Life Extension Magazine September 2001
Life Extension Is On Its Way To Becoming A Fact:
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“Growing old is a bad habit which a busy person can’t afford to develop,” was one of the many striking statements made at the Alcor conference in Monterey, California. It wasn’t meant as a joke. At long last, the hope that growing old would mean personal development rather than deterioration, a growth in wisdom and productivity rather than mental decline, “sage-ing” rather than aging, is becoming realistic. What yesterday sounded like science fiction is rapidly becoming fact.
by Ivy Greenwell
Dr. Tomas Prolla of the University of Wisconsin at Madison discussed the way certain genes change expression with aging. Dr. Prolla and Dr. Richard Weindruch are pioneers in the use of microarray-based gene profiling to study aging. A gene microarray is a small glass slide (it easily fits into a shirt pocket) that shows thousands of genes in a regular layout. The use of these microarrays represents a major breakthrough in aging research, enabling scientists to detect aging-related changes at the level of molecular genetics. Ultimately, the unraveling of the aging process at the genetic level may lead to truly significant anti-aging intervention.
There is a technique for measuring messenger RNA (mRNA) for each gene, i.e. the “expression” of that gene. Using gene microarrays, Dr. Prolla and colleagues compared gene expression in five-month-old “young adult” mice and elderly 30-month-old mice. Certain genes showed much more activation in old mice. Those were the genes that have to do with the stress response. Genes that govern DNA damage control were also upregulated, as were the genes that code for heat shock proteins (special proteins that repair other body proteins).
Neuronal injury genes were likewise upregulated with aging. “With aging, there is a marked increase in oxidative stress and inflammatory response in the brain,” Prolla said. He referred to the “gero-inflammatory manifold”—the widespread immune activation that is part of the inflammatory cascade.
This immune activation, as shown by higher levels of inflammatory prostaglandins and cytokines (IL-6, for instance), increases with age. Thus, aging means a progressive increase in chronic inflammatory status. The activation of the inflammatory response system (including the activation of the immune system) accompanies not only specific diseases such as atherosclerosis, osteoporosis and Alzheimer’s disease, but also so-called “normal aging.” In a way, our immune system increasingly becomes our enemy, destroying our own tissue.
Why this harmful over-response to stressors? Apparently evolution favored individuals showing a strong immune response to pathogens, so they could survive and reproduce. But what is optimal for survival and reproduction in youth may become harmful in post-reproductive years, as the amount of tissue damage accumulates while the energy output and capacity to repair tissue keep decreasing. At the same time, the immune function also deteriorates, with auto-immune disorders increasing, while the ability to defend against pathogens declines.
This is not to say that the older body doesn’t try to repair damage. On the contrary, Prolla and colleagues found that various types of “repair” or “stress response” genes are expressed much more during aging. At the genetic level, the aging process resembles a state of chronic injury. Possibly the aging organism is devoting its resources increasingly to trying to repair damage, and not to building new tissue. In fact, Prolla did find lower expression of what might be called “biosynthetic” or tissue-building genes in old animals. Hence the well-known shift from the chiefly anabolic (tissue-building) state of youth to the catabolic (tissue-wasting) state of old age. The shift toward catabolism may have a lot to with diminished energy production by the mitochondria. Genes that govern energy production were likewise downregulated with aging, Prolla found.
Perhaps if the medical profession and the broader public realized that on the genetic level aging presents a picture of chronic injury and chronic inflammation, we could finally get rid of the misleading term “normal aging,” and address aging as a multifaceted disease for which remedies need to be found.
The remarkable discovery made by the Wisconsin team was that calorie restriction significantly dampened these aging-related changes in gene expression. “Calorie restriction partially or totally prevents the changes in gene expression due to aging,” Prolla said. The “repair” genes were clearly less activated in calorie-restricted animals. The simplest explanation is that there was less damage to be repaired. On the other hand, DNA synthesis was upregulated in the brains of calorie-restricted mice.
“Even when calorie restriction is started late in life, there is a visible impact on gene expression,” Prolla said. However, there is a consensus that calorie restriction extends youth, and should be started as early as possible. One comforting finding is that even slight (10%) calorie restriction produces some life extension. Calorie restriction is also an excellent means of preventing or retarding aging-related diseases such as cancer, Alzheimer’s and Parkinson’s disease. There are several theories trying to explain the effectiveness of calorie restriction in producing life extension. One of them emphasizes the finding that calorie restriction slows down the deterioration of the immune system.
One use of the technique developed at the University of Wisconsin is that for the first time we are going to be able to measure, at the gene level, whether certain supplements retard aging. We will be able to pinpoint the effects of drugs and dietary regimens. Likewise, once we more fully understand what happens to gene expression during calorie restriction, we should be able to find ways to produce the same benefits without needing to resort to calorie restriction. At this point, calorie restriction is the most powerful known way to retard aging, but it is also the least acceptable to the average person. Finding an equivalent anti-aging regimen that does not leave us emaciated, libido-less and depressed is a major challenge.
