Sci. Aging Knowl. Environ., 28 June 2006
Vol. 2006, Issue 10, p. pe20
[DOI: 10.1126/sageke.2006.10.pe20]


The Unusual Genetics of Human Longevity

Giovanna De Benedictis, and Claudio Franceschi

The authors are in the Department of Cell Biology at the University of Calabria, Rende, Italy (G.D.B.), the Interdepartmental Center "L. Galvani" at the University of Bologna, Bologna, Italy (C.F.), and the Department of Gerontological Research, INRCA, Ancona, Italy (C.F.). E-mail: g.debenedictis{at} (G.D.B.)

Key Words: centenarians • human longevity • complex trait • genetic demographic approaches • antagonistic pleiotropy • complex allele timing • mitochondrial genome • homozygosity

Human Longevity as a Unique Source of Information

Longevity, the capability to survive beyond the species-specific average age of death, can be observed in all creatures. Experts agree that longevity is a complex trait, controlled by the classical three components that modulate multifactorial phenotypes: genes, environment, and chance. However, in humans, social and cultural habits also contribute to this trait. In fact, history in the broadest sense of the word (encompassing all events that happened in the past), deeply affects the probability of achieving longevity by acting at both the individual and population levels. Therefore, to disentangle human longevity, the above three components must be revisited under a perspective that takes into account the peculiarities of this trait in humans.

The study of human longevity, however, may also provide general insights that can be applied to other species. In all cases, the biological question is: What are the forces that let an organism survive beyond its reproductive age? To answer this basic question, the model of centenarians may give information that no other experimental model can provide. First, unlike model organisms, centenarians represent the longevity phenotype naturally occurring in an outbred species. Second, the entire life of a centenarian has taken place in an environment that continuously pushed the organism to cope with intrinsic and extrinsic antigenic loads, in contrast to the environment of a typical lab organism. Third, no other organism has experienced the rapid changes in hygiene, disease prevention, technology, and other areas as those that occurred to human populations in the last century, chiefly in developed countries. Therefore, the model of centenarians is not simply an additional model with respect to well-studied organisms such as yeast, worms, flies, and mice, but also provides unique insights into the complex network of biological and nonbiological factors that guide individual survival at old age.

In this Perspective, we will focus on the peculiar genetics of centenarians, with the objective of shaping a picture of the gene pool of these individuals who survived such a long time after the end of the reproductive life. Then we will deal with the core question: What does the gene pool of centenarians tells us about "longevity genes"?

The Centenarian Phenotype: The Impact of Geography and Demography

A useful rule when tackling the genetics of a complex trait such as longevity is to consider an extreme phenotype. From this perspective, centenarians are a good choice, because they represent the survival tail of the population. People who today celebrate their 100th birthdays escaped neonatal mortality, pre-antibiotic era illnesses, and fatal outcomes of age-related complex diseases. However, two points must be underscored when centenarians are considered as representatives of the longevity phenotype: (i) the possible role played by the genetic structure of a given population on longevity and (ii) the impact of demographic changes on longevity.

The impact of geography

Longevity likely results from a myriad of susceptibility factors, both biological (allelic variants) and nonbiological (environmental and stochastic factors). Therefore, assuming the existence of major genes that determine longevity in humans--as observed in model organisms (1, 2) (see Warner Subfield History)--may be an over-simplification. 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 (3).

One piece of evidence for a role played on the longevity trait by population-specific genetic factors is given by the observation that the male/female (M/F) ratio in centenarians differs among countries whose populations have different gene pools. For example, the M/F ratio increases from northern to southern Europe; it varies from 1:4 to 1:7 in northern European countries (1:6 in northern Italy) (4) to 1:2 to 1:1 in southern Italy (5) and in some areas of Sardinia island, Italy (6). The causes of such geographic gradients are not known, but two observations suggest that genetic variability might contribute: (i) a map of the genetic variability in the Italian population obtained by principal component analysis (a form of statistical analysis that can reveal patterns in complicated data sets) overlaps well with the M/F ratio in centenarians (7) and (ii) in Sardinia, centenarians are clustered in restricted areas characterized by a high level of geographic isolation and endogamy (inbreeding), suggesting that each cluster might have a distinct genetic makeup, and the centenarian M/F ratio varies among these areas (6). These findings suggest that different susceptibility genes underlie the longevity phenotype in genetically different populations. The consequences are crucial as regards replication studies--that is, studies that aim to confirm the associations between genetic loci and traits found in one population in another.

