Cause and effect human life in gentics influence

The heritability of longevity appears to be low, as it aggregates in families rather than segregating. Genes implicated in longevity probably affect responses to life-threatening factors, rather than directly regulating maximum life span as a distinct trait. Compensatory adaptation is an important factor in aging, involving a long-lasting adaptation in response to a defect in some organic subsystem. Such adaptation leads to a decrease in viability and possibly to irreversible and life-threatening damage associated with aging.

Genetic Polymorphism of Longevity

The seemingly fanciful hope of finding single mutations that confer long life has been realized in the nematode Caenorhabditis elegans. Since the initial discovery of age-1, 10 different gerontogenes—genes involved in life prolongation—have been found (Finch and Tanzi 1997). The life extension displayed by the mutant nematodes may be as much as fivefold in certain double-mutant strains, and it stems at least in part from slower aging. In Drosophila, protocols of selection for delayed fertility have yielded strains with a more-than-twofold-increased life span, but so far no individual gene effect has been identified. Rather, it appears that heritable shifts in MLS depend on the natural variability at hundreds of polymorphic loci. In mammalian species, allometric equations link MLS with brain weight and body weight, allowing the former to be deduced from estimates of the latter traits in fossil specimens. Applied to hominid species, this approach suggests a doubling of the MLS within the past 3 million years along the evolutionary line that leads to modern man. This conclusion may indicate that relatively few genes, in the range of 40–250, are involved in controlling MLS (Cutler 1975). The spectacular recent increase in the mean longevity of human populations has not been accompanied by an increase of MLS, which has remained stable, at 120 years of age, over historically recorded times. A lasting question is whether there exists a polymorphism of MLS in present human populations or only interindividual differences in longevity. In the former case, one might expect to find major-gene effects in centenarians, whereas in the latter case, many genetic variants would contribute to survival through advanced ages.

The impact of apolipoprotein E (APOE) alleles on survival in different pathological contexts has been amply confirmed (Finch and Tanzi 1997). Since causal variants were identified from the outset, these epidemiological data have opened new avenues for probing into molecular mechanisms of cardiovascular and neurodegenerative diseases. Contradictory reports on the human leukocyte antigen (HLA) locus have fueled controversy for >2 decades. A sufficiently large number of long-lived probands has now revealed the influence of three alleles: HLA-DR7, DR11, and DR13 (Ivanova et al. 1998). The first two alleles displayed interactions with sex in their effect on survival, which is most interesting in view of the sex-specific effects on life span of autosomal quantitative-trait loci (QTLs) found in Drosophila (Nuzhdin et al. 1997). The QTLs that affect life span in Drosophila also had age-specific effects on mortality. This is reminiscent of the late-acting (10th decade) effects of HLA-DR alleles on human survival, effects that were missed in previous studies that applied an age cutoff of 80 or 90 years. A study of genetic hemostasis factors in Italian centenarians reported a higher frequency of a variant of the plasminogen activator inhibitor 1 (PAI-1) that has been associated with elevated plasma levels of this protein as well as with heightened risk of myocardial infarction in adults (Mannucci et al. 1997). This finding, like our results on the angiotensin-converting enzyme (ACE) polymorphisms (Schächter et al. 1994), provides a genetic background to the surprising phenotype of hypercoagulability described in centenarians (Mari et al. 1995).

These scattered data should not obscure the fact that association studies aimed at identifying such loci are still in their infancy. However, the four genes so far implicated in longevity, APOE, ACE, HLA-DR, and PAI-1, share common features: (1) they have an impact on intermediary traits, such as plasma levels of a homeostatic protein or immune response, and (2) they display gene-environment interactions in normal adult populations. These are general features of common multifactorial diseases with polygenic effects and environmental components (Sing and Reilly 1993), which should not surprise us, since such diseases are leading causes of death and thus limit life span. Hence, these genes appear to affect longevity by modulating an individual's responses to life-threatening disorders, not by regulating MLS as an intrinsic physiological trait.