Nadège Chéry, PhD

If physical appearance owes its beauty to strong, shapely muscles, it is a rather short-lived feature of human charm, as nice biceps, sculpted thighs and other graceful or bulging aspects of our musculature eventually wither as we age. Far more than our attractive physique is altered, unfortunately, since with advancing age the loss of muscle strength and mass also greatly contributes to frailty (resulting in falls and fractures).¹ Nevertheless, this undeniable consequence of the aging process is not entirely unavoidable. Indeed, simple, effective strategies that can significantly slow (or perhaps reverse) the age-related decline in muscular performance exist, yet they are often overlooked (or even feared) by the elderly.

In an individual between 30 and 80 years of age, muscle, the largest tissue of the human body,1 undergoes important decreases (up to 40%) in both strength and mass.¹⁰ This age-related loss of muscle strength and mass is typically referred to as "sarcopenia".^3,9,10 The expression "muscle wasting" is also used in geriatric medicine in reference to unintentional loss of weight, when fat mass and fat-free mass decrease, as occurs following starvation (at any age) or in geriatric failure to thrive.^7,8

The extent of the loss of strength is not the same across different types of muscles, and also varies greatly among individuals.

Fall Avoidance Dependent on Exquisitely Sophisticated Neural Control System

Brian E. Maki, PhD, PEng
Professor, Department of Surgery and
Institute of Medical Science,
University of Toronto and Senior Scientist,
Sunnybrook and Women's College Health Sciences Centre

It is well known that aging brings an elevated risk of falls and serious injuries, as well as other adverse medical and psychosocial outcomes. In recent years, exercise has been widely promoted as a potential means of reducing the risk of falling in older adults. There is no doubt that exercise and physical fitness is associated with a myriad of health benefits, and that older adults are able to improve strength, flexibility, aerobic capacity and other fitness measures as a result of exercise programs.^1-4 Even the very frail and very old have shown that they can improve their functional fitness through exercise.⁵ But what is the evidence to support the view that exercise and fitness could actually help to prevent falls and their consequences?

Certainly, there is evidence supporting an association between strength and falling risk. Severe compromise in the strength of the ankle dorsiflexors has been documented in nursing home residents with a history of falling.⁶ Other studies of less impaired individuals have also found evidence of associations between leg muscle weakness and an increase in the risk of falling.

 

Tracey Tremayne-Lloyd
and Lonny J. Rosen
Tremayne-Lloyd Partners
Toronto, Ontario

Elder abuse is an unfortunate and undiscussed phenomenon in our society, yet it is one that many physicians will encounter in the treatment of their elderly patients. Although there is little agreement on the definition of elder abuse, it can generally be defined as 'any act of commission or omission that results in harm to an elderly person.'¹ The types of harm suffered by elderly patients generally include physical, psychological, and financial abuse as well as neglect. Various studies conducted throughout North America have reported the incidence of elder abuse to be anywhere from 1%-10%. Since elder abuse is such a prevalent problem, it is critical for physicians to be aware of their statutory and professional reporting obligations.

Statutory Reporting Obligation
At present, there is no federal statutory obligation on the part of physicians across Canada to report elder abuse. Such obligations are set by provincial governments, and each of the provinces of Newfoundland, New Brunswick, Nova Scotia and Prince Edward Island have enacted some type of adult protection legislation. These laws impose on all persons the obligation to report a situation where a person is suffering from abuse or is otherwise in need of protection. The legislation in these provinces includes not only abuse of the elderly, but also usually covers all adults over the age of 16 or 18 years, who are in need of protection.

Lilia Malkin, BSc

Throughout the centuries, people have turned to medicinal substances to improve their health and quality of life. Today, medi-cations continue to be invaluable partners in humanity's war against disease. However, each person has a unique response to his or her medication(s). The differences among patients' reactions to pharmaceutical therapy can be at least partially explained by the inter-individual variation in drug metabolism. As biotechnology continues to make progress, the genetic foundation for illness and the consequent response to treatment is becoming increasingly apparent.^1,2 The basis for patient-to-patient variability in the effects of pharmaceutical agents has thus far been attributed predominantly to the drug-metabolizing capacity of the liver.¹ Accordingly, this article will focus on the hepatic biotransformation enzymes and the contribution of genetic polymorphism to individuals' thera-peutic responses and to treatment-related complications. It should be noted that tissue receptors and transporter proteins are also often subject to polymorphic variations, contributing to the variable response to medications and toxins; a discussion of this topic is, however, beyond the scope of this paper.

Hepatic Drug Metabolism Enzymes: An Overview
The metabolism and elimination of pharmaceutical agents may occur at several sites in the human body, including the liver, kidneys, gastrointestinal (GI) tract, lungs, and skin.

