LONGEVITY: SELECTION

One way scientists study a phenomenon is that they change it. In the study of aging, organisms with altered longevity are systems of choice for the unraveling of the biological mechanisms controlling aging. Selection is one of the tools that biologists use to alter the characteristics of organisms, from their size to their shape to their physiology. In this context, it is only natural to strive to alter longevity using selection, as a preamble to detailed analysis of the genetic control of longevity.

Design problems

It is one thing to select on coat color in mammals or bristle number in insects, but another to select on a functional character that depends on many distinct biochemical pathways. As dog breeding shows, it is possible to select stringently on relatively arbitrary features, like the color or oiliness of fur. But dog breeding also shows that selection programs that use a small number of breeders run into problems of inbreeding depression : infertility, structural defects, blindness, deafness, and so on. This is not a special problem to the breeding of dogs or even mammals. Breeding insects for increased fecundity using small selected groups usually runs into problems of inbreeding depression, such as inviability, reduced male fertility, and reduced longevity.

A further problem arises when selection breeds for reductions in functional characters. Sexual outbreeding populations carry numerous recessive deleterious alleles at very low frequencies. When there is no deliberate breeding, natural selection keeps these alleles rare, and they play little role in the physiology or development of most organisms in the population. Human populations are good examples of this. There are many human genetic diseases caused by recessive deleterious alleles: cystic fibrosis, Tay-Sach's disease, and so on. But most people do not develop ailments due to such genes. They die instead of commonplace diseases, both contagious and degenerative, that do not depend on such genes. But populations that undergo selection for reductions in functional characters will show rises in the frequencies of alleles that are generally deleterious, alleles that do not play an important role in shaping these characters for most individuals in the population.

For this reason, it is unlikely that selection for reduced longevity or selection using small population sizes will reveal the genetics of longevity in the vast majority of individuals within a population. Thus, for example, the 1920s studies of longevity by Raymond Pearl using Drosophila mutants are of no value for uncovering the genetics of longevity in fruit flies that have not been inbred or mutated. Longevity is not a well-defined character like eye color, which can be analyzed using mutations of large effect or selective screening for pathological extremes. Longevity is not unique in this respect. The same problem applies to such characters as fecundity and developmental speed.

This makes the appropriate experimental design for selection on longevity some type of mass selection for increased longevity. Unfortunately, this experimental design will usually be very difficult to sustain, because it takes a long time to collect longevity data and it has to be done every generation in a selection experiment. Furthermore, if longevity is defined as the age at death, selection requires the collection of progeny from the selected group before that group has actually died. Many of these problems can be overcome by the use of laborious experimental designs, but these are rarely used in selection studies.

Fortunately, there are experimental designs for selection on longevity that evade many of these problems, yet produce healthy animals with greater mean and maximum longevities. We turn to these designs now.

Selection design for postponed aging

Longevity is difficult to select on because it is tied up with the action of natural selection. One way out of this difficulty is to turn it on its head. Since natural selection acts to mold survival automatically, then perhaps it can be used to do the work in selecting on longevity.

This basic strategy is the foundation of most successful schemes to select on longevity. It is implemented in the following way. Natural selection acts powerfully to screen out alleles that reduce survival before the onset of reproduction. The reason for this is simple. If organisms do not survive long enough to reproduce, then the genes that they bear will be eliminated from the population. In the case of organisms with lethal genetic disorders, when those disorders kill before the start of reproduction, the alleles that cause these disorders will be completely eliminated from the population in a single generation. An example of this is Hutchinson-Guilford progeria, a human genetic disease. This is one of the rarest of genetic diseases. Only a few dozen victims are alive at any one time. All of these progerics die before they can reproduce. It is thought that it is caused by a dominant allele, because the disorder does not increase in frequency with inbreeding, unlike disorders caused by recessive alleles. The alleles that causes progeria are eliminated every time they occur, so all cases represent new mutations. Natural selection's stringent elimination of all the victims of this disease reveals its power to maintain high survival before the onset of reproduction.

The key to this selective process is the point at which reproduction occurs. In laboratory populations, culture reproduction usually occurs at an arbitrary age that is convenient for the experimenter. The adults that have reproduced are then usually discarded. But the age at which cultures are reproduced can be changed by altering culture methods. When the age of reproduction is early, natural selection stops working to screen genes affecting survival that have effects at later ages. When the age of reproduction is later, natural selection will screen the genes affecting survival at all ages before the reproduction of the culture. This will take place automatically, without the experimenter having to measure the longevities of individual organisms. This allows selection for increased survival in very large laboratory populations, forestalling the problem of inbreeding.

