Genetics and Geriatrics

A Promise of Breakthroughs in Geriatric Medicine with the Imminent Completion of the Human Genome Project

Barry Goldlist, MD, FRCPC, FACP
Editor in Chief,
Geriatrics & Aging

When I started practicing geriatric medicine in 1979, I felt that I had left genetic diseases behind. Little did I know how much medicine would change with the advent of molecular genetics. One of the crucial changes in geriatrics is, of course, the elucidation of the genetic nature of Alzheimer's disease. Although currently only symptomatic treatments for the disease are available, an understanding of the genetics of the disease is helping us understand where we should target therapeutic strategies. There is great hope that modulating the metabo- lism of the amyloid precursor protein will allow us to influence the course of Alzheimer's disease. Understanding molecular genetics has been crucial in the development of a mouse model for Alzheimer's disease, which will likely speed the pace of discoveries in the future. Families of patients with Alzheimer's disease are aware of these genetic links, and they require an explanation of the risks that they personally face.

In fact, chronic diseases that have strong genetic contributions dominate geriatric medicine. Examples include diabetes mellitus and coronary artery disease. The genetics are often not simple, and currently modification of risk factors is the only therapeutic strategy that is commonly used. However, it is not inconceivable that this will change in the future and we will be better able to predict who is at risk, and perhaps even use specific therapies that directly modulate the genetic risk. Our experience with most modern medical therapies indicates that the elderly benefit at least as much as younger people. It will be interesting to see if this holds true for more specific interventions directed at the proteins for which specific genes code.

One of the greatest issues in geriatric medicine is that of 'polypharmacy'. Clearly the elderly have more diseases, and are more likely to require medications than younger patients. However, they are more prone to side effects as well. Our ability to tailor medications is very limited because we are often unable to accurately predict the likelihood of side effects. It is possible that a greater understanding of the genetic variability of drug metabolism will allow us to predict more accurately who will benefit from certain drugs and who will not.

These breakthroughs will all be brought about through the growth in knowledge of the human genome. Clearly the field of molecular genetics will dominate medical progress for years to come. This journal has an article on the human genome project. One of the major controversial issues currently is who 'owns' the rights to the human genome. I am one of those who firmly believes it should be in the public domain. I think there is an analogy here from the era of colonial exploitation. When European explorers 'discovered' new areas (ones that were already inhabited!) their actions resulted in untold human misery. Millions perished, some after enduring unimaginable agony. In fact, the explorers had not really discovered anything. North America and Africa had always been there, and had been inhabited by sophisticated societies. Similarly, the human genetic code has 'always' been there. If private concerns 'own' rights to the genome I feel we open up the process to great abuse, and might actually increase human misery.

I don't have the same concerns when it comes to new drugs or therapies, based on an understanding of genetics, being developed. Profit from such endeavors is a spur to innovation and improvements in health care and patent protection is clearly appropriate. However, no one created the human genetic code, and I feel no one should have exclusive rights to any part of it.

Enough moralizing! We have some very interesting interviews for you this month. To complement our article on the Human Genome Project, we have questioned Dr. Jamie Cuticchia, Head of the Bioinformatics Group at the Hospital for Sick Children, on the Genome Project and how having the entire human sequence may one day alter the field of medicine. We also have a fascinating interview with Dr. Tomas Prolla, an Assistant Professor in the Department of Genetics and Medical Genetics at the University of Wisconsin, who discusses recent evidence that the biology of aging is actually controlled by a very small set of genes. Finally, an interview with Dr. John Phillips from the University of Guelph, a specialist in 'oxygen toxicity', reveals that data from his research into fruit fly genetics led to important discoveries about how antioxidants may prevent some of the ravages of old age.

I hope you enjoy this issue, and its emphasis on genetics. I also hope you appreciate the irony for those specializing in geriatrics once again being overwhelmed by trying to understand genetics.

Genetic Markers in Mental Illness--A New Era of Predictive Screening

Genetic Identification Promises Individually-tailored Treatments

Julia Krestow, BSc MSc

Mental illness is a term describing a group of disorders, all of which profoundly affect an individual's ability to think, feel, and act, and which result in a substantially diminished capa-city to cope with the ordinary demands of life. Mental illness can strike irrespective of age, gender, or race.¹ Although mental disorders were recognized as illnesses in the mid-18th century, suspicion and fear often overshadowed understanding. Gradually, advances in the fields of psychiatry, behavioural science, neuroscience, biology, and genetics have replaced trepidation with knowledge. Some common mental illnesses are schizophrenia, bipolar affective disorder and depression.

Researchers and clinicians have worked for decades to reduce the suffering of those with disabling disorders, and current treatments can alleviate symptoms for many. Unfortunately, there is no curative treatment, and the treatments which do exist can have side effects. Research has long shown that the risk of developing mental illness increases if another family member is similarly affected; this suggests a strong hereditary component. Exciting developments in molecular genetics and the neurosciences explain the cautious optimism in terms of insight gained into the causes of mental disorders.

Why Do We Age? What Do Dolly’s Telomeres Tell Us?

Two Theories Linking DNA Damage and Aging: Free Radical/Oxidation vs. Telomere Shortening

Ruwaida Dhala-Vakil, BSc, MSc

There are many factors involved in human aging, and significant progress has been made in this field over the last few decades. Recent evidence from cloned calves suggests that scientists may not merely be able to reverse the cellular damage accumulating with age--they may, in fact, be able to prolong cell life. The cells from these cloned animals lived longer in culture and had longer telomeres than their normal counterparts. If this extension of the cellular life span can be translated into longer life for the entire organism, the calves may live fifty percent longer than normal.¹ Additionally, studies on antioxidants show that transgenic Drosophila (the fruit fly), which overexpress antioxidant genes, live 34% longer than controls.² This article will focus on both the free radical/oxidation theory of aging, and the role of telome-rase in aging.

Free Radical/Oxidation Theory of Aging
In 1956, Denham Harman suggested that there is an age-related accumulation of reactive oxygen species (ROS) which causes damage to cellular components. The damage is targeted to the proteins and DNA in the nucleus and mitochondria, as well as to the proteins and lipids in the cell membrane, and the proteins of the cytoplasm. Mitochondrial DNA is located near the inner mitochondrial membrane, close to the sites where free radicals form.