Down's Syndrome, a potential model for the pathogenesis of Alzheimer's disease

Nariman Malik, BSc

Alzheimer's disease (AD) is the most common cause of dementia in the elderly.¹ It affects more than 5% of all people age 65 and over and about 25% of those aged 85 and over.^2,3 This devastating disease is characterized by a progressive loss of cognitive abilities, usually beginning with short-term memory difficulties and progressing to include language, visuospatial and executive dysfunction.¹ Mean survival time following a diagnosis of Alzheimer's disease is about 8 years and death usually occurs as a result of intercurrent disease.⁴ In 1991, the Canadian Study of Health and Aging estimated that over 160,000 Canadians met the criteria for Alzheimer's disease.⁵ If the current trends continue, by the year 2031 the number of cases are predicted to triple while the population will have only increased by a factor of 1.4.⁵

The main risk factors for developing AD are advancing age and family history. The disorder can be classified as familial or sporadic. Familial cases are usually early-onset (onset before age 65), while sporadic cases are usually late-onset (onset after 65). The majority of cases of AD are sporadic. Individuals with a first degree relative with sporadic AD, are at twice higher risk of developing the condition.

 

David Kaplan, MSc(HA)
Joint Centre for Bioethics
Faculty of Medicine, University of Toronto

As the international quest to map and sequence the entire human genome continues, myriad medi-cal conditions of a genetic origin will be recognized, and tests to identify individuals at risk for these conditions will become available. An enormous amount of medical information can be gleaned from testing a person's genetic material. Health care providers could use this information to predict, and possibly prevent, future disability and disease. For over a decade, physicians have referred patients for genetic testing. In the early part of the last decade, this testing was often done without proper counselling. Numerous questions should be considered before referring an individual for genetic counselling and testing. Which patients should be sent for genetic testing and for which diseases should testing be available? Do traditional ethical and legal concepts of patient confidentiality, consent and disclosure apply to genetic information in the same manner as they apply to a patient's medical history? Are physicians liable for negligent counselling on the part of a non-physician genetic counsellor? This paper will highlight the ethical issues and legal implications of referring adult patients for genetic testing and counselling.

 

Anna Liachenko, BSc, MSc
Managing Editor,
Geriatrics & Aging

A number of groundbreaking studies seem to suggest that only a few genes are responsible for the multiple changes in our bodies, which lead to the gradual physiological decline, we call aging. The small number of genes involved in aging supports a thesis that was first proposed by Dr. George Martin of the University of Washington.

Using a new technology called oligonucleotide microarrays (or gene chips), to detect the rates of gene transcription, Dr. Richard A. Lerner together with Dr. Peter G. Schultz and other colleagues, recently examined 6000 genes expressed in human fibroblasts from both young and aging humans. They found that only 61 genes consistently showed changes in levels of expression with aging. More than half of these genes were involved in either cell cycle progression or remodeling of extracellular matrix. These cellular markers of aging may be fibro-blast-specific or at least mitotically-active-tissue specific as they are different from those found in post-mitotic tissues. Indeed, Dr. Tomas A. Prolla, who examined transcription rates in post-mitotic mouse gastrocnemius muscle, found a different (but, interestingly, just as narrow) subset of genes, for which the transcription rates were significantly altered with age.

In light of the small number of genes that presumably are able to cause the decline of multiple physiological systems, it is interesting to look at a group of genetic disorders called progerias. Progeria means early aging, in Greek.

Anna Liachenko, BSc, MSc
Managing Editor, Geriatrics & Aging

Despite the fact that colon cancer is preventable, over 16,000 elderly Canadians were diagnosed with the disease in 1999. One out of every three patients diagnosed with the disease, died. Prevention of colon cancer requires discovery and removal of the precursor polyp at an early stage. However, elderly patients, who are at risk of developing colon cancer are largely underscreened. The reasons range from high invasiveness of current techniques and, thus, poor patient acceptance, to inability of the current methods to efficiently detect small polyps. Fortunately, a new non-invasive and highly efficient technique--virtual colonoscopy--has recently been introduced. This article will describe the technique and compare this technique with the traditional methods of colonoscopy and barium enema.

David J. Vining and associates, at the Bowman Gray School of Medicine first described virtual colonoscopy in 1994. It is based on analysis of two sets of axial images obtained from thin-section helical computed tomography (CT) scans of the abdomen and pelvis. The procedure starts with cleansing the patient's bowel (using a standard barium enema or colonoscopy bowel preparation) followed by colonic insufflation with room air or carbon dioxide. Then, the abdomen and pelvis are scanned with the patient holding their breath for the first 15 to 20 seconds (to cover the upper abdomen) and gently respiring for the remainder of the scan.

