Elsevier

Experimental Gerontology

Volume 43, Issue 2, February 2008, Pages 53-60
Experimental Gerontology

Mini Review
Human longevity within an evolutionary perspective: The peculiar paradigm of a post-reproductive genetics

https://doi.org/10.1016/j.exger.2007.06.004Get rights and content

Abstract

The data we collected on the genetics of human longevity, mostly resulting from studies on centenarians, indicate that: (1) centenarians and long-living sibpairs are a good choice for the study of human longevity, because they represent an extreme phenotype, i.e., the survival tail of the population who escaped neonatal mortality, pre-antibiotic era illnesses, and fatal outcomes of age-related complex diseases. (2) The model of centenarians is not simply an additional model with respect to well-studied organisms, and the study of humans has revealed characteristics of ageing and longevity (geographical and sex differences, role of antigenic load and inflammation, role of mtDNA variants) which did not emerge from studies in laboratory model systems and organisms. (3) All the phenotypic characteristics of nonagenarians and centenarians fit the hypothesis that ageing is a remodelling process where the body of survivors progressively adapts to internal and external damaging agents they are exposed to during several decades, largely unpredicted by evolution. (4) Such a remodelling process, which can be considered a Darwinian process occurring at the somatic level within the framework of the evolutionary constraints, established by evolution for Homo sapiens as a species, may explain why the same gene polymorphism can have different (beneficial or detrimental) effects at different ages. (5) Geographic and demographic evidence suggest that longevity can be achieved by different combinations of genes, environment, and chance quantitatively and qualitatively different in many geographic areas, and that population-specific genetic factors, play a role on the longevity trait. (6) The concomitant and integrated use of new in silico and high throughput strategies will greatly accelerate the identification of new longevity genes in humans.

Section snippets

The peculiar geography and demography of centenarians

Human populations are characterized by specific gene pools that arise from the particular group’s history in terms of chance (genetic drift) and environment (natural selection). Furthermore, humans are unique in having linked cultural and biological inheritance. Accordingly, human longevity is a very complex trait and its study is quite difficult and still in its infancy. An useful rule when tackling the genetics of a complex trait, such as longevity, is to consider an extreme phenotype. From

Familiarity and genetics play a role in attaining extreme old age in humans: evidence from centenarians and their family members

Actually, an impressive and coherent series of epidemiological data from different populations (White Americans from New England, Mormons from Utah, Ashkenazi Jewish living in USA, Icelanders, Japanese from Okinawa, Netherlanders from Leiden) suggests the presence of a strong familiar and genetic component of human longevity. All these studies demonstrate that parents, siblings and offspring of long-lived subjects have a significant survival advantage and a higher probability to have been or to

The genetics of human longevity and the results of association studies on candidate genes: longevity genes can be population-specific

We recently reviewed the data obtained in our and other laboratories suggesting that polymorphisms of genes involved in immune response/inflammation, response to stressors including oxidative stress, insulin/IGF1 signalling pathway, among others, have a different frequency in centenarians in comparison to younger controls (young and old people) (Franceschi et al., 2005). We also recently reviewed (Salvioli et al., 2006a) the data suggesting that both inherited and somatically-acquired

How to overcome the “cohort effect” and to take advantage from demographic data and the use of different age groups

Most of the above-mentioned limitations are common to other type of association studies on complex traits. Indeed, in the case of association studies on human longevity another limitation is present, i.e., the so called “cohort effect”, due to the unavoidable comparison of people belonging to different cohorts. The cohort effect assumes that the variation in longevity may be caused by different social and environmental factors experienced by distinct birth cohorts. We and others tried to

The rationale of and the working hypothesis behind the association studies in centenarians

Today the available genetic methodologies allow to perform genome-wide association studies with several hundred thousands polymorphisms scanning the entire genome in order to find polymorphisms associated with a defined phenotype without any a priori hypothesis. This was not the case in previous studies performed on a limited number of candidate genes and polymorphisms. It is interesting to remind the theoretical assumptions that led us to focus of the specific genes we have investigated in

Conclusions

In spite of the growing amount of genetic data regarding longevity, genetics can account only for a part of the phenomenon. This is demonstrated by different experimental evidence: (i) syngenic animals have different mortality curves, suggesting the presence of a stochastic component; (ii) many genetic variants considered unfavourable for longevity and associated to an increased risk of disease are found in centenarians with the same frequency observed in the general population (Franceschi et

Acknowledgements

This work has been supported by grants from EU (European Union) 6th FP Project “GEHA – Genetics of Healthy Ageing”, “T-CIA - T-Cells Immunity and Ageing”, EU (fondi strutturali Obiettivo 2), the PRRIITT program of the Emilia-Romagna Region, MIUR (Italian Ministry of University) Programmi di Ricerca di Interesse Nazionale (PRIN) protocol #2003068355_002, Fondo per gli Investimenti della Ricerca di Base (FIRB) protocol #RBNE018AAP and #RBNE018R89 to C.F.; and from Italian Ministry of Health

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