Genetics of Healthy Aging in Europe

Abstract

The aim of the 5-year European Union (EU)-Integrated Project GEnetics of Healthy Aging (GEHA), constituted by 25 partners (24 from Europe plus the Beijing Genomics Institute from China), is to identify genes involved in healthy aging and longevity, which allow individuals to survive to advanced old age in good cognitive and physical function and in the absence of major age-related diseases. To achieve this aim a coherent, tightly integrated program of research that unites demographers, geriatricians, geneticists, genetic epidemiologists, molecular biologists, bioinfomaticians, and statisticians has been set up. The working plan is to: (a) collect DNA and information on the health status from an unprecedented number of long-lived 90+ sibpairs (n = 2650) and of younger ethnically matched controls (n = 2650) from 11 European countries; (b) perform a genome-wide linkage scannning in all the sibpairs (a total of 5300 individuals); this investigation will be followed by linkage disequilibrium mapping (LD mapping) of the candidate chromosomal regions; (c) study in cases (i.e., the 2650 probands of the sibpairs) and controls (2650 younger people), genomic regions (chromosome 4, D4S1564, chromosome 11, 11.p15.5) which were identified in previous studies as possible candidates to harbor longevity genes; (d) genotype all recruited subjects for apoE polymorphisms; and (e) genotype all recruited subjects for inherited as well as epigenetic variability of the mitochondrial DNA (mtDNA). The genetic analysis will be performed by 9 high-throughput platforms, within the framework of centralized databases for phenotypic, genetic, and mtDNA data. Additional advanced approaches (bioinformatics, advanced statistics, mathematical modeling, functional genomics and proteomics, molecular biology, molecular genetics) are envisaged to identify the gene variant(s) of interest. The experimental design will also allow (a) to identify gender-specific genes involved in healthy aging and longevity in women and men stratified for ethnic and geographic origin and apoE genotype; (b) to perform a longitudinal survival study to assess the impact of the identified genetic loci on 90+ people mortality; and (c) to develop mathematical and statistical models capable of combining genetic data with demographic characteristics, health status, socioeconomic factors, lifestyle habits.

Remodelling of biological parameters during human ageing: evidence for complex regulation in longevity and in type 2 diabetes

“…These results also confirmed that the imbalance between inflammatory and anti-inflammatory networks result in low-grade chronic pro-inflammation, 'inflammaging' which is mainly due to a genetic predisposition (Franceschi et al 2007a, b;Franceschi 2007;. Interestingly, a recent meta-analysis of age-related gene expression profiles revealed several common signatures of ageing, including overexpression of inflammation and immune response genes and an underexpression of genes associated with lipid and glucose metabolism (de Magalhães et al 2009a, b).…”

“…These indices are not fixed for the entire life course but change over ageing, suggesting that the determinants of exceptional survival could have 'age-trajectories' rather than fixed values (Yashin et al 2009). It is now becoming evident that while genetic differences contribute modestly to life expectancy before the age of 60 years, their impact on survival becomes more prominent at the extreme ages (Franceschi et al 2007a, b;Gögele et al 2011).…”

Aging of the Immune System as a Prognostic Factor for Human Longevity

“…Inflamm-aging is the end result of such a process characterized by activation of macrophages and expansion of specific clones (megaclones) of T lymphocytes directed toward antigens of common viruses such as cytomegalovirus (CMV) or Epstein-Barr virus (EBV) (FIGURE 1; Refs. 31,49,81,85,116). All these phenomena have a strong genetic component, as shown by studies in old people and centenarians, which collectively established that the frequency of several variants (polymorphisms) of important genes involved in immune responses and inflammation are present at a different frequency in long-lived people compared with young subjects (FIGURE 1; Refs.…”

Does the longevity of one or both parents influence the health status of their offspring?

“…Longevity is known to have a strong familial (and genetic) component (De Benedictis and Franceschi, 2006;Franceschi et al, 2007a) and recent studies suggest that the offspring of centenarians have a significant survival advantage, a higher probability to become longlived and a lower risk of age-related diseases, such as cardio-and cerebro-vascular diseases, compared to control subjects (Adams et al, 2008;Atzmon et al, 2004;Perls et al, 2002;Terry et al, 2003Terry et al, , 2004a. At the same time, the study of the offspring of centenarians reduces or resolves the disadvantages related to research on centenarians themselves.…”