Let us consider two parallel studies that we carried out in Italy and Denmark. First, by analyzing a large sample of southern Italians, we found that genotypes homozygous for a particular genetic marker--short alleles (fewer than 35 repeats) of the 3'APOB-VNTR polymorphism--are quite common in people who are about 40 to 60 years old but rare in centenarians, suggesting that such genotypes do not favor longevity (8). When we replicated the study in a Danish sample, we did not find this correlation (9). Interestingly, we also found that the short alleles are significantly associated with low concentrations of serum cholesterol in the Italian population, and this finding could explain their negative effect at the oldest ages: Because cholesterol naturally declines in very old people, further decreases could be harmful (10). Cholesterol metabolism involves a number of genes, whose variability in the gene pool is probably different between Italy and Denmark. Therefore, the contrasting results obtained in Italian and Danish samples could be explained by different gene pools shaped by different histories, climates, and diets (see "Greasing Aging's Downward Slide" and "Centenarian Advantage" for further discussion of centenarians and cholesterol metabolism).

The impact of geography in replication studies may be even stronger if we consider the heavy effect played by nonbiological factors on the probability of attaining longevity. For example, we recently found that, in the elderly, the hand-grip strength (an important marker of physiological aging) decreases significantly from northern to southern Europe (11), roughly according to the socioeconomic level of the country. The consequence is that, from a genetic point of view, centenarians across Europe should be considered phenocopies who display the same phenotype (longevity) but who have received different gene/environment contributions. In fact, the genetic contribution to the longevity phenotype could vary according to nonbiological factors; if so, the poor quality of aging in southern Europe suggests that a better genetic makeup is required to attain longevity in this area than in northern Europe.

In summary, longevity can be achieved by different routes, resulting from different combinations of genes, environment, and chance that vary quantitatively and qualitatively in different geographic areas. Although well established rules require that positive results must be replicated before concluding that a certain gene is associated with a complex trait, we wonder whether replication can reasonably be expected for longevity in light of the above considerations.

The impact of demography

Databases exist for exploring the demography of the oldest old people, including centenarians, and these are precious: for example, the Kannisto-Tatcher Database on the Oldest Old (Max Planck Institute for Demographic Research, Germany), the Human Mortality Database, and the Danish Centenarian Register (University of Odense, Denmark), which collects historical data on centenarians from Nordic countries back to the 1700s. From these information sources, it is clear that the number of centenarians has greatly increased in recent decades. The causes of this proliferation of centenarians is not known, but it is reasonable to assume that a sustained application of resources and knowledge about public health and mortality reduction have played major roles. The impact of nonbiological factors on survival at old age further confounds the identification of genes that contribute to such history-dependent changes in longevity. Such changes may be a major source of false positive associations that are pursued when the gene pool of centenarians is compared with that of younger cohorts. Researchers have recently attempted to overcome this problem by creating algorithms that add demographic information to gene data; this practice aims at estimating the association between gene variants and survival/mortality parameters without generating bias due to cohort effects (the variation in longevity caused by different social and environmental factors experienced by distinct birth cohorts) (12-14).

The most intriguing finding revealed by genetic demographic (GD) approaches is the discovery that the composition of the gene pool in terms of allele frequencies changes in the aging population according to nonmonotonous trajectories. An example is provided by recent data we obtained by applying a GD approach to a large data set relevant to APOE and HSP70.1 (heat shock protein 70.1) gene variability (15). In both cases, we found that, at a certain age, the survival curve of carriers of a specific allele crosses with the survival curve of non carriers, thus implying that a given allele is beneficial at younger ages and detrimental when people get older (or vice versa). Such unusual patterns can be interpreted in several ways: Perhaps, for example, the environmental changes that people encounter have a positive or negative impact depending on an individual's age. However, when functional studies are correlated with age-related variations of the gene pool (16, 17) some clues suggest that the same allele has different effects on health and survival depending on the physiological state of the organism, which changes with increasing age. In other words, an age-related remodeling of a number of physiological parameters may change the effect of a susceptibility allele on health and survival (18). We define such a phenomenon as "complex timing" of the alleles involved in longevity.

