I. THEORIES OF AGING AND LIFE EXTENSION

Theory without fact is fantasy, but fact without theory is chaos. C. O. Whitman (1894)

An old adage says that nothing is certain except death and taxes. That is true, but it does not say anything about four score being the absolute measure of a person's years. That is good because knowledge about the biology of aging is changing, and with it people's expectations of what they can do about it. This new knowledge and the likely uses people will make of it will challenge perceptions of what constitutes a full human life as well as force people to rethink the increasing ability to alter aging. However, it is necessary here to define what is being talked about. What exactly do people mean when they talk about aging and senescence, and what is known about how aging comes about?

One goal of the material that follows is to answer the first question briefly in modern biological terms. Another goal is to describe the current understanding of the biological mechanisms that underlie aging. The final goal is to review successful cases of longevity intervention in laboratory animals and discuss their implications for humans. More extensive details and references on these general topics can be found in Arking (1998), Masoro and Austad (2001), and the Science of Aging-Knowledge Environment website.

The twenty-first century is forecast to be "the century of biology." Not only has the genome of many organisms been sequenced, scientific understanding of the way in which a fertilized egg transforms itself into a complex multicellular organism has taken giant strides to the point where developmental biology in the twenty-first century is taught as a complex series of gene-environment interactions. An out-come of these investigations has been the realization that there are few truly different developmental mechanisms. Apparently disparate organisms such as flies and humans use the same basic mechanisms in somewhat different ways. The modular nature of living organisms makes it possible to translate findings obtained with one species (e.g., flies or worms) to another species (e.g., humans). However, the adult that arises from this developmental process goes on to age and senesce and die. Somehow the sophisticated interactions fail to keep working. This seems paradoxical. As the Nobel laureate Francois Jacob wrote, "It is truly amazing that a complex organism, formed through an extraordinarily intricate process of morphogenesis, should be unable to perform the much simpler task of merely maintaining what already exists" (1982, p. 50).

Jacob's paradox contains two different questions. The first is the longtime philosophical poser: Why do people age? The second is the mechanistic consideration: How do people age? In the terminology of Ernest Mayr, the first component addresses the nature of the ultimate processes and the second addresses the details of the proximate mechanisms. Therefore, the answer to Jacob's paradox must be bipartite because the understanding of the mechanistic processes of aging depends crucially on an understanding of the evolutionary rationale for aging.

Definition of Aging

Aging is not a single biological event but a process in which multiple biological events accumulate in different tissues over time. Despite the complexity of this process, a workable operational definition is that "aging is the time-independent series of cumulative, progressive, intrinsic, and deleterious (CPID) functional and structural changes that usually begin to manifest themselves at reproductive maturity and eventually culminate in death" (Arking, p. 12).

Although senescence often is used interchangably with aging, here it will be used to refer specifically to the changes that underlie the loss of biological function that are characteristic of aging. Studies at the cellular level have shown that the inability of cells to continue dividing in vitro is accompanied by substantial alterations in patterns of gene expression. These SAGE (i.e., senescence-associated gene expression) patterns are objective although complex indicators of a phenotype that differs from that of a normal (i.e., "young") cell primarily in its altered repertoire of expressed functions. It is the author's belief that the term senescence soon will gain a more precise meaning as these SAGE patterns are cataloged and those associated with a loss of function are identified. Tissue-specific manifestations of age-related disease, such as congestive heart failure, are being characterized in terms of their own particular SAGE patterns. Aging was defined above as being time-independent, for which there is strong theoretical support, but this has been demonstrated empirically in only a few instances (e.g., Finch). The existence of tissue-specific changes in SAGE patterns supports this concept by providing a mechanism by which functional loss can occur independently of time.

