-assurance genes. Recently, Richard Miller proposed a classification of longevity genes in different categories; the first one includes genes that cause or accelerate aging, even though it is a point of debate whether or not genetic mutations exist in nature that actually either cause or accelerate aging (e.g., P53 gene, telomerase gene). The second category concerns genes that increase the risk of a specific illness early in life but do not appear to be related to aging (e.g., CF gene and cystic fibrosis), or alternatively, genes that increase the risk of specific illness that resembles some of the consequences of aging. The third category consists of genes that influence or cause age-related diseases (e.g., Alzheimer disease [AD] and apolipoprotein E [APOE] ε{lunate}4 allele). Because variations in these genes are also associated with increased mortality risk, it is likely that centenarians do not have many of these predisposing variations. However, because the frequency of disease alleles is reduced in centenarians versus younger controls selected from the population, the statistical power of an association study between centenarians and subjects with a specific disease should be increased. This should be particularly true when searching for alleles that have a relatively high frequency in the general population. The fourth class includes low-fitness genes that extend maximum life span, probably by slowing down aging, as observed in lower organism mutations. One approach to determining the significance of such genes in humans is to screen for polymorphisms of their human homologs and to determine the allele frequencies among specific human phenotypes such as centenarians and to compare them to ethnically matched younger controls or controls predisposed to premature mortality. The fifth and sixth categories concern, respectively, polymorphic genetic loci that influence the rate of aging, and genes that influence differences in life span among species (e.g., longevity-enabling genes). A useful approach to finding these life span genes may be association studies using centenarian sibships. Families highly clustered for longevity, with five or more centenarian siblings and multiple centenarian cousins, provide the potential opportunity to perform linkage studies, linking the extreme longevity phenotype to a specific gene or genes. The aim of this chapter is to examine in depth the current knowledge of the role of different genetic determinants in modulating aging and in reaching of extreme longevity in humans, with particular interest in centenarian studies. We reviewed studies belonging to the third Miller's class of longevity genes, concerning those genes that influence or cause age-related diseases. First, we focused our attention on genes involved in vascular risk and vascular-related diseases and discussed the evidence that genetic factors, likely to be linked to both vascular disease and AD, may have an additional role in determining human longevity. Second, we reviewed principal findings on genetic factors linked to inflammation (interleukin 6 [IL-6] gene and other cytokine genes) and regulating immune response.