"Who wants to live forever?" asks the title song of the 1986 blockbuster Highlander that deals with immortality; yet we should ask, who doesn't? Wouldn't you like to be a frisky 200-year-old if it were possible to maintain your health and well-being?

In past WWNK issues, we have examined anti-aging remedies and treatments, from the sound to the silly. This two-part article deals with scientific findings of the last three years that--in the not-too-far future--may well provide us with the cure for mankind's most lethal disease.

The Human Genome Project, a government-funded 'mapping' of some 30,000 human genes, is on the way to becoming our greatest scientific resource. As geneticists proceed with gene therapy experiments based upon direct expression and inhibition of genes and also the repair of gene mutations and malfunctions, such work will both depend on, and contribute to, the continuous updating of the Human Genome Project database. This database is the repository of all our genetic knowledge and will carry us well into the next century. Likewise, medical innovations are leading the way for 21st- century medicine, and new techniques for creating more effective, low side- effect drugs are revolutionizing bio-engineering and pharmacology.

Let's take a look at some of the latest studies, their status, and their potential for future breakthroughs in anti-aging therapy.

Mitochondrial Mutations

The human genome is an ecosystem in which thousands of enzymes continuously interact with, and alter, both each other and the larger RNA and DNA molecules. As RNA and DNA molecules replicate, errors can and do accumulate. Many of these anomalies and mutations in the human genome are eliminated through natural selection (about 20%), but a majority manage to slip through the cracks, being copied into the next generation DNA.

Most people with a basic knowledge of cell biology know that DNA--the 'blue print' molecule that governs all living forms--resides in the nucleus, which is the 'control center' of every animal cell. However, it was discovered some 30 years ago, that a cell's mitochondria--its 'energy factories'--also possess their own copy of their host's DNA. In both structures, DNA molecules can accumulate errors and mutations. After many years of analysis of mitochondrial DNA (mtDNA) strands, biologists began to realize that mutations accumulate as an animal grows older.

Nature has provided some defense from this. Our DNA encodes enzymes that have the sole function of repairing their own mutations and replication mistakes. DNA polymerase-gamma is one such enzyme; it 'proofreads' mtDNA to ensure correct replication, aiding in DNA repair.

In order to pinpoint a more causative role for this enzyme, geneticist Aleksandra Trifunovic and her colleagues of the Karolinska Institute in Sweden engineered a line of mice to produce a "compromised", i.e., non- functioning, version of this enzyme. Later biopsy analyses of heart, brain, and liver samples revealed up to five times as many errors in their mtDNA as in similar tissue from normal mice. These younger, transgenic mice began to exhibit the typical signs of aging

While this is very exciting news for our understanding of aging, researchers are quick to point out that DNA polymerase-gamma is only one of several molecules that play an important role in cellular aging and longevity. However, while there have been several previous studies that correlate this enzyme with aging symptoms, the Swedish study results are the first strong evidence that mtDNA mutations actually cause aging.

Geneticists hope to soon be able to manufacture an enhanced form of this DNA polymerase-gamma--or the gene that encodes it--giving the patient extra mtDNA protection.

Protein Mapping

One of the most exciting and important fields in bio-technology today is proteomics, the study of protein structure and function. Its goal is to understand protein expression at the cellular level and apply this information to scientific and medical problems

Proteins bind to other molecules to orchestrate a myriad of physiological processes. When a malfunction occurs in the protein binding process, the result can be disease. There are about seventy different types of protein binding structures--or domains--within any given somatic cell. The binding loci for each domain are also known as receptors.

The Princeton, New Jersey-based bio-tech company AxCell Biosciences, a subsidiary of Cytogen Corporation, has mapped all of the ways that proteins with the same type of binding structure interact and connect to one another. In the past three years, aided by cutting-edge technologies such as protein chips, 2DE Gell Imaging, and capillary electrophoresis, AxCell has been hard at work mapping the protein domains associated with cancer, diabetes, heart disease and several other major killers. Current evidence strongly indicates that these diseases result from defective proteins. Proteomics research seeks to identify normal and altered protein expression in biological systems as they respond to environmental or pathological stresses.

Like mapping the human genome, mapping protein-binding structures generates huge amounts of data. This explosion of new information is feeding another emerging field: bioinformatics, which is about managing this data to yield commercially significant results.

AxCell's protein binding database--an outgrowth of the Human Genome database--has become an invaluable resource for the emerging science of pharmacogenetics, as pharmaceutical companies seek a safer and more cost- effective alternative to 'trial and error' approaches in the development of new drugs. Proteomics also has application in agricultural bio-science, wherein plant diseases are a major concern.

Despite this potential, there remains a high degree of uncertainty, and many more years of experimentation. The work involves manufacturing 'peptide chains' and then combining these with engineered proteins. Analyses of these protein mixtures seek to determine 'the strength of attraction' between each peptide chain and protein. The working theory is that strong affinity shows these two components might interact with each other naturally, and thus drugs made to inhibit those interactions might alleviate some disease symptoms. A lot of 'mights', few concrete results-- at least for now.

MRI Scans see aging brains

One of the biggest problems researchers face who seek to understand age- related changes in human brains is identifying (and excluding) patients who already have early-stage Alzheimer's but have not yet been diagnosed.

In seeking a 'control' population, Scott A. Small of Columbia University and his colleagues resorted to studying rhesus monkeys and rats. Both species experience brain changes as they age, but do not develop Alzheimer's-type diseases.

Visualizing blood flow in the body and brain is one of the most valuable functions of Magnetic Resonance Imaging (MRI) technology. Using MRI scans on the monkeys first, the Columbia team was able to view differences in blood flow to the brain. Researchers discovered that older monkeys displayed a "significant decline in blood volume" in a section of the hippocampus (responsible for processing memories) known as the dentate gyrus.

In studying the smaller rat brain, the research team decided to focus on gene activity in the hippocampus instead of blood flow. A gene in the cells of the dentate gyrus called 'ARC'--a gene connected with learning--was closely monitored to determine its activity level, or expression, in different age rats. When scientists speak of gene expression, they are referring to the 'switching on' of a gene. Results of these scans showed that the older the rat, the lower the level of ARC expression. This may indicate a cause for cognitive impairment in human, age-related diseases.

The dentate gyrus seems to be the area most sensitive to aging in these species. Scientists have known that Alzheimer's Disease affects the hippocampus, but now they are beginning to see how. By permitting researchers to distinguish normal, age-related brain changes from those created by disease, MRI technology is opening the door for earlier diagnosis, even new therapies.

Even though the above-mentioned research is still years away from producing full-fledged treatments for anti-aging and longevity, it definitely is a step in the right direction... and one that we should keep an eye on. In next week's part two of this article, we'll talk about RNA Interference, the Genome Assembly Archive, and the INDY ("I'm Not Dead Yet") gene.

Posted 11-15-2004 12:58 AM by Doug Casey