Kimby N. Barton, MSc
Assistant Editor,
Geriatrics & Aging

Dramatic results presented in Cell have demonstrated that turning off the expression of a mutated protein in mice with Huntington's disease, results in either a cessation or a reversion of the symptoms associated with the disease.

Huntington's disease (HD) is an autosomal dominant inherited disorder characterized by motor disturbances such as chorea and dystonia, personality changes, and cognitive decline. These symptoms seem to result from neural degeneration, which occurs primarily in the striatum and cortex of the brain. HD typically manifests in mid-life and death follows 10 to 20 years after disease onset. Currently, no specific cure or treatment is available.

HD is caused by an expansion of glutamine (CAG) repeats near the 5' end of the gene that codes for a protein called huntingtin. The translated protein then contains an expanded glutamine (polyQ) sequence in the N-terminal portion. Normal individuals possess a polyQ length of approximately 6 to 34 repeats whereas individuals with more than 40 repeats develop HD. The longer the polyQ expansion, the earlier the onset of symptoms.

The pathogenesis of HD is poorly understood. It is believed that somehow the expansion of the polyQ sequence in the N-terminal portion of the protein results in a deleterious gain of function mechanism. Neuronal nuclear aggregates are found in the brains of patients with the disease as well as in transgenic animal models studied to date. These aggregates contain the mutant huntingtin protein and are also often found to be ubiquitinated suggesting that they have been targeted for proteasomal degradation. However, it remains to be determined whether these nuclear aggregates are themselves responsible for the neural degeneration or whether they are merely a byproduct of some other toxic response.

Amazingly, suppression of the mutant protein in mice between the ages of 18 and 34 weeks either halted or reversed the different aspects of the HD-like phenotype.

In this study, researchers created a conditional model of HD by expressing a mutated huntingtin protein under the control of a tet-regulated system. Essentially, they expressed a mutant protein in mice and looked at the effect it had on neuropathology of the brain and on the behaviour of the mice. Mice with the mutated huntingtin protein 'turned on' developed neuronal nuclear aggregates and showed behaviour consistent with that of having HD. Mice, as young as 4 weeks of age, were beginning to exhibit unusual behaviour. By 20 weeks, some, but not all, of the mice began to show a mild tremor that developed into a jerking motion. By 36 weeks the HD mice were clearly hypoactive and remained so until their death.

The most interesting part of the study, was when the researchers were able to turn the mutant protein 'off'. Adding an antibiotic to water consumed by the mice, turned off gene expression of the mutated protein. Amazingly, suppression of the mutant protein in mice between the ages of 18 and 34 weeks either halted or reversed the different aspects of the HD-like phenotype. Specifically, the neuronal and nuclear aggregates in the brain disappeared, the number of reactive astrocytes decreased, and the progressive striatal atrophy along with the decrease in D1 receptor levels was halted. In addition, stopping the expression of the HD gene prevented the further exacerbation of the HD behavioural characteristics and ameliorated their condition to a degree approaching those in control mice.

This is the first study that has ever demonstrated that the symptoms and characteristics of HD are reversible, implying that irreversible changes which commit the cell to neuronal dysfunction or death have not necessarily taken place. The findings also suggest that therapeutic approaches to target and specifically destroy the mutant huntingtin protein may be effective in returning patients with HD to a normal phenotype. Understanding the mechanisms responsible for this disease may provide new targets for therapeutic interventions in patients suffering from HD and other progressive neurodegenerative disorders.

Source

1. Yamamoto A., Lucas JJ. and Hen R. 2000. Cell. 101:57-66.

Philip Dopp, BSc

The disturbing statistics with regard to the prevalence of osteoporosis among older women are well known. By 65 years of age, one in four women have experienced an osteoporotic fracture, and the rate of incidence rises to one in two by the age of 75. The incidence of hip fractures among women in the United States is 2 per 1000 patient years by the age of 65 and 30 per 1000 patient years by the age of 85.1 More importantly, hip fractures in the elderly are associated with a high mortality rate. Both men and women are between two and five times more likely to die during the first 12 months following a hip fracture when compared to age and sex matched controls without hip fractures. Given this and other serious consequences, there is much interest in discovering factors that can prevent or slow the rate of development of this disease.¹

Pathophysiology of Osteoporosis
Osteoporosis is the generalized, progressive diminution in bone tissue mass per unit volume which causes skeletal weakness, even though the remaining bone is normal morphologically. It is well known that factors that decrease bone mineral density (BMD) and increase the risk of osteoporotic fractures include family history, white race, female gender, estrogen deficiency, low dietary levels of calcium and vitamin D, limited physical activity or immobility and medications such as corticosteroids.^1,2 Currently, there has been an increased interest in determining the role that genetic factors play in the pathogenesis of osteoporosis.