The Complex Timing of Alleles Involved in Longevity

The physiological changes that characterize the bodies of old people probably result from adaptive strategies at the molecular and cellular levels, aimed at compensating for damage that accrued over time. In such an adaptive process, the cell microenvironment plays a pivotal role. Recent studies provide evidence of rejuvenation of aged progenitor cells by exposure to a young systemic environment (19) and suggest that even very old stem cells may be capable of maintaining and repairing aged tissues if provided with optimal environmental features (20) (see "Buddy System"). These recent findings fit with our previous observations that hematopoietic progenitor cells (CD34+ cells) present in the peripheral blood of centenarians, although decreased in absolute number, are capable of forming erythroid, granulocyte-macrophagic, and mixed colonies that are indistinguishable from those of young subjects in terms of number, size, and morphology, when exposed in vitro to optimal concentrations of hemopoietic cytokines. Thus, factors controlling the in vivo concentration of these cytokines, rather than the hematopoietic potential of the progenitor cells themselves, appear to undergo a complex age-associated remodeling (21).

On the whole, such studies highlight the importance of the cell microenvironment in modulating gene expression pathways during an individual's life span, in a continuous interplay among deterministic (alleles), stochastic (somatic mutations), and extrinsic factors. Therefore, the assumption that a given allele has the same biological effect(s) in the body (internal environment) of young, adult, old, and very old people is simplistic. On the contrary, we expect that the same allele changes its adaptive significance according to cell microenvironments that characterize the various ages of life. The first evidence in support of such "complex allele timing" was obtained by studies showing that alleles associated with a high risk for complex diseases in middle-aged and younger old people were overrepresented in the centenarians' gene pool (22-26). The complex allele timing concept provides an explanation for this seemingly paradoxical result as well as for the crossing of the survival curves shown by the GD approach discussed above.

The importance of physiological remodeling in modulating the chance of survival at old age should be revisited and reevaluateded in the light of this idea. The most important consequence of this complex game played by genes, chance, and time is that genetic risk factors are age specific and that the physiology of centenarians may be profoundly different from that of the younger elderly. This phenomenon may have important consequences with regard to social and medical strategies aimed at improving the quality of life in a segment of the population that is expected to increase dramatically in the future.

Remodeling versus Antagonist Pleiotropy?

From a genetic point of view, the crossing of survival curves observed for some alleles by the GD approach can be explained by both the antagonistic pleiotropy theory and the complex allele timing (remodeling) theory. What is the conceptual difference between the two theories? They differ in their starting assumptions. The antagonistic pleiotropy theory [first proposed by Williams in 1957 (27); see Williams Classic Paper and "Aging Research Grows Up"] assumes that the same allele acts not only on the probability of survival but also on an antagonistic trait, the best candidate being fertility. Thus, an allele that favors high fertility early in life might also inhibit survival later in life. The remodeling theory assumes that the same allele has different effects on the probability of survival according to time-related factors that modify gene expression, and therefore cell microenvironment, and again gene expression, in a circular game whose outcome is the probability of survival. In this model, the alleles in question do not necessarily affect the expression of distinct traits, such as fecundity, that are antagonistic to survival. Of course, the two theories are not mutually exclusive and both mechanisms could coexist in the organism. Evidence in favor of the antagonistic pleiotropy theory is quite strong in model organisms (28, 29) (see "Paying the Price") but weaker in humans (30-32). A surprising piece of evidence in favor of the remodeling theory could be provided by the high level of homozygosity that is observed in the centenarian gene pool.

Increased Homozygosity and Longevity

Evidence of a negative correlation between population heterozygosity and human longevity was first furnished by Altukhov and Sheremet'eva (33). Studies in centenarians confirmed this result: By using a technique that detects interindividual differences in the genomic regions flanked by Alu repetitive sequences (interAlu fingerprinting), a positive correlation was observed between homozygosity and life span (34). Thereafter, one of these anonymous polymorphisms was identified as a (TG)n microsatellite in the YTHDF2 gene in one of the chromosomal regions with the highest density (more than 40%) of Alus, in 1p35. We confirmed an increased homozygosity at this locus in additional samples of centenarians and a concomitant increased frequency of the most common allele, with respect to younger controls (35). In addition, screening our data set on 10 autosomal loci in individuals aged from 20 to more than 100 years of age confirmed the age-related trend toward increased homozygosity for the majority of the genes considered (36).

