Télomères, télomérase et vieillissement

Télomères, télomérase et vieillissement

Conférencière : Chantal Autexier, Ph. D., Institut Lady Davis de recherches médicales, Hôpital général juif et Centre Bloomfield de recherche sur le vieillissement; départements de médecine et d’anatomie et de biologie cellulaire, Université McGill, Montréal (Québec).

La D^re Chantal Autexier a discuté du rôle des télomères dans le maintien de l’intégrité génétique et cellulaire, et du rôle de la perturbation des télomères dans la sénescence cellulaire et le vieillissement.

Télomères : description et rôle dans l’intégrité cellulaire
Les télomères sont des séquences répétitives d’ADN non codant (TTAGGG) qui protègent les extrémités des chromosomes eucaryotes linéaires. Chez les hommes, un complexe shelterin, formé de six protéines, se lie aux télomères¹. La structure et la taille des télomères sont importantes pour le maintien de l’intégrité cellulaire (Figure 1). Les télomères empêcheraient les mécanismes de réponse aux lésions cellulaires de considérer les extrémités des chromosomes linéaires comme des cassures d’ADN double brin (notamment comme des lésions chromosomiques provoquées par des stress, tels que des radiations ionisantes). Une perturbation de la structure ou de la taille du télomère peut entraîner des fusions entre les extrémités des chromosomes, une instabilité et des anomalies chromosomiques, et des troubles de la division cellulaire (sénescence cellulaire; mort cellulaire; les cellules deviennent cancéreuses).

La majorité des cellules de l’orga-nisme sont incapables de conserver la taille du télomère d’une division à l’autre, car la machine de réplication de l’ADN est incapable de répliquer la totalité des extrémités chromosomiques. Par conséquent, le télomère se raccourcit avec chaque division cellulaire. Une fois une certaine limite atteinte (la limite de Hayflick), la majorité des cellules sortent du cycle cellulaire et rentrent en sénescence. Cependant, une petite proportion de cellules est capable de réintégrer le cycle cellulaire : ce phénomène est en général associé à une élongation des télomères et à une expression de la télomérase, une enzyme impliquée dans la formation et le maintien des télomères. Bodnar et ses collègues ont montré qu’une expression forcée de la télomérase inhibe la perte des télomères et l’arrêt de la croissance de fibroblastes humains normaux en culture, et suffit à l’élongation du télomère et à l’immortalisation cellulaire (prolongation de la durée de vie)². À la différence de la majorité des cellules, certaines cellules, comme les cellules souches, les cellules de la lignée germinale et 85 % des cellules cancéreuses, expriment la télomérase. Par conséquent, ces cellules sont capables de maintenir la taille et la structure des télomères durant un grand nombre de cycles de division cellulaire.

Raccourcissement des télomères, sénescence cellulaire et vieillissement tissulaire
On appelle sénescence réplicative le processus par lequel une cellule sort du cycle cellulaire. Ce processus peut être déclenché par différents stress, comme des lésions dues aux radiations ou un stress oxydatif^3,4. Dans de nombreux cas, une perte de l’intégrité des télomères est responsable de la sénescence ou y est associée.

Le cycle cellulaire est contrôlé par de multiples mécanismes de vérification qui détectent les lésions de l’ADN, activent les mécanismes de réparation et déclenchent la mort cellulaire lorsque les lésions ne peuvent être réparées. Les suppresseurs de tumeurs sont d’importants régulateurs du cycle cellulaire. Ils régulent la sénescence et la mort cellulaire, veillant à ce que toute cellule très abîmée meurt ou arrête de se diviser. Lorsque ces protéines de contrôle sont absentes ou ne fonctionnent pas correctement, les cellules porteuses de lésions continuent à se développer. Bien que les suppresseurs de tumeurs protègent un organisme, en empêchant l’accumulation de cellules abîmées, ils contribuent également au vieillissement tissulaire. En effet, à mesure que les cellules abîmées qui rentrent en sénescence sont éliminées, le pool des cellules responsables du renouvellement des tissus et du maintien de la fonction tissulaire diminue.