Aging thus should be viewed as being composed of a series of such patterns of gene expression, certain of which when induced by a variety of internal or external stimuli result in (or inhibit) a SAGE cascade, leading to the alteration of cellular and tissue functions. The large differences in life span between mice and humans, for example, can be ascribed in part to the greater efficiency of the cellular anticancer defenses in humans and thus their gene expression patterns, not to the circular observation that mouse cells live "faster" than do human cells. Also, the differences in life spans between individuals in one species, such as humans, can be ascribed to the genetic and contingent factors that collaborate to confer some extraordinary stability (in the case of centenarians) or instability (in the case of premature mortality) of their SAGE patterns. Time is, for a number of technical and conceptual reasons, a poor measure of age; and researchers will likely use SAGE patterns and other biomarkers of aging in the future. The candles on the physiologically correct (P.C.) birthday cakes of the future might be based on gene expression patterns.

The Ultimate Explanation: Evolutionary Considerations

"Nothing in biology makes sense except in the light of evolution." This statement by the well-known geneticist Theodosius Dobzhansky has been verified by the study of aging. The operation of natural selection means that some genetic variants of any population will be more successful (i.e., leave more copies of their genes in the next generation) than will other variants, and the first variant will be favored.

Most known populations are structured by age; that is, the population is composed of individuals of different age classes, each of which represent a different proportion of the population. The high mortality rates resulting from predation, illness, and accidents that are common among wild populations indicate that only a few, if any, individuals live long enough to show signs of aging and senescence. Thus, in any wild population there are many more young breeding adults than old adults, and in each generation the genetic contributions to the next generation come predominantly from young adults. One consequence of this age structure is that deleterious genetic variants that act late in life are not selected against because their carriers probably will have died from environmental hazards before they reach old age or will have survived, but as postreproductive adults. In either case they are invisible to the operations of natural selection. Another consequence is that long-lived genetic variants will not be selected because they are expressed only in those few surviving postreproductive individuals.

From an evolutionary point of view, the "name of the game is to play again"; that is, the whole point of being a reproductive adult is to pass copies of one's genes to the next generation. This is a game that no one can win but anyone can lose simply by not transmitting sufficient copies of his or her genes to the next generation. There is no evolutionary value (i.e., Darwinian fitness) in any trait, including extended longevity, if that trait does not materially assist one in playing the game. There is evolutionary value in living long enough to reproduce, but there usually is no increased fitness associated with living so long that an individual is postreproductive (see Rose for review and references).

However, because people live so long already, why are they not capable of reproducing and living indefinitely or at least much longer than they do now? The answer to this question involves energy. Organisms must channel and apportion their energies into reproductive activities as well as into the maintenance and repair of the soma. Although the energy cost of making an egg or sperm probably stays more or less constant over time and is therefore the same for both young and old, this is not the only energy cost incurred in reproduction. The energy costs of courtship, pregnancy, and child rearing are high and represent a significant investment of energy by an organism. In addition, some energy must be devoted to the repair and maintenance of the soma if an organism is to survive reproduction. It is reasonable to assume that even a well-fed organism has only a limited amount of energy available to it. Thus, the problem facing the organism is how best to allocate its finite metabolic energy to maximize both reproduction and repair.

A theoretical analysis by Kirkwood (1987) showed that increasing the amount of energy expended on somatic repair results in increased survivorship but decreased fecundity, and vice versa. A choice must be made. Reproduction requires less energy than does repair. Therefore, allocating sufficient energy to maximize somatic repair will reduce fecundity and thus decrease an organism's Darwinian fitness. In contrast, increasing fecundity will decrease the energy available for repair and thus probably result in shortened longevity. In most cases decreased fecundity over a longer life span yields fewer copies of an individual's genes in the next generation than does higher fecundity over a shorter lifetime. Thus, fitness is maximized at a repair level lower than that required for indefinite somatic repair. Hence, people die. It is easy to see how this theory came to be known as the disposable soma theory. This process is nothing more than the cost-benefit analysis most people make when faced with the decision whether to continue to invest their hard-earned money in repairs to the old car or invest it in purchasing a new car. At some point the cost of repairs exceeds the cost of purchase, and so the old car is junked and a new one is obtained.

