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In this paper, we review data of recent literature on the distribution in centenarians of candidate germ-line polymorphisms that likely affect the individual chance to reach the extreme limit of human life. On the basis of previous observations on the immunology, endocrinology and cellular biology of centenarians we focused on genes that regulate immune responses and inflammation (IL-6, IL-1 cluster, IL-10), genes involved in the insulin/IGF-I signalling pathway and genes that counteract oxidative stress (PON1). On the whole, data indicate that polymorphisms of these genes likely contribute to human longevity, in accord with observations emerging from a variety of animal models, and suggest that a common core of master genes and metabolic pathways are responsible for aging and longevity across animal species. Moreover, in the concern of our plan to discover new genetic factors related to longevity, we explored the possibility to by-pass the need of an a-priori choice of candidate genes, extending the search to genes and genomic regions of still unknown function. Alu sequences may be considered as good markers of highly variable and potentially unstable loci in functionally important genomic regions. We extensively screened Alu-rich genomic sites and found a new genomic region associated with longevity.

Cancer rates increase sharply with age in both sexes, and the majority of cases of cancer occur in patients over the age of 65 years. However, the incidence and mortality for cancer level off around 85-90 years of age, followed by a plateau, or even a decline in the last decades of life. Therefore, it seems reasonable to conclude that centenarians are endowed with a peculiar resistance to cancer. Tumor progression is a complex process that depends on interactions between tumor and host cells. One aspect of the host response, the inflammatory response, is of particular interest because it includes the release of proinflammatory cytokines, some of which may promote tumor growth and hence influence survival. Data in the literature reviewed in this paper suggest that some kind of solid tumors are affected by regulatory cytokine genotypes. In particular proinflammatory genotypes characterized by a low IL-10 producer or a high IL-6 producer seem to be associated with a worse clinical outcome. On the other hand, recent evidence has linked IL-10 and IL-6 cytokine polymorphisms to longevity. In fact, those individuals who are genetically predisposed to produce high levels of IL-6 have a reduced capacity to reach the extreme limits of human life, whereas the high IL-10-producer genotype is increased among centenarians. This opposite effect of IL-6 and IL-10 common gene polymorphisms in cancer and longevity is intriguing. These data prompt considerations of the role that antagonistic pleiotropy plays in disease and in longevity. Inflammatory genotypes may be both friends and enemies. In fact, they are an important and necessary part of the normal host responses to pathogens, but the overproduction of inflammatory cytokines might cause immune-inflammatory diseases and eventually death. In fact, our immune system has evolved to control pathogens, so proinflammatory responses are likely to be evolutionarily programmed to resist fatal infections, and a high IL-6 or a low IL-10 production is associated with increased resistance to pathogens. However, decreased level of IL-6 or increased level of IL-10 might better control inflammatory responses and cancer development. These conditions might result in an increased chance of long-life survival in an environment with a reduced antigen (i.e., pathogen) load.

Investigates the frequency of the -1082g→A IL-10 promoter single nucleotide polymorphism (SNP) in a larger cohort of 72 centenarian men, including 25 typed in a previous study, and the interaction of this polymorphism with -308A↠G TNF-α SNP. Conclusion that inflammatory markers predict disability and mortality in elderly cohorts; Suggestion that a persistent inflammatory state is involved in the causal pathway of certain age-related chronic conditions.