Chez l’homme et d’autres organismes, les tissus qui se renouvellent rapidement (paroi de l’intestin, peau, follicules pileux et moelle osseuse) sont les premiers affectés par le raccourcissement des télomères et la sénescence et la mort cellulaires. De nombreux troubles liés au vieillissement affectent ces tissus.

Selon la Dre Autexier, de nombreuses études ont montré une corrélation entre le raccourcissement des télomères et la sénescence réplicative, la mort cellulaire et le vieillissement, d’une part, et entre la préservation de la taille des télomères, la présence d’une activité télomérase et l’immortalisation cellulaire, la longévité ou la formation d’un cancer, d’autre part.

Perturbation des télomères et vieillissement
La D^re Autexier a expliqué que de nombreuses caractéristiques du vieillissement naturel chez l’homme sont liées à un déclin des mécanismes nécessitant un renouvellement cellulaire constant, ou à un défaut des mécanismes de protection empêchant l’apparition ou la survie de cellules présentant des anomalies génomiques. Il s’agit notamment d’une diminution des fonctions immunitaires et de la moelle osseuse, d’une modification de l’épaisseur de la peau, d’une moins bonne cicatrisation des blessures, de modifications structurales des tissus épithéliaux, d’une perte de la fécondité et d’une augmentation de l’incidence du cancer. Les recherches suggèrent maintenant qu’une perte de l’intégrité des télomères est l’un des mécanismes clés à l’origine des pathologies liées à l’âge et au vieillissement.

La D^re Autexier a expliqué qu’il existe des similarités phénotypiques entre des syndromes de vieillissement prématuré chez l’homme, comme l’ataxie- télangiectasie, le syndrome de Werner et la dyskératose congénitale (DC), et le vieillissement normal, notamment des cataractes, une ostéoporose, un grisonnement des cheveux et une neurodégénérescence⁵. Ces syndromes sont associés à une défectuosité des gènes jouant un rôle dans le maintien de l’intégrité génomique et télomérique. Les phénotypes associés à la DC s’observent d’abord dans les tissus soumis à un renouvellement cellulaire constant, comme l’intestin, l’épiderme et la moelle osseuse^6,7. Les populations de patients atteints d’une forme dominante autosomique de la maladie ont des télomères plus courts, montrent des signes de la maladie plus tôt et une aggravation des symptômes à chaque génération successive. Les résultats sont en accord avec un mécanisme défectueux de maintien des télomères.

Effectivement, diverses formes de DC dérivent de mutations touchant des gènes directement impliqués dans le maintien de l’intégrité des télomères. À ce jour, les mutations identifiées comme étant associées à la DC affectent la télomérase, un élément du complexe télomérase appelé hTR (human Telo-merase RNA; ARN de la télomérase humaine) et un gène codant pour la dyskérine, une protéine qui se lie à l’hTR^8,9.

Un modèle murin dans lequel le gène mTR a été inactivé a permis de confirmer la relation entre une activité défectueuse de la télomérase et le processus de vieillissement. Bien que ces souris fussent viables, les générations successives montraient un raccourcissement progressif des télomères et une diminution de la fertilité (la 6e génération étant infertile)¹⁰. Il est intéressant de noter que ces souris présentent également une mauvaise cicatrisation, une perte et un grisonnement des poils, une diminution du poids corporel, une atrophie des villosités intestinales, une insuffisance médullaire et une augmentation de l’incidence du cancer^11,12.

La majorité des phénotypes observés dans ce modèle murin sont semblables à ceux des patients atteints de DC et, à un certain point, ressemblent aux pathologies liées à l’âge associées au vieillissement humain normal¹³.

Conclusion
La D^re Autexier a terminé sa présentation en observant que de nombreuses études au cours de ces quatre dernières années corrélaient la taille des télomères à la mortalité, la maladie d’Alzheimer et la longévité. Bien que ces études soient généralement des études de corrélation, il est intéressant de voir que la recherche s’intéresse à la longueur des télomères comme marqueur potentiel de certaines maladies associées au vieillissement^14,15,16.

L’intégrité des télomères est un régulateur essentiel du vieillissement humain et de la formation de cancers. Cette observation suggère que des protéines impliquées dans le maintien des télomères pourraient représenter des cibles moléculaires d’interventions thérapeutiques dans le domaine du cancer et d’autres maladies liées au vieillissement.