Because modern humans have a very low and culturally controlled rate of reproduction, it is reasonable to question whether the disposable soma theory still applies to human beings. It does, for people evolved under its aegis and the control mechanisms of the body that set fitness and repair levels are not reversed by one or two centuries of nonheritable demographic change. This concept provides a plausible mechanism by which evolution can act and has made people what they are today. Shakespeare foresaw this relationship in Sonnet 12:

When I do count the clock that tells the time,
and see the brave day sunk in hideous night; …
Then of thy beauty do I question make,
That thou among the wastes of time must go, …
And nothing 'gainst Time's scythe can make defence
Save breed, to brave him when he takes thee hence.

Therefore, people age not because of a philosophically satisfying cosmic reason that requires senescence and death but simply because the body's energy allocations are such that failure to repair ensures that there is no reason not to age. This biological conclusion may seem dark:. Who, after all, wants to believe that his or her death serves no larger purpose? The major religions of the world are based on the opposite premise (but see Holliday). Some people, however, find it liberating. Jacob compared embryonic development to adult aging and saw a paradox. What biogerontologists see in the early twenty-first century is the fact that there is no evidence for the existence of a genetically based aging program. People do not have an organismal death program built into their genes. Human beings are not required to age. It follows that if people age only because there is no biological reason for them not to age, this clearly implies that people need not age (or at least not age so quickly) if they can supply their bodies with a relevant biological reason not to age. It is the business of biogerontologists, then, to provide those reasons (de Grey, 2002).

Penultimate Explanations: Mechanisms of Aging

How good are those reasons? The categorization of the reasons leads to the different mechanisms that are known to be involved in the aging process. There are several methods by which one can organize the different theories of aging. None of these systems is fully satisfactory, but the origins of the change and its level of action both appear to be reasonable and logical pegs from which to hang these descriptions. Here a dual classification scheme is employed in which one considers whether the theories suggest that their particular effects are exerted within all or most cells (intracellular theories) or whether they are exerted mostly on the structural components and/or regulatory mechanisms that link groups of different cells (intercellular theories). In addition, the following paragraphs will consider simultaneously whether the effects postulated by each theory are conjectured to take place accidentally (stochastic theories) or are the result of the hierarchical feedback cascades characteristic of the species (systemic theories). Table 1 lists fourteen major theories sorted out by this dual classification scheme, and Table 2 offers a very brief summary of each theory. The highlighted terms in both tables indicate those theories for which the empirical data support their playing a central and important role.

The experimental data also show that certain aging phenomena are observed in almost all species. For example, experimental organisms extend their life spans significantly if those organisms are maintained under a reduced food intake regime but under conditions that maintain good nutrition. This method, called caloric restriction (CR), has worked in almost all species tested. It also is generally accepted that longevity is inversely related to early adult fecundity or reproduction. Elevated resistance to oxidative stress is observed commonly in many longevity mutants.

Interestingly, all these phenomena appear to be interrelated. For example, experimental organisms maintained under CR conditions have higher levels of antioxidant defense system (ADS) activities and lower levels of fecundity compared with controls. In addition, the mild dwarfism noted in CR-raised animals also is observed in mutants screened for longevity. Finally, it has been demonstrated

TABLE 1

that the stimuli used to extend longevity experimentally are not maximally effective (i.e., do not induce a delayed onset of senescence) unless those stimuli are capable of bringing about a particular type of metabolic reorganization and energy economy in the organism. Thus, metabolic profiles, caloric intake, growth, stress resistance, fecundity, and longevity are all empirically intertwined (see Arking et al., 2002a, or Tatar et al., 2003 for references).

