Demography of genotypes: failure of the limited life-span paradigm in Drosophila melanogaster.

Experimental systems that are amenable to genetic manipulation can be used to address fundamental questions about genetic and nongenetic determinants of longevity. Analysis of large cohorts of ten genotypes of Drosophila melanogaster raised under conditions that favored extended survival has revealed variation between genotypes in both the slope and location of age-specific mortality curves. More detailed examination of a single genotype showed that the mortality trajectory was best fit by a two-stage Gompertz model, with no age-specific increase in mortality rates beyond 30 days after emergence. These results are contrary to the limited life-span paradigm, which postulates well-defined, genotype-specific limits on life-span and brief periods of intense and rapidly accelerating mortality rates at the oldest age.

Slowing of age-specific mortality rates in Drosophila melanogaster.

We have studied age-dependent mortality in large cohorts of male and female D. melanogaster from four inbred lines. Average longevity varies substantially between genotypes (broad-sense heritability = 22%). Contrary to the predictions of the Gompertz model, mortality rates tend to decelerate at the most advanced ages. Fitting Gompertz, Weibull, Logistic, and Two-stage Gompertz mortality models to the data, we find that the best fit is obtained with the two-stage model, with exponentially increasing mortality at early ages, and zero or nearly zero increase at older ages. There is little microenvironmental effect from cage to cage. There is a sex-dependent mortality crossover: males and females differ in initial mortality rate and degree of acceleration of mortality rate, but the ordering of the sexes according to mortality parameters depends on genotype. Model fitting can be affected by gaps between deaths in the tail of the survivorship distribution. The observations are inconsistent with the limited life-span paradigm, which predicts sudden and well-defined drops in survivorship and corresponding sharp increases in mortality at advanced ages for large cohorts of genetically identical individuals.

Deceleration of age-specific mortality rates in chromosomal homozygotes and heterozygotes of Drosophila melanogaster.

Age-specific mortality trajectories were estimated in mixed-sex cohorts of D. melanogaster. We studied 22,000 flies that were either second-chromosome homozygotes or heterozygotes with a randomized genetic background. Broad-sense heritabilities for longevity were estimated to be 6% for males and 9% for females. Heterozygotes lived longer than homozygotes on average, but there were exceptions to the usual heterotic pattern; in several crosses parental homozygotes had average life spans as long as that of their F1 heterozygotes. Estimated age-specific mortality rates were found to decelerate at advanced ages in both homozygotes and heterozygotes. The mortality models that best fit the data are the logistic model and the two-stage Gompertz model, both of which produce mortality trajectories that level off at advanced ages. Old-age mortality deceleration is not peculiar to inbred Drosophila.

Genetic basis for remating in Drosophila melanogaster. IV. A chromosome substitution analysis.

Drosophila melanogaster lines previously selected for fast and slow return of female receptivity were subjected to a chromosome substitution analysis. Chromosomal effects on direct response to selection were distinctively different between selection lines derived from two different base populations. All three chromosomes tested affect the trait in the JEFFERS selection lines. In contrast, only chromosome II was found to have a main effect in the COMP selection lines. Significant interactions between chromosome II and the other chromosomes were also found in both of the selection lines. All of the components of virgin fly mating behavior measured were affected by chromosome II.

Genetic basis for remating in Drosophila melanogaster. V. Biometrical and planned comparisons analyses.

Drosophila melanogaster lines previously selected for fast and slow return of female receptivity were crossed to produce 16 lines (2 parental, 2 F1, 4 F2, and 8 backcross lines). Several genetic hypotheses could be tested both through particular planned comparisons among these 16 crosses and with a biometrical analysis. Both analyses identified the difference between the fast and the slow remating speed in these lines as having an autosomal basis. This is in agreement with observations from previous chromosome-substitution analyses. However, the planned comparisons yielded no significant deviations from expectations based on no dominance, no X-chromosomal factors, and no permanent cytoplasmic factors, whereas the biometrical analysis yields the best fit when some of these factors are included.

Genetic basis for remating in Drosophila melanogaster. VI. Recombination analysis.

Drosophila melanogaster lines previously selected for fast and slow return of female receptivity were used for two different recombination analyses. Major loci affecting the difference between the fast and the slow remating speed map to the right arm of chromosome II to the right of welt (wt).

Selection for increased longevity in Drosophila melanogaster: a response to Baret and Lints.

Baret and Lints [Gerontology 1993;39:252-259] have questioned the interpretation of artificial selection experiments for increased longevity in Drosophila. They suggest that such experiments cannot demonstrate the genetic determination of longevity, because line differences in mean longevity are confounded with erratic temporal variations in life span. Using 15,000 flies from selected and control lines developed by Luckinbill and Clare [Heredity 1985;55:9-19], we show here that when lines are tested simultaneously in a carefully controlled environment, they exhibit markedly different average life spans: selected males live 20 days longer than controls, and selected females live 10 days longer. These and other observations leave no doubt about the existence of heritable variation influencing longevity in Drosophila.

Genetic analysis of extended life span in Drosophila melanogaster. I. RAPD screen for genetic divergence between selected and control lines.

Using lines selected for long life by Luckinbil and his co-workers, we screened two selected and two control lines for allelic frequency differences at 1200 randomly chosen RAPD marker loci. Twenty-three marker loci showed frequency differences in excess of 80%, and five were greater than 90%. Age-specific effects of the five most differentiated loci were estimated by collecting complete survival data in segregating backcross populations. Alleles at four of the five marker loci were associated with significant extension of life span in males, while two marker loci had significant effects in females. Eighty percent of the total selection response in males can be explained by the identified QTL's, under the assumption of additivity. The N14+ marker allele accounted for a 12-day life span extension in males, but had little effect in females. Both sex-limited and sex-shared effects were observed. Analysis of age-specific mortality rates suggests that life span extension occurs by a combination of genetic factors that moderate both the level of mortality and the rate at which mortality increases with age.

Genetic variation and aging.

Life span is subject to genetic modification in yeasts, nematodes, fruit flies, mice, humans, and other vertebrates and invertebrates. There are a few single-gene mutants known that extend life span in yeast and nematodes; in other experimental systems the character is treated quantitatively, and generally has a low to moderate heritability. Life span responds to artificial selection in Drosophila and Caenorhabditis. There are many candidate genes presently under investigation, including the anti-oxidizing enzymes and heat-shock proteins. The main evolutionary models of senescence are antagonistic pleiotropy and mutation accumulation, neither of which has substantial experimental support. The incorporation of analytical techniques from demography is playing an increasing role in research on aging.