Possible Molecular Therapies To Alter Maximal Life Span
The treatment of age-related diseases must be distinguished from attempts to change the aging process per se. By definition, aging comprises those processes that ultimately limit life span by affecting all individuals within a population. On the other hand, diseases of aging are specific pathological processes that affect the older individuals within a population, but nevertheless can be separated from aging because not all individuals are affected and because there are other causes of the disease in addition to age itself.
The development of therapies for aging per se, leading to life span extension or immortality, is a popular theme in literature—the "fountain of youth". The idea that such a therapy might at some point be applicable to humans has been strengthened by recent findings that genetic changes in other organisms can lead to substantial increases in maximal life span. For example, in the nematode Caenorhabditis elegans and in the fruit fly Drosophila melanogaster, mutations of genes have been discovered that cause substantial extensions of life span. In the mouse there are several examples of life span extension by the inactivation of single genes. Particularly noteworthy are the large extensions in life span that result from inactivation of any of a group of genes that affect body size, including growth hormone and other genes of the growth hormone axis. These genetic changes affect maximal life span and not average life span. The maximal life span of a species is the length of life of individuals of that species under circumstances in which they do not die prematurely due to predation, starvation, or specific disease processes such as infections or cancer. It is usually thought that maximal life span changes very slowly over evolutionary time, whereas the average life span achieved by individuals within a population can change rapidly over historical time. It is also relevant to consider here that maximal life span in rodents can be extended by a nongenetic manipulation, caloric restriction; the lifetime feeding of substantially reduced calories robustly leads to an extension of maximal life span.
It is a simple extrapolation from these results in other organisms to suggest that the manipulation of the same genetic processes in humans would lead to similar extensions of life span. However, it is not clear that the potential for manipulation of life span exists in humans as it does in rodents, C. elegans, and Drosophila. If a single gene mutation can cause extension of life span in the mouse, why is this genotype a mutant and not the wild type? The answer must lie in the concept of antagonistic pleiotropy, i.e., the gene must provide a benefit to the animal in early life, such as increased reproduction or increased fitness for survival in the wild, despite conferring a shorter overall life span. A mutation in such a gene then confers longer life, but will have a trade-off in the form of some negative effect in early life, which might not even be apparent under laboratory conditions. The presence of such genes in the genome requires that the species has experienced recent evolutionary selection pressure to change from slower reproduction/longer life span toward rapid reproduction/shorter life span. The present-day life history of many rodent species is consistent with this assumption. Because of cyclical variations in food supply, the population must be able to undergo rapid increases when food is plentiful, in order to allow for decreases later, as food becomes scarce. Similarly, the modulation of life span by caloric restriction in rodents may reflect a switch between two physiological states—one with slower reproduction/ longer life span and one with rapid reproduction/shorter life span. In rodents, and in short-lived species generally, maximal life span has evolved to an optimum that is neither longer nor shorter than is required by the demands of their life history. From an anthropocentric viewpoint it may be difficult to understand that a shorter life span in some species may be a recently evolved, more "advanced," state. An analogy is provided by the existence of cave-dwelling fishes that have no eyes as adults. In the laboratory, such species can be made to develop almost normal eyes. The loss of eyes is a recent evolutionary event, and the genome retains almost full capacity for normal eye development. Similarly, rodents and other short-lived species may have evolved from ancestors that were longer-lived, and therefore may retain in their genome the potential for a longer life span, which is normally latent until genetic or other manipulations reveal it.
However, the same is probably not true of humans as a species. There is no evidence that the current maximal life span of humans is in some way a compromise between a potentially longer life span with less reproduction and a shorter life span with greater reproduction. In fact, Homo sapiens represents an extreme of longevity among mammals, even among primates. Therefore, it is unlikely that a mutation in a human gene could lead to a dramatic extension in maximal life span. It follows that it would be unlikely that a molecular therapy could be developed that extends human life span either by germ-line manipulation (which would also raise severe ethical questions) or by a somatic process that has an effect equivalent to inactivating a gene (such as antisense RNA, which inactivates the normal RNA product of a gene, or dominant negative proteins, which bind normal proteins and prevent them from activity).
Another approach to changing the rate of aging would be to devise therapies to counteract known or suspected molecular aging processes. For example, in very old persons telomere shortening may compromise the potential for extensive cell division in the hematopoietic (blood-forming) system. It is possible that preventing this by introduction of telomerase reverse transcriptase (TERT), a gene that is not expressed in most somatic cells, might improve immune function or prevent some types of anemia. Other possibilities include new therapies based on enzymes designed to repair or prevent molecular damage. For example, one form of molecular damage that accumulates in aging, and is thought to be a contributing factor to many age-related pathologies, is the formation of advanced glycation end products (AGE: complex reaction products of proteins with sugars and oxygen). It may be possible to devise a form of gene therapy to eliminate these molecules. However, therapies based on reversal and prevention of molecular damage would require solutions to many problems, such as at what age the therapy would have to begin; what fraction of the overall damage in the body would need to be prevented to have an effect on tissue and organ function; and whether, even if the therapy were successful, it would have any effect on maximal life span.
This analysis suggests that finding molecular therapies that produce substantial increases in maximal human life span would be very difficult, principally because our genomes do not harbor latent mechanisms for increased longevity; to put it another way, our genes are already fine-tuned for maximal life span. This is not to say that such therapies are inherently impossible. Understanding the mechanisms for life span extension in rodents and other species, including the molecular basis for the action of caloric restriction in modulating life span, may enable the development of new therapies, but at the present time it seems equally possible that no therapy that actually affects the rate of aging per se in humans would be possible.