This observation is important, for it demonstrates that the theories listed in Tables 1 and 2 are not the discrete entities presented there but involve different facets of the same process. What is needed are much wider and more inclusive theories of the biology of aging that emphasize the interactions between these different components. One such integrative theory addressing the relationships at the organismal level among metabolism, stress resistance, and longevity has been put forth by Arking et al. (2002a). Another integrative theory that addresses the relationships at the cellular level of the roles of DNA damage, cell division, genomic stability, and longevity was put forth by Guarente et al. (2001) and Hasty et al. (2003).

Perhaps the most successful integrative theory that has been propounded is that involving the insulinlike signaling system (ISS) (Braeckman et al.; Tatar et al.). Insulin is a protein hormone that plays a vital role in regulating a cell's response to glucose. Insulin and the subcellular signaling system associated with it are not unique to humans but are widespread in animals, being found even in species in which molecules different from but similar to insulin are used for this purpose. It is an example of the modular organization of living organisms.

This ISS is thought to play a major role in an organism's response to CR because decreasing the intake of calories has the effect of partially repressing the activity of the ISS. If one uses mutations to inactivate components of the ISS and thus bring about a genetically based repression of the ISS, one finds that the mutated flies and worms live long and express a delayed onset of senescence. The molecular basis for the apparent ability of the ISS to bring about a shift in the body's emphasis from growth to repair lies in the fact that the subcellular signaling system controlled by the insulin molecule eventually results in the activation or repression of two diametrically opposed sets of genes. One set includes the ADS genes discussed above, and the other set includes genes that bring about the rapid bodily growth and high reproductive rate of the organism. When the ISS is activated by high amounts of insulin in the blood (as a result of a high-calorie diet), the ADS genes are repressed and the pro-growth genes are activated. When the ISS is repressed because there are low amounts of insulin in the blood (as a result of caloric restriction), the ADS genes are activated and the growth genes are repressed. It seems that the ISS may be one of the body's conserved molecular switches that bring about the change in energy allocations and reproduction predicted by evolutionary theory.

Laboratory Interventions into the Aging Process

An obvious limitation of the laboratory record is that there are few human data: One cannot experiment on humans for both ethical and practical reasons. There are four species of multicellular animals that account for most of the recent research into longevity extension. Two of those "model systems," the mouse and the rat, are mammals commonly used in biomedical research. The other two are invertebrates beloved of geneticists: the fruit fly and the worm. Also, some laboratories focus on the use of in vitro cell cultures with which to investigate the biology of the individual cells of the mammalian organism. Modular organization and common descent ensures that the genes each of these organisms carries are homologous to the genes humans carry and often have similar if not identical functions. For example, some 62 percent of the genes that are recognized to cause human diseases are known to exist in flies and to give rise to similar disorders when mutated. By investigating these model organisms, human beings investigate themselves by proxy.

PATTERNS OF AGING. When people intervene in the aging process, how can they tell if they are successful? Obviously, by extending longevity, but it turns out that there are at least three different manners of extending longevity, and only one of them is likely to be useful (Arking et al., 2002b). Compared with their normal-lived controls, experimental animals can live long by (1) increasing their early survival

TABLE 2

rate, (2) increasing their late survival rate, or (3) delaying the onset of senescence. The first two longevity patterns are conceptually interesting but have no practical application because neither affects the basic aging rate. The organisms age normally but seem to be somewhat more resistant to the various stresses that kill off their normal comrades. For example, exercising humans have a higher early and midlife survival and a lower level of morbidity. They age, however, in a normal fashion and show no real decrease in mortality later in life. Centenarians, in contrast, seem to have a higher late-life survival rate, but although they have a lower rate of morbidity and mortality, no one would mistake a centenarian for a middle-aged person. They have aged in a normal fashion but are simply a bit healthier than their normal fellows. Their health span is not affected, only their late-life mortality. These two extended longevity patterns are not useful clues to the attainment of people's longevity goals.

