Genes involved in immune response/inflammation, IGF1/insulin pathway and response to oxidative stress play a major role in the genetics of human longevity: the lesson of centenarians

Abstract

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.

Introduction

Aging is a universal phenomenon that affects nearly all of animal species. It can be considered as the product of an interaction among genetic, environmental and lifestyle factors, which in turn influence longevity, a biological phenomenon which shows a large inter-species as well as inter-individual variability. A variety of models in lower organisms and in mammals demonstrate that genetic mutations in single genes are able to induce a consistent and marked increase of the lifespan. As most of these genetic variations which significantly impact upon longevity, regard a limited number of pathways highly conserved in evolution, and assuming that Homo sapiens did not escape this strong evolutionary perspective, we know for the first time where to focus our attention in order to understand the genetics of human aging and longevity. In order to identify the determinants of human longevity we proposed since several years the model of centenarians, as these rare exceptional individuals represent the best example of successful aging in our species. These studies have shown that centenarians largely escaped most of the major age-related diseases (Bonafè et al., 2001a) and that they are characterized by a complex remodeling of immune responses (Franceschi et al., 2000a), and particularly by a largely conserved or even up-regulated innate immunity, the most ancestral of immune responses (Franceschi et al., 2000b). Indeed, innate immunity is a major component of inflammation, and a chronic, low-grade inflammatory status we proposed to call inflamm-aging (Franceschi et al., 2000c) appears to be a major component of the most common age-related diseases, such as diabetes, osteoporosis and osteoarthritis, dementia, cardiovascular diseases and cancer. Moreover, we showed that glucose utilization is remarkably well conserved and insulin resistance remarkably absent or very low in centenarians suggesting that they are also characterized by a well conserved IGF1/insulin pathway (Paolisso et al., 2001). Finally, data in animal models as well as circumstantial evidences in centenarians suggest that longevity is associated with the capability of cells to cope with a variety of stressors, including oxidative stress (Monti et al., 2000). Within this scenario and taking into account the data emerging from pedigree studies suggesting a significant familial and possibly genetic component of the ability to survive to extreme old age, we and others started a large scale investigation in centenarians on gene polymorphisms related to immune response/inflammation, IGF1/insulin pathway and oxidative stress. Ultimately this research approach should lead to the discovery of genes related to healthy aging and drugs capable of slowing down the aging process and facilitate people's ability to delay and perhaps escape age-associated diseases.