Dr. Prolla did not go into the therapeutic aspect of trying to attenuate the “gero-inflammatory manifold” of aging. However, there are inescapable implications for anti-aging medicine based on mounting evidence that inflammation does indeed play a huge role in the aging process, and in the particularly devastating diseases of aging such as Alzheimer’s disease and cancer (not to mention such relatively “minor” problems as cognitive decline, osteoporosis or gum disease). Developing better anti-inflammatory drugs, as well as using potent (and safer) natural anti-inflammatories, such as green tea extract and ginger, seems a very important aspect of the struggle against aging. Before we know how to manipulate genes to achieve more regeneration, we can already use current discoveries to try to reduce deterioration.
For all the excitement about the genetics of aging, however, Dr. Prolla stressed that any single-factor theory of aging is bound to be wrong. For instance, telomere shortening is important in those cells that divide. It is non-dividing cells, however, that are regarded as most critical. Perhaps at this point we should try to answer the most basic questions, such as “how can we measure aging?” It is very exciting to speculate about conquering aging, but first we should pay more attention to investigating and measuring the aging process.
Addressing the same topic from a different angle, Glenna Burmer, MD, PhD, of LifeSpan BioSciences, Inc., gave a presentation on cutting-edge developments in decoding the genome in terms of aging-relating changes in gene expression. We need to know more about which genes are expressed more when the organism is young, and which are expressed more when the organism is old. One way to do it to use gene chips (microarrays) that compare side by side tissue from a young individual with the same type of tissue from someone over 70. Such comparative research is currently being done, mostly in order to pinpoint genes related to specific diseases of aging.
Burmer would agree, however, that the underlying disease is the aging process itself. “Aging is a universal genetic disease,” Burmer said. Current medical thinking, however, separates aging into different diseases: cardiovascular disease, brain aging, kidney aging and so forth, rather than investigating the underlying pathology of aging. Hence the emphasis on trying to find genes that are upregulated or downregulated in particular diseases, and can be targeted with drugs for that particular disease. But it is now obvious that many genes change their expression simply as a function of aging rather than a particular disease.
“Hundreds of genes go up or down with aging,” Burmer said. When we compare young skin with old skin, for instance, we see that some genes are expressed much more in young skin, and other genes in old skin. The gene for apolipoprotein A2 is more expressed with age, as is one for the prostacyclin receptor. Genes that govern energy generation or utilization change their expression with aging, as do those that govern the response to oxidative stress. Also upregulated are various pro-inflammatory genes, such as the 5-lipoxygenase gene, which controls leukotriene production.
We are just beginning to decipher genes and make sense of certain gene clusters. The goal is to analyze 500 genes a day. Another goal is to use multi-tissue arrays to compare gene expression in a tissue from a 20-year-old with that in a tissue from a 75-year-old. Some of the most interesting genes have very few copies per cell, Burmer stated. For these, special sensitive arrays must be used.
Thanks to gene chips, we finally have a feasible way to hunt for “longevity genes.” It turns out that such genes not only extend life span, but also delay senescence. They keep an individual young and healthy for a longer time. Theoretically at least, longevity genes would make people in their 60’s or even 70’s enjoy the kind of vigor that is now associated with one’s 30’s and 40’s. They would not be plagued with arthritis, bone and muscle atrophy, creeping obesity, diminishing eyesight and hearing, forgetfulness, sleep disorders, thinning, graying hair and all the other dreary signs that physical and mental decline have begun in earnest. Does this sound like science fiction? The recent studies on centenarians have confirmed that these exceptional individuals enjoy a slower rate of aging, and typically remain in good health until the very end.
So far, 20,000 genes have been analyzed, with 500 identified as “aging genes.” Does the progress in mapping the genome and identifying genes mean that gene therapy will soon become commonplace? Not really. Burmer pointed out that the delivery mechanism for gene therapy has to be very precise. We must improve the vectors (such as viruses, which can carry a gene inside the target cells). The new-generation vectors are already more promising, but much work remains to be done in order to resolve the issues of safety, precision and long-lasting results. Thus, somewhat surprisingly, the more likely result of genetic research development in the near future is going to be not gene therapy per se, but the creation of better, more precise drugs that can modulate the expression of certain critical genes. Some of these drugs could be “smart drugs” that will boost intelligence. Eventually the developments in genomics are likely to lead to a “healthy doubling of the human life span,” Burmer predicts.
Dr. Burmer also observed that if all genomic research were collaborative, with shared data, progress would be faster. Pharmaceutical companies, however, want to “own” a gene for which they try to target a drug. Genomic research is expected to speed up the creation of new and better drugs—hence the great interest of drug companies in molecular genetics. At present it is difficult to find a solution to this conflict between the ideal of open scientific communication and the economic imperatives of drug research.
One participant wished to know if genes characterizing various ethnic groups are going to be compared. Burmer replied that it is too early in the game for that. First we need to answer basic questions about the “meaning” of individual genes. In addition, human genetic variation is huge, and millions of tissue samples will need to be analyzed. At this point, Burmer said, we have not yet deciphered 90% of the human genome. In fact, there is not even a consensus as to how many genes there are. All agree that most genes have not yet been identified, and we don’t know what huge portions of our DNA “mean.” Nevertheless, this is the birth of a scientific revolution. Burmer compared the gene-decoding work currently being done with Leeuwenhoek’s first beginning to look at cells through a microscope. It is a start of a new era.