Bibliographie

1. Blasco MA. Telomere length, stem cells and aging. Nat Chem Biol 2007;3:640-9.
2. Bodnar AG, Ouellette M, Frolleis M, et al., Extension of life-span by introduction of telomerase into normal human cells. Science 1998;279:349-52.
3. Campisi J. Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell 2005;120:513-22.
4. Ithana K, Campisi J, Dimri GP. Mechanisms of cellular senescence in human and mouse cells. Biogerontol 2004;5:1-10.
5. Hasty P, Campisi J, Hoeijmakers J, et al. 2003. Aging and genome maintenance: lessons from the mouse? Science 2003;299:1355-9.
6. Kirwan M, Dokal I. Dyskeratosis congenita: a genetic disorder of many faces. Clin Genet 2008;73:103-12.
7. Marciniak R, Guarente L. Human genetics. Testing telomerase. Nature 2001;413:370-3.
8. Mitchell JR, Wood E, Collins K. A telomerase component is defective in the human disease dyskeratosis congenital. Nature 1999;402:551-5.
9. Dokal I, Vulliamy T. Dyskeratosis congenita: its link to telomerase and aplastic anaemia. Blood Rev 2003;17:217-25.
10. Blasco MA, Lee HW, Hande MP, et al. Telomere shortening and tumor formation by mouse cells lacking telomerase RNA. Cell 1997;91:25-34.
11. Rudolph KL, Chang S, Lee HW, et al. Longevity, stress response, and cancer in aging telomerase-deficient mice. Cell 1999;96:701-12.
12. Lee HW, Blasco MA, Gottlieb GJ, et al. Essential role of mouse telomerase in highly proliferative organs. Nature 1998;392:569-74.
13. Marciniak RA, Johnson FB, Guarente L. Dyskeratosis congenita, telomeres and human ageing. Trends Genet 2000;16:193-5.
14. Cawthon RM, Smith, KR, O’Brian E, et al. Association between telomere length in blood and mortality in people aged 60 years or older. Lancet 2003;361:393-5.
15. Panossian LA, Porter VR, Valenzuela HF, et al. Telomere shortening in T cells correlates with Alzheimer’s disease status. Neurobiol Aging 2003;24:77-84.
16. Nakamura K, Takubo K, Izumiyama-Shimomura N, et al. Telomeric DNA length in cerebral gray and white matter is associated with longevity in individuals aged 70 years or older. Experimental Gerontology 2007;42:944-50.

Telomeres, Telomerase and Aging

Telomeres, Telomerase and Aging

Speaker: Chantal Autexier, Ph.D., Lady Davis Institute for Medical Research, Jewish General Hospital, and Bloomfield Center for Research in Aging; Departments of Anatomy and Cell Biology, and Medicine, McGill University, Montreal QC.

Dr. Chantal Autexier discussed the role of telomeres in the maintenance of genetic and cellular integrity, and how telomere disruption is involved in cellular senescence and the aging process.

Telomeres and Their Role in Cellular Integrity
Telomeres are noncoding repetitive DNA sequences (TTAGGG) that protect the ends of linear eukaryotic chromosomes. In humans, a shelterin complex of 6 main proteins binds telomeres.¹ Both the structure and the length of telomeres are important for cellular integrity (Figure 1).

The telomeres are thought to prevent the cell’s damage response mechanisms from recognizing the ends of linear chromosomes as double-stranded DNA breaks, including those arising when chromosomes are damaged by stresses such as ionizing radiation. Interfering with telomere structure or length can lead to end-to-end fusions between chromosomes, chromosome instability and abnormalities, and cell division problems (cell senescence, cell death, or cells becoming cancerous).

In the body, most cells are unable to maintain telomere length from one division to the next, as the DNA replication machinery is unable to fully replicate the ends of chromosomes, leading to telomere shortening every time cells divide. Once a critical point—the Hayflick limit—is reached, most cells exit the cell cycle and undergo cell senescence. However, a small proportion of cells are able to re-enter the cell cycle, and this is usually associated with the lengthening of telomeres and the expression of telomerase, an enzyme directly involved in telomere formation and maintenance. Bodnar et al. have shown that forced expression of telomerase prevents telomere loss and growth arrest of normal human fibroblasts in culture and is sufficient for telomere lengthening and cell immortalization (extended lifespan).²

While most cells do not express telomerase, some cells do, such as stem cells, cells of the germ line, and 85% of cancer cells. Such cells are therefore able to maintain telomere length and structure through a large number of cell division cycles.

