A MODEL FOR ANTAGONISTIC PLEIOTROPIC GENE-ACTION FOR MORTALITY AND ADVANCED AGE

Association or linkage studies involving control and long-lived popula tions provide information on genes that influence longevity. However, the relationship be;tween allele-specific differences in survival and the genetic structure of aging cohorts remains unclear. We model a het erogeneous cohort comprising several genotypes differing in age-specif ic mortality. In its most general form, without any specific assumptio n regarding the shape of mortality curves, the model permits derivatio n of a fundamental property underlying abrupt age-related changes in t he composition of a cohort. The model is applied to sex-specific survi val curves taken from period life tables, and Gompertz-Makeham mortali ty coefficients are calculated for the French population. Then, adjust ments are performed under Gompertz-Makeham mortality functions for thr ee genotypes composing a heterogeneous cohort, under the constraint of fitting the resultant mortality to the real French population mortali ty obtained from life tables. Multimodal curves and divergence after t he 8th decade appear as recurrent features of the frequency trajectori es. Finally, a fit to data previously obtained at the angiotensin-conv erting-enzyme locus is realized, explaining what had seemed to be para doxical results-namely, that the frequency of a genotype known as a ca rdiovascular risk factor was increased in centenarians. Our results he lp explain the well-documented departure from Gompertz-Makeham mortali ty kinetics at older ages. The implications of our model are discussed in the context of known genetic effects on human longevity and age-re lated pathologies. Since antagonistic pleiotropy between early and lat e survival emerges as a general rule, extrapolating the effects measur ed for a gene in a particular age class to other ages could be mislead ing.