The death spiral: predicting death in Drosophila cohorts.

Drosophila research has identified a new feature of aging that has been called the death spiral. The death spiral is a period prior to death during which there is a decline in life-history characters, such as fecundity, as well as physiological characters. First, we review the data from the Drosophila and medfly literature that suggest the existence of death spirals. Second, we re-analyze five cases with such data from four laboratories using a generalized statistical framework, a re-analysis that strengthens the case for the salience of the death spiral phenomenon. Third, we raise the issue whether death spirals need to be taken into account in the analysis of functional characters over age, in aging research with model species as well as human data.

Predicting death in female Drosophila.

We have previously described a phenomenon called the death spiral that is characterized by a rapid decline in female fecundity 6-15 days prior to death in Drosophila. To carry out destructive physiological analyses of females in the death spiral would require a method to reliably classify individual females via the prediction of their age at death. Using cohorts of Drosophila we describe how to use the observed mortality prior to some target day and a female's fecundity 3 days prior to the target day to determine if the female is in the death spiral. The method works at all ages and although the method does not result in perfect classification, with sufficient sample sizes any physiological trait whose means differ between the groups can be detected.

Interactions between injury, stress resistance, reproduction, and aging in Drosophila melanogaster.

An important aspect of the aging process in Drosophila melanogaster is the natural loss of antennae, legs, bristles, and parts of wings with age. These injuries lead to a loss of hemolymph, which contains water and nutrients. Stress-resistant lines of D. melanogaster are sometimes longer-lived than the populations from which they are derived. One hypothesis tested here is that increased stress-resistance fosters longevity because it allows fruit flies to cope with the loss of hemolymph due to injury to the aging fly. We tested the effects of surgically induced injury on the aging and reproduction of five replicate populations. We then tested the effects of injury on populations that had been selected for different levels of stress resistance and on control populations. Injury affected aging more in males than in females, in part because of a counter-balancing reduction in female reproduction brought about by injury. More specifically, injury reduced female fecundity and male virility. Injury significantly reduced the starvation resistance in some groups of flies, but not in others. These findings undermine any simple interpretation of the interactions between injury, reproduction, and aging based on stress resistance. But they do indicate the existence of significant interactions between these biological processes, interactions that should be resolved in greater mechanistic detail than has been managed here.

Hamilton's forces of natural selection after forty years.

In 1966, William D. Hamilton published a landmark paper in evolutionary biology: "The Moulding of Senescence by Natural Selection." It is now apparent that this article is as important as his better-known 1964 articles on kin selection. Not only did the 1966 article explain aging, it also supplied the basic scaling forces for natural selection over the entire life history. Like the Lorentz transformations of relativistic physics, Hamilton's Forces of Natural Selection provide an overarching framework for understanding the power of natural selection at early ages, the existence of aging, the timing of aging, the cessation of aging, and the timing of the cessation of aging. His twin Forces show that natural selection shapes survival and fecundity in different ways, so their evolution can be somewhat distinct. Hamilton's Forces also define the context in which genetic variation is shaped. The Forces of Natural Selection are readily manipulable using experimental evolution, allowing the deceleration or acceleration of aging, and the shifting of the transition ages between development, aging, and late life. For these reasons, evolutionary research on the demographic features of life history should be referred to as "Hamiltonian."

An evolutionary heterogeneity model of late-life fecundity in Drosophila.

There is now a significant body of research that establishes the deceleration of mortality rates in late life and their ultimate leveling off on a late-life plateau. Natural selection has been offered as one mechanism responsible for these plateaus. The force of natural selection should also exert such effects on female fecundity. We have already developed a model of female fecundity in late life that incorporates the general predictions of the evolutionary model. The original evolutionary model predicts a decline in fecundity from a peak in early life, followed by a plateau with non-zero fecundity in late life. However, in Drosophila there is also a well-defined decline in fecundity among dying flies, here called the "death spiral". This effect produces heterogeneity between dying and non-dying flies. Here a hybrid evolutionary heterogeneity model is developed to accommodate both the evolutionary plateau prediction and the death spiral. It is shown that this evolutionary heterogeneity model gives a much better fit to late-life fecundity data.

A revolution for aging research.

In the year 1992, two publications on age-specific mortality rates revealed a cessation of demographic aging at later ages in very large cohorts of two dipteran species reared under a variety of conditions. Despite some initial concerns about possible artifacts, these findings have now been amply corroborated in the experimental literature. The eventual cessation of aging undermines the credibility of simple Gompertzian aging models based on a protracted acceleration in age-specific mortality during adulthood. The first attempt to explain the apparent cessation of aging was extreme lifelong heterogeneity among groups with respect to frailty. This lifelong heterogeneity theory assumes an underlying Gompertzian aging affecting every member of an adult cohort, with a merely apparent cessation of aging explained in terms of the increasing domination of a slowly aging group among the survivors to late ages. This theory has received several experimental refutations. The second attempt to explain the cessation of aging applied force of natural selection theory. This explanation of the cessation of aging has been corroborated in several Drosophila experiments. In particular, this theory requires that both age-specific survival and age-specific fecundity cease declining in late life, which has now been experimentally established. This theory also predicts that the timing of the cessation of aging should depend on the last age of reproduction in a population's evolutionary history, a prediction that has been corroborated. While lifelong heterogeneity should reduce average age-specific mortality in late life whenever it is pronounced, the cessation of aging in late life can be explained by plateaus in the forces of natural selection whether lifelong heterogeneity is present or not. The discovery that aging ceases is one of the most significant discoveries in recent aging research, with potentially revolutionary scientific implications.

The evolution of late life.

