Narrow Results

At the onset of post-implantation embryonic development, the specification of human primordial germ cells (hPGCs) marks the preparation to attain the totipotent state through the extraordinary features of extensive epigenetic reprogramming (in terms of DNA demethylation and chromatin reorganization), a mitochondrial bottleneck, and a characteristic gene regulatory network, which are in stark contrast with those of the somatic lineage. Together, they provide for the attribute of immortality to the germ cell lineage, reflecting their significance in transgenerational inheritance. Interestingly, these features are the antithesis of the several hallmark phenotypes of aging, which gradually accumulate in the somatic lineage over time. In this chapter, we discuss the salient features of hPGC development, the hallmarks of aging, the application of cellular reprogramming as a therapeutic route to rejuvenation, and the intriguing translational potential of the lessons learned from the immortal human germline lineage in the field of anti-aging research.

The effects of superoxide dismutase on aging were tested using two differt experimental approaches. In the first, replicated populations with postponed aging were compared with their controls for frequencies of electrophoretic alleles at the SOD locus. Populations with postponed aging had consistently greater frequencies of the allele coding for more active SOD protein. This allele was not part of a segregating inversion polymorphism. The second experimental approach was the extraction of SOD alleles from different natural populations followed by the construction of different SOD genotypes on hybrid genetic backgrounds. This procedure did not uncover any statistical effect of SOD genotype on longevity or fecundity. There were large effects on longevity and fecundity due to the family from which a particular SOD genotype was derived. To detect the effects of SOD genotypes on longevity with high probability would require a ten-fold increase in the number of families used.

Five populations of Drosophila melanogaster that had been selected for postponed aging were compared with five control populations using two-dimensional protein gel electrophoresis. The goals of the study were to identify specific proteins associated with postponed aging and to survey the population genetics of the response to selection. A total of 321 proteins were resolvable per population; these proteins were scored according to their intensity. The resulting data were analyzed using resampling, combinatoric, and maximum parsimony methods. The analysis indicated that the populations with postponed aging were different from their controls with respect to specific proteins and with respect to the variation between populations. The populations selected for postponed aging were more heterogeneous between populations than were the control populations. Maximum parsimony trees separate the selected populations, as a group, from their controls, thereby exhibiting a homoplastic pattern.

Drosophila melanogaster populations that exhibit constrasting life histories as a result of laboratory selection were compared at several potentially relevant enzyme loci. Selection regimes included postponed reproduction, accelerated development, and intermediate generation time. Each selection regime was represented by fivefold replicated populations maintained for between 50 and 500 generations. For each population, allele frequencies were calculated from frequencies of electrophoretically distinguishable allozymes of alcohol dehydrogenase, α-glycerol-3-phosphate dehydrogenase, phosphoglucomutase, and CuZn-superoxide dismutase. Based on allozyme frequency changes consistent across replicate populations, two of the studied loci responded to both selection for postponed reproduction and selection for accelerated development. The responses to contrasting selection regimes were in opposing directions, suggesting antagonistic pleiotropy.

This study used reverse selection on populations of Drosophila melanogaster to test the evolutionary theory of aging, including antagonistic pleiotropy and mutation accumulation, the two non-exclusive population genetic mechanisms of aging. Specifically, reversed demographic selection was imposed on five populations selected for late-life fertility for 83 generations (O_1-5), returning them to an ancestral demographic schedule of 14 days. The five ancestral populations (B_1-5) were assayed each generation to serve as a control for environmental fluctuations over time. Relaxing selection for late-fecundity and imposing selection for early fecundity resulted in a rapid drop in longevity, and an increase in early fecundity, suggesting that longevity and some early life fitness component(s) are subject to antagonistic pleiotropy. As longevity fell, the frequency of the S allele of Pgm also decreased. Starvation resistance fell dramatically in reverse-selected males, and remained unchanged in females, suggesting that different physiological genetic mechanisms control resistance to starvation in the two sexes. Desiccation resistance remained unchanged under reverse demographic selection, implicating mutation accumulation as the primary mechanism for its evolution. Overall, these results provide some support for evolutionary theories of aging.