The most interesting alteration involves the third type: the delay in the onset of senescence. There are many examples of this pattern in animals but none in humans, yet this is the one people want. Figure 1 shows the survival curves of normal-lived and long-lived fruit flies created in the author's laboratory by means of artificial selection for increased longevity. It is clear that both the mean and maximum life span values are shifted to the right. If one assumes that the flies' health span covers the period of time from birth until 10 percent of the initial population has died, the low mortality and high survival characteristic of the first thirty days of the normal-lived animals' life span has been extended so that it now spans the first sixty days of the long-lived animals' life span. The health span has been doubled, but the senescent period occupies the same length of time (approximately thirty-five days) in both strains and thus represents a smaller proportion of the maximum life span in the long-lived flies.

These data demonstrate that the health span and the senescent span are two separate phases of the life span and that longevity extension through a doubling of the health span is possible. The fact that each of the model organisms can express this "delayed-onset extended-longevity phenotype" strongly suggests that the potential to double the health span is built into each species, including mammals. The task is not to introduce alien mechanisms into organisms but instead to discover how to activate the already existing longevity mechanisms effectively and safely. In this sense, what is being done is "natural."

What would be the outcome if this knowledge was applied to humans? If one projects a survival curve for contemporary U.S. females on the simplifying assumption that they would follow the same survival and mortality kinetics as do long-lived fruit flies, there would be no real decrease in survival (and therefore no increase in age-related mortality) until the age of about 102 years. The 82-year health span in this projected population is double that of the 40 years (i.e., 20 to 60 years) characteristic of contemporary normal-lived humans. If it is possible to understand the mechanisms in the fly that delay the onset of senescence and make them happen in humans, the goal will have been achieved.

Is it realistic to believe that the extension of longevity in laboratory organisms foretells a comparable achievement in humans? All the genes known to be involved in delaying the onset of senescence in the author's laboratory model systems are known to have homologues in humans. This implies that the relevant mechanisms are in place. In light of this fact, it seems reasonable to conclude that the failure to induce the delayed-senescence extended-longevity phenotype in humans represents a transient limitation of knowledge rather than a permanent limitation imposed by human biology. Thus, the question becomes one of understanding the biological mechanisms that regulate this pattern and deciphering the cellular signals that control its expression by the organism.

EXAMPLES OF PROVEN LABORATORY INTERVENTIONS.

The delayed-senescence extended-longevity phenotype has been induced successfully in laboratory animals as a result of genetic interventions designed to decrease oxidative stress and/or alter the energy metabolism of the organism.

Decreasing oxidative stress. People need oxygen. Without it, human beings cannot generate enough energy to live and quickly die. However, the oxygen that keeps people alive is a double-edged sword, for it also can break down within the cell to yield highly chemically reactive molecules of various kinds that are termed collectively reactive oxygen species (ROS) or, less accurately, free radicals. These ROS chemically combine with any of the cell's components and transform them into oxygen-based damage products, a process referred to as oxidative stress. In lay terms, one might envision the cell undergoing something akin to self-perpetuating rusting.

Organisms have within them a very elaborate system with which to defend themselves against the depredations of oxidative stress. That system seems to be reasonably effective at getting rid of most (but not all) of the ROS molecules that are generated in young animals and thus keeping the level of oxidative stress to a low (but measurable) level. But even this low level of oxidative stress causes some damage, which accumulates. Eventually the failure to repair completely causes increasing inefficiencies in the body's ADS. This then allows the rate of oxidative stress and cell damage to increase at a compound rate, and the age-related loss of function soon

FIGURE 1

becomes apparent. This process is sped up in mutant flies and in worms and mice in which the ADS genes have been made inactive. In the laboratory such mutant organisms aged and died very quickly. The mice exhibit systemic failures similar to those observed in various age-related diseases.

