Molecular therapy comprises methods to provide a needed gene product to a patient, with the intent to produce a desired effect on health. Genetically engineered viruses can be used to deliver genes to cells in the body, and the cells that receive the gene then synthesize the protein that the gene encodes. Alternatively, in a cell-based form of gene therapy, termed ex vivo gene therapy, the patient receives cells that have been engineered to produce the required gene product. No forms of gene therapy are currently in use for the treatment of aging and age-related diseases, but it is widely anticipated that these medical technologies will be used to treat age-related diseases in the future. This article describes the possible types of therapies that could be used, and their limitations and potentials.
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.
Molecular therapies for age-related diseases
Realistic forms of gene therapy that are likely to be applied in the near future are those that affect diseases of aging rather than aging processes. Some of the potential future therapies are listed in Table 1, but this is not a comprehensive list. Because these therapies have the aim of restoring normal health by correcting an abnormal condition, and do not involve germ-line manipulations, they do not have the ethical problems associated with attempting to change maximal life span. Some of these therapies are close to being used in human subjects, having been successfully demonstrated in experimental animals. The idea of using gene therapy is especially attractive for chronic diseases in which current forms of medication must be administered frequently, often several times per day; compliance with such regimens is a problem, especially for older people. There is an obvious advantage to replacing drug therapy with a form of molecular therapy if the effects are equivalent. Moreover, for many diseases of older individuals, present treatments are inadequate or nonexistent, making the development of new therapies very desirable.
Since the beginning of gene therapy as an idea, different delivery methods have been developed in parallel, without any one of them eclipsing the others, and the existence of multiple strategies for gene delivery is likely to persist in the foreseeable future. Different genes may require different delivery methods for optimal effects. Several recombinant (genetically engineered) viruses can be used as vectors (i.e., carriers of genes). Adenovirus-mediated gene delivery has been used successfully in young individuals, and has the advantage of very efficient delivery to nondividing cells, particularly the liver. However, earlier generations of adenovirus vectors were highly immunogenic, leading to dangerous patient reactions. These problems appear to have been solved in later generations of these vectors, but all adenoviruses exert a therapeutic effect only over a short time. Longer-term effects have been achieved with vectors based on the adeno-associated virus (AAV) and the herpes simplex virus, and with lentivirus vectors based on components of HIV (human immunodeficiency virus). These vectors can infect nondividing cells, and their genetic material becomes stably integrated into the infected cell's DNA. Vectors based on other retroviruses, such as mouse leukemia virus, can be used only to infect dividing cells, and so have not been particularly successful in in vivo applications, but they can be very useful in ex vivo cell modification. Gene delivery can also be accomplished without the use of viruses. Nonviral DNA delivery suffered until recently from a lack of efficiency, making it impractical, but trials of newer versions of liposomes have been very promising. Nonviral vectors could be just as efficient as viruses and could obviate the problems associated with viruses—not only side effects but also public acceptance of the therapy, especially for the treatment of diseases that are not immediately life-threatening.
An inherent problem with the use of viral and nonviral vectors is the difficulty of ensuring that the gene is delivered to the appropriate number of the patient's cells. The number of cells infected, and hence the amount of product delivered, is hard to control. A second major problem is maintaining long-term gene product delivery, so as to avoid the necessity for repeated administration of the vector. Another concern is that because gene therapy either intentionally modifies cells of the body (introduces genes into the host genome) or has the potential for accidental permanent genetic modification, expression of endogenous genes in the modified cells could be altered, potentially causing the cells to become cancerous. A concern that is of more importance in young patients is that germ-line cells will be unintentionally modified. More generally, it may be undesirable to create the potential for continued production of the gene product in cases where only temporary delivery is required. These concerns are less important in critically ill patients, of course, but must be satisfactorily addressed before these forms of gene therapy are widely adopted.