Selection on Drosophila aging

While there are other organisms that have been subjected to this type of selection, some insects and mice in particular, most of the studies that use natural selection to increase longevity have employed Drosophila melanogaster, the common laboratory fruit fly. Though a handful of experiments of similar design were performed in the period before 1980, none were designed specifically to increase longevity using natural selection. Since 1980, a variety of laboratories have employed the basic method of delaying fruit fly culture reproduction to increase longevity using natural selection.

The most consistent result found in these experiments is an increase in adult longevity, often by more than 50 percent. Another common result has been improvement in stress resistance in flies that live longer, although not all laboratories have found identical results with respect to increased stress resistance. A few laboratories have studied other aspects of the functional biology of longer-lived fruit flies. Such fruit flies appear to conserve water and store calories. There is no general reduction in metabolic rate: longer-lived fruit flies do not appear to "live less, longer." This is a notable contrast with nematode mutants having increased longevity, but decreased metabolic rate. Longer-lived fruit flies also appear to have improved flight stamina, along with increased reproductive performance in mid- and late-life. The general impression that the data give is that longer-lived fruit flies are more robust adults.

There are some controversies, however. The most prominent of these concerns the relationship between early fertility and longevity. In some of the populations selected for increased longevity, early female fecundity has been reduced. But in other populations that have shown increased longevity, early female fecundity has not been reduced. To some extent this disparity has been put into perspective by the experimental demonstration that the correlation between selection for increased longevity and any secondary effect on early reproduction depends on the specific environment in which early fecundity is measured. The same population may show a trade-off between early reproduction and longevity, or an absence of this trade-off, depending on such details as the amount of dietary yeast, the period of egg-laying, and so on. The most reasonable conclusion is that the trade-off between early reproduction and longevity is environment-dependent, rather than universal.

Overall, Drosophila have been successfully selected for increased longevity by manipulating natural selection. These organisms are largely free of inbreeding depression. Another notable feature of these experiments is that they have been extensively replicated, in several laboratories, with multiple selected populations and multiple control populations. This makes them excellent material for further research.

Use of populations with selectively increased longevity

The key to the use of organisms with increased longevity is that they must have slowed or abrogated the normal processes of aging. Organisms with reduced longevity may die because of novel pathologies, unrelated to normal mechanisms of aging. But this problem does not apply to longer-lived organisms. Consistent differences between organisms with increased longevity and closely related, normal-lived, controls must be related in some way to the control of aging.

An important qualification is the term consistent. If one longer-lived population is compared with one control population, then there may be genetic or physiological differences between them that are due solely to genetic drift. This problem can be solved, however, by replication of selected and control populations, since such random differentiation will separate selected populations from each other, as well as differentiating controls from each other. Such differentiation can then be partitioned out using analysis of variance techniques, leaving only the differences between selected and control that are specifically associated with the effects of selection. This method is now routinely used in studies of increased longevity in fruit flies.

An additional qualification is that some changes that are produced by selection for increased longevity may not themselves increase longevity. They could instead be side-effects of the changes that increase longevity. This problem may be resolvable through the use of further selection. For example, one character associated with increased longevity in some fruit fly populations is resistance to dying from total starvation. Additional selection for increased starvation resistance also increases longevity, indicating that starvation resistance is part of a mechanism controlling longevity.

One benefit of the comparison of longerlived with normal organisms is that any kind of character can be studied. In fruit flies, researchers have already studied life-history characters, behavioral performance, organismal physiology, biochemical composition, single-locus genetics, and gene expression. A general pattern is that, while many characters and genes have little association with increased longevity, a moderate number of characters are associated with increased longevity. This shows that selection can indeed be used to reveal the controls on longevity.

Human applications

A common misunderstanding of research that uses selection to increase longevity is that the researchers propose to select on humans as a next step. But this approach is not only unethical, it would also be extremely inefficient. Humans have only a few generations each century, making the prospect of a significant response to selection on human longevity dim within the near future.

A more appropriate approach is to use selection on other animals as a tool to learn about the genetics and physiology of increased longevity, with a view to applying that knowledge to the postponement of human aging using pharmaceutical and other medical approaches. The prospects for such applications are now much greater with the complete sequencing of the human genome as well as the nematode and fruit fly genomes. Nematodes and fruit flies with increased longevity have been created by mutagenesis and selection. Some concerns have been raised about the value of the nematode mutants, but no such concerns apply to selected fruit flies. If genomic research applied to selected Drosophila reveals the specific loci controlling aging in fruit flies, there may well be homologues for those genes in humans. These homologues could be found by analyzing the full genomic sequences of the two species. Such human homologues would then be useful targets for research targeted at the problem of increasing human longevity. In this way, the humble fruit fly could, by way of selection, be of major medical value for increasing human lifespan, even though humans themselves would never be a target of selection.

Michael R. Rose

See also Genetics; Life Span Extension; Pathology of Aging: Animal Models.

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