It occurred to many investigators that perhaps one could extend an organism's health span by increasing the level of its ADS mechanisms. Genetic engineering techniques were used independently in several laboratories to introduce extra copies of certain ADS genes into otherwise normal flies. The flies then lived longer, displaying a delayedsenescence extended-longevity pattern (Parkes et al.). Equally interesting was the observation derived from the author's selection experiments, in which a normal-lived population gave rise eventually to long-lived descendants because only the longer-lived flies of each generation were bred. After some twenty-two generations the descendants had a much higher level of ADS activities, a lower level of oxidative damage, and a significantly delayed onset of senescence, as is shown in Figure 1. Other experiments showed that certain mutants in the nematode worms also up-regulate (i.e., turn on to a higher degree) certain ADS genes—the same ones that are operative in the fly—and the resulting worms also live long because of a delayed onset of senescence (Honda and Honda). The ISS-based interventions mentioned above bring about the delayed onset of senescence inevitably coupled with an enhanced resistance to oxidative stress and an altered metabolism; this finding may well identify an evolutionarily conserved regulatory mechanism (Tatar et al.).

Altering energy allocations. The first intervention known to delay the onset of senescence in mammals and increase the health span significantly was reported in 1934. Reducing the amount of calories in an animal's diet by about 40 percent while keeping the different nutrients at normal levels results in healthy and long-lived mice and rats (and flies and worms as well). These findings have been replicated literally hundreds of times and are probably the most robust experimental findings in the field. However, it has also been noted that these long-lived animals cannot withstand as much stress as can their normally fed littermates (Hopkins). Similar experiments are under way in primates such as macaque monkeys; although these long-term experiments are still in progress and thus incomplete, the available data suggest that a similar response may be happening in primates. The limited human data that are available lead to the same conclusion (Walford et al.).

CR radically changes an animal's metabolism and SAGE patterns so that the animal becomes a physiologically different organism than is its normally fed sib. Many, perhaps all, of these differences can be attributed to a shift in the animals' functions from growth and reproduction to repair, possibly as a result of altering the output signals of the ISS, as was described above.

Pharmaceutical Interventions into the Aging Process

The genetic manipulations used in the laboratory are not likely to be well received as therapeutic tools. Once the longevity extension mechanisms described above were identified, many scientists independently tried to develop pharmaceutical interventions by feeding various drugs suspected of regulating those two processes to their laboratory animals. Five of those experiments have shown signs of success. Although those independent experiments used different intervention strategies and administered different molecules to the laboratory animals, they all recorded significant increases in the animals' health span (comparable to those in Figure 1) and/or a significant extension of the animals' functional and mental abilities.

A recent experiment done by Kang et al. (2002) may serve as an example of this category of data. Those researchers fed a drug called 4-phenylbutyrate to fruit flies throughout all or part of their lives. This dietary pharmaceutical intervention resulted in a delayed onset of senescence in the treated flies, with survival curves similar to those shown in Figure 1. It turns out that this drug alters the manner in which DNA normally wraps itself around certain chromosomal proteins, in what appears to be an evolutionarily conserved manner (Hekimi and Guarente), and this alteration significantly changes the pattern of gene expression in the animal. Some genes are repressed, and others are enhanced. One of the genes most significantly enhanced is an ADS gene identical to that found to be highly effective in extending longevity in genetically engineered flies and worms. Thus, it is possible, although not yet proved, that this drug can bring about its longevity extension effects because it increases an animal's resistance to oxidative stress. Another interesting observation from this experiment is the fact that different strains of flies needed different drug doses to yield the same result. This implies the existence of genetically based individual differences in the response to drug-based longevity interventions. No reports are available regarding the existence of various side effects or trade-offs in any of these experiments.

Is a Complete Understanding of Aging Needed Before Intervening in the Process?

