Genetic Therapies For Aging Will Face Many Challenges

But there is still reason for optimism, says Dr. George Martin, professor of pathology, adjunct professor of genetics, and associate director of the Alzheimer Disease Research Center at University of Washington School of Medicine, Seattle.

"A study of evolutionary biology offers both good and bad news. The good news is that life span, like all life-history traits, is plastic. We know this because in the laboratory, you can take fruit flies and select for fruit flies that can live 50 percent longer than usual," Martin says. "If nature is given a chance to devise better alleles and mechanisms for protecting macromolecules, that will happen. So there is an opportunity for substantial increments in human life span.

"The bad news is that there are so many different things that can go wrong as we age. These can be affected by an enormous number of potential inborn genetic variations that can modulate how we age; they come in different combinations in different individuals. Difficult, expensive and customized interventions may therefore be required to achieve substantial gains in life span."

Martin discussed the topic of genetics and aging during "How Long Can Humans Live?" as a panelist at the American Association for the Advancement of Science annual meeting on Feb. 18.

Martin established one of the earliest Alzheimer's research centers, where he and his research team recently mapped two of the genes responsible for early-onset Alzheimer's disease. He is the author of more than 250 articles and book chapters, has served on the National Advisory Council of the National Institute on Aging and has been elected to membership in the Institute of Medicine of the National Academy of Sciences.

Some scientists think changes in amino acid sequences of proteins may be important in the evolution of longevity among species. But Martin points out that the proteins of chimpanzees are 98 to 99 percent identical to those of humans, and yet chimps live only about half as long. So Martin says the difference in species-specific life spans may be largely due to variations in the regulation of the expression of genes -- although changes in the amino acid compositions may also be important. Changes in gene regulation could have a direct effect on development and on the maintenance of macromolecular integrity within our bodies. If that’s so, then changing the regulation of gene expression for adult humans could influence the speed of response to injury -- for example, the speed with which DNA is repaired.

"These ideas have encouraged the optimists among us to believe that a relatively small number of regulatory genes may make a large difference in the potential to live a long life," Martin says.

So that’s the good news. However, we have genes that do us wonders during our reproductive years, but then fail to continue doing so -- or even backfire on us -- as we age. As we experience structural and functional declines after the peak of reproduction, the body tries to adapt by altering gene expression. Martin has referred to that period in our lives when this is most noticeable as "sageing." It extends from the age of 40 or 50 to 70 or 80. An example of an adaptation during sageing is the process of neuritic sprouting, when neurons sprout compensatory branches to make up for the neuronal shrinkage that occurs with age. But this compensatory system eventually ceases or slows down as we age.

Here’s an example of a gene that helps us, but then sabotages us as we get older. This example also illustrates the complexity of individual variations in the genome. There is a gene in men that codes for the androgen receptor, which boosts the effect of the masculine hormone testosterone. There are variants of that gene (those with rather few repeats of a triplet of nucleotides, CAG) which code for more receptivity to hormones, leading to bigger, stronger and more aggressive males than average. Those are great qualities from an evolutionary point of view. But there is a "price to pay," as these men are more susceptible to prostate cancer late in life. Moreover, these prostate cancers tend to be more aggressive. Other men have larger numbers of these triplet repeats within the coding region of the gene.

To add to the complexity, different genetic-based problems seem to arise during different ages of a person. For example: Martin’s lab is studying an adapter protein, FE65, that binds to a specific domain of the beta-amyloid precursor protein. This binding may influence a chain of events that becomes part of the process that leads to brain degeneration in Alzheimer’s disease. A genetic variant of FE65 appears to alter one’s susceptibility to that disease, at least in some populations. In this respect, it resembles gene variants at a different genetic locus, which has the coding for Apolipoprotein E, also implicated in brain problems. It is very interesting, Martin says, that these two variants seem to have their major effects at different periods of the life span, the FE65 effects being observed among much older individuals.

"Each age window seems to provide you with a different smorgasbord of gene actions and gene-environmental interactions," Martin says.

Common gene variants, such as those discussed above, are known as polymorphisms. Other gene alterations, called mutations, are much rarer but can have powerful effects within an individual or a pedigree. The major dominant genes responsible for early-onset Alzheimer’s disease are good examples. They may all work by accelerating deposits of abnormal proteins in the brain known as beta amyloids. But there are many other types of amyloids, each coming from a different precursor protein, and most of them showing increasing effects as we age. These can affect the brain, heart, intestines, kidneys, the immune system, skin, endocrine organs, muscles and more. People vary widely in where, when and if they develop these deposits.

Again, these mutations that show up late in life will escape the force of natural selection.

"While these mutations are individually rare, they are collectively numerous," Martin says. "The picture that emerges is that there are many ‘Achilles heels’ within each of us."

A newer and less discussed issue in aging research is to understand the genetic basis for those individuals who have unusually good preservations of structure and function late in life. Some of this is due to genes, some to environment, and some to just plain good luck. The challenge is to sort out the details of how those good genes and good environments work. Some of the good genes could be variants of the large family of genes that maintain the integrity of our DNA.

"There are at least 100 genes involved in the repair of damage to DNA in the lowly bacterium, E. coli. There are certainly many more within our genome -- likely many thousands," Martin says. He theorizes that as much as 7 percent of the human genome could produce allelic variants or mutations that modulate how we age, and thus produce individually distinct patterns of aging.