Cell-based delivery, or ex vivo gene therapy, uses genetically modified cells as the gene product delivery system. In this method, possible unintended alterations in gene expression can be tested before the cells are used. There is no potential for accidental germ-line modification. However, two disadvantages to cell-based therapy are that introduction of the cells into the patient requires a surgical procedure, and that cells must be protected from immune rejection. The cell transplantation procedure may require only minor surgery, however, and in some sites in the body the cells could be removed after their task is completed. In other sites into which they might be transplanted, such as the brain, implantation would be intended to be permanent. Immune rejection is the most severe problem, especially if cells are derived from nonhuman animals (e.g., cows or pigs). Although the problems of rejection of xenotransplants are substantial, great progress has been made in understanding the host response and modulating it so as to improve long-term graft acceptance. Immune rejection could also be avoided by encapsulation, so that cells are physically protected from host immune cells. Most promising is the prospect of genetically modifying cells so that they are "invisible" to the host immune system. Alternatively, the patient's own cells could be used in ex vivo gene therapy, but such customized cell therapy would be much more expensive than using "off-the-shelf" cell lines, and the time involved in preparing the cells would prevent this method from being used in diseases where treatment is needed urgently.
The cell types that could be used in cell-based therapies are those that can act as vehicles for a variety of gene products (such as myoblasts and keratinocytes) or those intended to directly replace or restore damaged tissues (such as neurons and chondrocytes). In the latter case various forms of stem cells could be used. Recent advances in stem cell biology, such as the isolation and characterization of human embryonic stem cells, neural stem cells, and mesenchymal stem cells, have brought therapy based on these cell types closer to reality.
Because of the large expansion of the cell population needed in culture, any cell type used in cell therapy must avoid the shortening of telomeres that limits the proliferative potential of somatic cells. Many forms of stem cells are normally telomerase positive, but cells that are not telomerase positive will require genetic modification to prevent telomere shortening. This could be done by introduction of the telomerase reverse transcriptase gene, thereby producing "telomerized" cells. A concern about the use of telomerized cells is that they might have a propensity to undergo neoplastic conversion, but experiments on transplantation of telomerized cells in experimental animals have shown that they produce normal tissue. Another method that has been proposed is to take advantage of the fact that nuclear transfer, the passage of a nucleus and its progeny through the environment of the fertilized egg and early embryo, can restore telomere length when this process is used on cells with short telomeres (senescent cells).
It is important to realize that the same goal (restoration of healthy tissue and prevention of further damage) can potentially be achieved by two forms of cell therapy. In the first, gene products are delivered from transplanted cells and act to affect the behavior of host cells; in the second, the transplanted cells themselves replace the function of the host tissue. Both strategies would be applicable to the treatment and prevention of age-related diseases (see Table 1).
A full treatment of the possible uses of stem cells in human medicine is beyond the scope of this entry. Also not covered are other important topics within the fields of tissue engineering and regenerative medicine, such as the concept of growing or constructing entire organs in vitro, as a source of organs for transplantation, or the production of transgenic "humanized" animals (principally pigs) as a source of organs. In addition, some important molecular therapies are not covered, such as the use of gene therapy in cancer treatment, and possible therapies that use stimulation of the immune system to provide a protective response against the accumulation of damaged molecules, such as β-amyloid in Alzheimer's disease.
Since the beginning of gene therapy as a concept, it has been repeatedly predicted that the use of gene and cell therapy will have a major impact on human medicine, and the fact that no forms of these therapies are yet routine could be viewed as a failure of this technology. However, it must be remembered that most of the great advances in medicine did not find a place in everyday clinical practice for many years after their discovery. More than fifteen years passed between the discovery of penicillin and its routine use in treatment of infectious diseases. There is every reason to believe that gene and cell therapies will play significant roles in treatment of chronic diseases in the elderly, but therapies that aim to alter human aging and change maximal life span are unlikely in the foreseeable future.
See also Age-Related Diseases; Cellular Aging: Telomeres; Genetics; Molecular Biology of Aging; Mutation.
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