There are other mechanisms that the laboratory data suggest also may be involved in regulating the aging rate. Perhaps the most persuasive is the cell senescence/telomere theory. Except for stem cells, body cells either divide very rarely (i.e., nerve cells, muscle cells) or divide either continuously (i.e., blood cells, skin cells) or when stimulated (i.e., liver cells). Those cells that divide seem to have an upper limit on the number of divisions they can undergo. There is some evidence that the telomerase enzyme may play a still not quite understood role in regulating this process. The failure to maintain cell numbers in different tissues probably underlies some aspects of age-related loss of function. The operative part of the cell senescence theory may not be the actual number of divisions cells undergo but the probability that nondividing senescent cells alter their SAGE pattern from one that inhibits oxidative damage and permits division to one that permits oxidative damage and inhibits both cell repair and cell division. If this is the case, one could merge the cell senescence/telomerase theory, the oxidative damage theory, and the metabolic change theory into a single general aging theory based on harmful changes in gene expression that shift the cell from a "youthful" preventive stance to an "older" damage-permitting stance. Such a general theory of aging is reasonable although still under construction, and a persuasive data-based account of it can be found in Fossel.

However, the fact that researchers have accomplished successful interventions into the aging process in the absence of a complete understanding suggests that total comprehension is dispensable: It is desirable but not required. How can this be? The evolutionary considerations discussed above make clear that organisms usually are geared toward reproduction as opposed to repair. This means that any population of animals will contain very few, if any, individuals that are optimally configured for repair. Most, if not all, individuals will have one or more physiological processes that are less than optimal. Tweaking any one of them—oxidative stress resistance, metabolic change, for example—will have the effect of making that organism better in that one respect. Other physiological processes not directly affected by the intervention will show no change or a secondary and dependent change induced by the initial perturbation. The animal will have some measurable improvement in at least one of the several aging processes that operate in its body and as a result will age more slowly and live healthier and longer.

This is in effect what has been done with the flies, worms, and mice. The very specific interventions used appear to have brought about a global effect on the organism. The animals live longer despite the researchers' ignorance about exactly what kind of a control cascade brought this about.

An interesting implication comes out of this observation. The more complex an organism is, the greater the number it will possess of different regulatory and control processes that affect aging mechanisms. More complex organisms, which are organized in a hierarchical modular manner, should have more potential sites where intervention could take place. In principle, mammalian aging should be subject to alteration by more interventions than will work in flies and worms (see de Grey et al.). The greater role that cell division, for example, plays in mammalian aging relative to the invertebrates and the probable relationship between cell division and altered gene expression patterns bolster this point. However, having a greater number of potential drug targets is not an unmitigated blessing. The trade-off is that the mammalian interventions probably need to be very biologically specific in order to be effective. There have been interventions that work in flies and worms but so far have failed in mice, possibly because they were not specific enough to coax the mammalian regulatory systems into altering the organism's SAGE patterns. It is likely that deciphering these specificities will constitute much of the research necessary for the development of a successful mammalian pharmaceutical intervention.

The gap between the predicted and actual effects of extended longevity on human society is likely to be huge. All the writing in the world will not define the texture of that future society. Many people would not go forward without detailed knowledge of the consequences. In the twentieth century people faced the question of whether society should permit human flight. It is necessary to ask if people really wish the Wright brothers had failed (or, worse, that their success was suppressed) and that this was still a flightless society.

robert arking

SEE ALSO: Dementia; Genetic Engineering, Human; Health and Disease: History of the Concepts; Human Dignity; Justice; Long-Term Care; Medicare; Natural Law; Population Ethics; Transhumanism and Posthumanism; and other Aging and the Aged subentries

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INTERNET RESOURCES

de Grey, A. N. D. J. 2003. Strategies for Engineered Negligible Senescence. Available from <http://www.gen.cam.ac.uk/sens/index.html>.

Hopkins, K. 2003. "Dietary Drawbacks." Available from the Science of Aging Knowledge Environment website. Available from <http://sageke.sciencemag.org/cgi/content/full/sageke;2003/8/ns4>.

Science of Aging Knowledge Environment (SAGE-KE) website. 2003. Available from <http://sageke.sciencemag.org>.