Late life is a distinct phase of life characterized by a cessation in the deterioration of survivorship and fecundity characteristic of normal aging. Several theories have been proposed to explain non-aging at late ages, specifically with regards to late-life mortality-rate plateaus. All such theories must be compatible with formal evolutionary theory and experimental findings. Here, we develop a critique of theories of late life based on evolutionary biology.

Late life: a new frontier for physiology.

Late life is a distinct phase of life that occurs after the aging period and is now known to be general among aging organisms. While aging is characterized by a deterioration in survivorship and fertility, late life is characterized by the cessation of such age-related deterioration. Thus, late life presents a new and interesting area of research not only for evolutionary biology but also for physiology. In this article, we present the theoretical and experimental background to late life, as developed by evolutionary biologists and demographers. We discuss the discovery of late life and the two main theories developed to explain this phase of life: lifelong demographic heterogeneity theory and evolutionary theory based on the force of natural selection. Finally, we suggest topics for future physiological research on late life.

Lifelong heterogeneity in fecundity is insufficient to explain late-life fecundity plateaus in Drosophila melanogaster.

Previous studies have demonstrated that fecundity, like mortality, plateaus at late ages in cohorts of Drosophila melanogaster. Although evolutionary theory can explain the decline and plateau in cohort fecundity at late ages, it is conceivable that lifelong heterogeneity in individual female fecundity is producing these plateaus. For example, consistently more fecund females may die at earlier ages, leaving only females that always laid a low number of eggs preponderant at later ages. We simulated fecundity within a cohort, assuming the two phenotypes described above, and tested these predictions by measuring age of death and age-specific fecundity for individual females from three large cohorts. We statistically tested whether there was enough lifelong heterogeneity in fecundity to produce a late-life plateau by testing whether early female fecundity could predict whether that female would live to lay eggs after the onset of the population fecundity plateau. Our results indicate that heterogeneity in fecundity is not lifelong and thus not likely to cause late-life fecundity plateaus. Because lifelong heterogeneity models for fecundity are based on the same underlying assumptions as heterogeneity models for late-life mortality rates, our test of this hypothesis is also an experimental test of lifelong heterogeneity models of late life generally.

Testing whether male age or high nutrition causes the cessation of reproductive aging in female Drosophila melanogaster populations.

Fecundity seems to stop declining and plateaus at low levels very late in Drosophila melanogaster populations. Here we test whether this apparent cessation of reproductive aging by a population, herein referred to as fecundity plateaus, is robust under various environmental influences: namely, male age and nutrition. The effect of male age on late age fecundity patterns was tested by supplying older females with young males before average population fecundity declined to plateau levels. The second possible environmental influence we tested was nutrition and whether late-life fecundity plateaus arise from a decline in the calories available for reproduction. This hypothesis was tested by comparing average daily female fecundity with both low- and high-lifetime nutrition. Both hypotheses were tested by measuring mid- and late-life fecundity for each cohort under the various environmental influences, and statistically testing whether fecundity stops declining and plateaus at late ages. These experiments demonstrate that mid- and late-life population fecundity patterns are significantly affected by the age of males and nutrition level. However, male age and nutrition level did not affect the existence of late-life fecundity plateaus, which demonstrates the robustness of our earlier findings. These results do not address any issue pertaining to the possible role, if any, of lifelong inter-individual heterogeneity in Drosophila fecundity.

Aging, fertility, and immortality.

Evolutionary theory suggests that fecundity rates will plateau late in life in the same fashion as mortality rates. We demonstrate that late-life plateaus arise for fecundity in Drosophila melanogaster. The result qualitatively fits the evolutionary theory of late life based on the force of natural selection. But there are a number of alternative interpretations. Fecundity plateaus could be secondary consequences of mortality-rate plateaus. Female fecundity plateaus might arise from diminished male sexual function. Another alternative hypothesis is analogous to male sexual inadequacy: nutritional shortfalls. These may arise later in life because of a decline in female feeding or digestion. If some females have a life-long tendency to lay eggs at a faster rate, but die earlier, then aging for fecundity could arise from the progressive loss of the fast-layers, with the late-life plateau simply the laying patterns of individual females who were slow-layers throughout adult life. If this type of model is generally applicable to late life, then we should find that the females who survive to lay at a slow but steady rate in late life have a similar laying pattern in mid-life.

Evolution of late-life mortality in Drosophila melanogaster.

Aging appears to cease at late ages, when mortality rates roughly plateau in large-scale demographic studies. This anomalous plateau in late-life mortality has been explained theoretically in two ways: (1) as a strictly demographic result of heterogeneity in life-long robustness between individuals within cohorts, and (2) as an evolutionary result of the plateau in the force of natural selection after the end of reproduction. Here we test the latter theory using cohorts of Drosophila melanogaster cultured with different ages of reproduction for many generations. We show in two independent comparisons that populations that evolve with early truncation of reproduction exhibit earlier onset of mortality-rate plateaus, in conformity with evolutionary theory. In addition, we test two population genetic mechanisms that may be involved in the evolution of late-life mortality: mutation accumulation and antagonistic pleiotropy. We test mutation accumulation by crossing genetically divergent, yet demographically identical, populations, testing for hybrid vigor between the hybrid and nonhybrid parental populations. We found no difference between the hybrid and nonhybrid populations in late-life mortality rates, a result that does not support mutation accumulation as a genetic mechanism for late-life mortality, assuming mutations act recessively. Finally, we test antagonistic pleiotropy by returning replicate populations to a much earlier age of last reproduction for a short evolutionary time, testing for a rapid indirect response of late-life mortality rates. The positive results from this test support antagonistic pleiotropy as a genetic mechanism for the evolution of late-life mortality. Together these experiments comprise the first corroborations of the evolutionary theory of late-life mortality.