X-Message-Number: 15720
From: "Mark Plus" <>
Subject: "Genetic Therapies For Aging Will Face Many Challenges"
Date: Thu, 22 Feb 2001 10:33:50 -0800



Source:   University Of Washington (http://www.washington.edu/)

Date:   Posted 2/22/2001

Genetic Therapies For Aging Will Face Many Challenges

Efforts to help humans live longer will face big challenges: a genetic 
evolutionary system that has no particular interest in helping people live 
past their peak productive years, and thousands of genes that can go wrong 
in different ways in different people.
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 

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 


Note: This story has been adapted from a news release issued by University 
Of Washington for journalists and other members of the public. If you wish 
to quote from any part of this story, please credit University Of Washington 
as the original source. You may also wish to include the following link in 
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