Typically, a selection response is lost when a selection regime is relaxed or terminated. Some possible explanations for this result are a negative genetic correlation between selected characters and fitness, antagonistic pleiotropy and linkage involving alleles of opposed effect, or a side-effect of relaxed inbreeding. The current study relaxes selection on stocks selected for resistance to starvation and desiccation stress, and the response to relaxed selection is then observed. Contrary to many findings, we found maintenance of the selection response with respect to some characters upon relaxation of the stress selection regime. Specifically, after 35 generations of relaxed selection, longevity, early fecundity, and desiccation resistance have not changed significantly in the relaxed desiccation-selection populations, suggesting that the alleles affecting these characters lack significant antagonistic pleiotropy. Starvation resistance, on the other hand, rose significantly in the relaxed desiccation populations. After 20 generations of relaxed selection, starvation resistance fell dramatically in the relaxed starvation-selection populations relative to their ancestral populations. Longevity, however, has not dropped significantly from that of its ancestral population. When early fecundity in the relaxed starvation-selection populations is analyzed separately at each generation, there is a significant increase in this character. This increase in early-life fecundity in association with the decrease in starvation resistance may reflect antagonistic pleiotropy between these two characters in the relaxed starvation resistance system.

The role of development in the evolution of postponed senescence is poorly understood despite the existence of a major gerontological theory connecting developmental rate to aging. We investigate the role of developmental rate in the laboratory evolution of aging using 24 distinct populations of Drosophila melanogaster. We have found a significant difference between the larval developmental rates of our Drosophila stocks selected for early (B) and late-life (O) fertility. This larval developmental time difference of approximately 12% (O > B) has been stable for at least 5 yr, occurs under a wide variety of rearing conditions, responds to reverse selection, and is shown for two other O-like selection treatments. Emerging adults from lines with different larval developmental rates show no significant differences in weight at emergence, thorax length, or starvation resistance. Long-developing lines (O, CO, and CB) have greater survivorship from egg to pupa and from pupa to adult, with and without strong larval competition. Crosses between slower developing populations, and a variety of other lines of evidence, indicate that neither mutation accumulation nor inbreeding depression are responsible for the extended development of our late-reproduced selection treatments. These results stand in striking contrast to other recent studies. We argue that inbreeding depression and inadvertent direct selection in other laboratories' culture regimes explain their results. We demonstrate antagonistic pleiotropy between developmental rate and preadult viability. The absence of any correlation between longevity and developmental time in our stocks refutes the developmental theory of aging.

Laboratory natural selection for rapid development and extremely early reproduction in Drosophila melanogaster was applied to ten independent populations from a known stock phylogeny. These populations, designated ACB and ACO, were contrasted with ten ancestor/ control populations (CB and CO) and five long-established baseline (B) populations. After 100 generations of selection, these “accelerated” populations had evolved a total generation time of under eight days, compared with 12 days in their controls. Reduced pre-adult viability and pupation height were previously reported as costs of rapid development. Here we report that these populations also evolved substantially reduced body size (as measured by thorax length and dry weight), reduced early- and late-life female fecundity, reduced starvation resistance, and reduced longevity, while gaining only in the age of peak fecundity. These results suggest the strong and pervasive negative influence of selection for fast development and early fertility on fitness components expressed later in life. This syndrome of effects illuminates the direct connection of the preadult and adult stages through energetic trade-offs. We also discuss the potential role of antagonistic pleiotropy and mutation accumulation in the evolution of senescence in these populations, and the difficulty of dissecting the role of aging from the direct impact of miniaturization observed in the accelerated populations.

The following sections are included:

• Summary

• The Aging Process in Mice

• Mouse Models of Longevity

• Murine Reverse Genetics and Aging Research

• The p66^shcA Protein

• The Ablation of p66^ShcA Increases Lifespan in Mice

• Mammalian Aging Inducer Genes

• Conclusions

• References

The following sections are included:

• Summary

• The Role of Oxidative Stress in Aging

• Reducing Oxidative Stress — Lowering Exposure to Environmental Oxidants

• Reducing Oxidative Stress — Lower the In Vivo Generation of Oxidative Free Radicals

• Reducing Oxidative Stress — Increase the In Vivo Levels of Antioxidant Defenses

• Clinical Trials on Nutritional Supplements that May Reduce Oxidative Stress

• Extending Lifespan by Lowering Insulin and Glucose Levels

• Dietary Changes and Nutritional Supplements that Counteract

• Age-Related Diseases

• Conclusions

• References