On the whole, these findings indicate that increased homozygosity can occur in the subgroup of people selected for late survival, but the extension and the mechanism(s) of the specific advantage conferred by such an unpredicted genetic situation are far from being clear at present. In any case, the increased homozygosity observed in centenarians is in line with the remodeling model discussed above. We speculate that, at old ages, survival selection will favor people who carry two alleles that are equal at keeping pace with the complex allele timing discussed above. From this perspective, centenarians are the best adapted rather than the most robust individuals. A logical consequence of the considerations above is that the time has come to search for "adaptive genes" rather than "longevity genes." In this scenario, obtaining concordant results (through replication studies) in different populations becomes difficult, because the adaptive process may depend on the individual's entire genome. We believe, however, that there is a major locus in such a game: the mitochondrial genome.

Longevity and the Two Genomes

Increasing amounts of data are supporting the role of the mitochondrial genome on complex traits, including longevity (37) (see "Century Mark"), likely through its interaction with the nuclear genome (38). The strongest experimental evidence that the genomes interact in modulating complex traits is provided by an elegant experiment carried out by Roubertoux and co-workers (39). Using sex-specific backcrossing, the authors developed a quartet of mouse strains, consisting of two original strains plus two strains in which the mitochondrial DNA (mtDNA) of one strain was replaced with the mtDNA of the other. This approach allowed the authors to cross-check the interaction of the mtDNA of each strain with the reciprocal nuclear DNA (nDNA). They demonstrated that a variety of cognitive skills (learning, exploration, and sensory) as well as brain development and anatomy were deeply affected by the interaction between the two genomes; the effect was particularly evident in aged mice. This is so far the most convincing evidence in vivo that mtDNA inherited variability can modulate complex biological functions and parameters and that aging enhances the physiological effects of this interaction. As for longevity, only data on insects are available. A recent study in Drosophila showed important epistatic interactions between mtDNA and nDNA on longevity, which were more evident in interspecific introgression lines (specifically, Drosophila melanogaster lines carrying D. simulans mtDNA) than in intraspecific lines (40). The quantitative effect exerted by mtDNA variability on longevity might be highly dependent on all possible important interactions with nuclear allelic variants. Gene variants on X chromosomes could play a stronger role owing to their cotransmission with mtDNA (41) (see Rand Review).

Intriguing statistical evidence indicates that interactions between mtDNA and nDNA variability also occur in humans and emerge in very old people (42, 43). These findings can be interpreted within the more general framework of an ancestral mtDNA/nDNA cross-talk impinging on aging and longevity. A finely tuned, nuclear-mediated regulation of mitochondrial activity requires that the nucleus is constantly informed about the functional status of mitochondria in a classical feed-back loop fashion. Thus, a crucial component of cell signaling travels from the mitochondria to the nucleus (44). In fact, by using a cybrid model (which contains nuclei derived from one cell and mitochondria from another), we recently demonstrated that the expression of genes encoding cytokine and cytokine receptors is modulated by common variations in mtDNA (45). Whether such a phenomenon is restricted to stress responder genes in cancer cells (as those we used to assemble the cybrid lines) requires further investigation. In any case, to our knowledge, this is the first piece of experimental evidence that mtDNA neutral polymorphisms in human cells are able to modulate expression profiles of nuclear genes.

Concluding Remarks

The study of human longevity is a good example of both basic and applied research: basic research, because from these studies new paradigms can be formulated (for example, the concept of complex allele timing); applied research, because the dramatic extension of life span in developed countries requires a tremendous effort to improve the quality of life of older people, which make up a growing segment of population. From this perspective, the model of centenarians is a precious tool for answering a number of unsolved questions, as it represents an extreme phenotype of a "wild" species spanning its life in a environment that changes with considerable speed. The impact of cultural factors on longevity represents a further challenge for disentangling the complexity of the trait. Suitable strategies should be adopted to tackle the challenge. Toward that end, researchers should (i) adopt rigorous criteria in planning experimental designs, (ii) join the efforts of others who are studying centenarians of different populations to obtain a global, planetary perspective, and (iii) look at human longevity without forgetting the lessons from model organisms.

June 28, 2006
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  46. The authors acknowledge support from GEHA (Genetics of Healthy Ageing), European Union grant LSHM-CT-2004-503270.
Citation: G. De Benedictis, C. Franceschi, The Unusual Genetics of Human Longevity. Sci. Aging Knowl. Environ. 2006 (10), pe20 (2006).

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