Telomere Shortening, Cell Senescence, and Tissue Aging
The process by which a cell exits the cell cycle is called replicative senescence. This can be triggered by various stresses, such as radiation damage and oxidative stress.^3,4 In many cases, senescence is caused by, or associated with, loss of telomere integrity.

The cell cycle is controlled by multiple checkpoint mechanisms that sense DNA damage, activate repair mechanisms, and trigger cell death when damage cannot be repaired. Tumour suppressors are important cell cycle regulators that regulate cell senescence and death, ensuring that a cell with extensive damage dies or stops dividing. When these checkpoint proteins are absent or malfunctioning, damaged cells continue to grow. Although tumour suppressors protect an organism from the accumulation of damaged cells, they also contribute to tissue aging. As damaged and senescent cells are eliminated through cell death, cell pools responsible for tissue renewal and the maintenance of tissue function are depleted.

In humans and other organisms, tissues that undergo rapid self-renewal—lining of the gut, skin, hair follicles, and bone marrow—are the ones most affected by telomere shortening, cell senescence and cell death. Many age-related pathologies affect these tissues.

According to Dr. Autexier, many studies have shown a correlation between telomere shortening and replicative senescence, cell death and aging, and between telomere length maintenance, the presence of telomerase activity and cellular immortalization, longevity or cancer formation.

Telomere Disruption in Aging
Dr. Autexier explained that many characteristics of natural aging in humans are related to a decline in processes that require continuous cell renewal, or to defective safeguard mechanisms that prevent the occurrence and survival of cells with genomic abnormalities. These include declines in immune and bone marrow functions, skin thickness changes, reduced wound healing capacity, structural changes in epithelial tissues, loss of fertility, and increased incidence of cancer. Research now suggests that loss of telomere integrity is one of the key mechanisms that drive the aging and age-related pathologies.

Dr. Autexier described that premature human aging syndromes, such as Ataxia Telangiectasia, Werner Syndrome, and Dyskeratosis congenita (DKC), share phenotypic similarities with the normal aging process, such as cataracts, osteoporosis, hair graying, and neurodegeneration.⁵ These syndromes are associated with defects in genes implicated in the maintenance of genomic and telomeric integrity.

DKC phenotypes first present in tissues that undergo constant cell renewal, such as the gut, the epidermis, and the bone marrow.^6,7 Patient populations with the autosomal dominant form of the disease demonstrate shorter telomeres, earlier disease onset and more severe symptoms with each successive generation. These results are consistent with a defective telomere maintenance process.

Various forms of DKC indeed arise from mutations in genes that are directly involved in maintaining telomere integrity. So far, DKC mutations have been identified in telomerase, in a component of the telomerase complex called hTR (human Telomerase RNA) and in the gene encoding Dyskerin, a protein that binds to hTR.^8,9

The relationship between defective telomerase activity and the aging process was confirmed in the mTR knockout mouse model. Although these mice are viable, successive generations exhibit progressive shortening of telomeres and decreased fertility (the 6th generation being infertile).¹⁰ Interestingly, these mice also present reduced wound healing, hair loss and graying, reduced body weight, intestinal villi atrophy, bone marrow failure, and an increased incidence of cancer.^11,12

Most phenotypes observed in this mouse model are similar to those seen in DKC patients and, to a certain extent, to age-related pathologies associated with normal human aging.¹³

Conclusion
Dr. Autexier closed by observing that there have been numerous studies in the last 4 years correlating telomere length and mortality, Alzheimer’s disease status, and longevity. Although these studies are generally correlative, it is interesting to see that more research is being done to look at telomere length as a marker for some diseases associated with aging.^14,15,16

Telomere integrity is a key regulator of human aging and cancer formation, suggesting that proteins involved in telomere maintenance could represent molecular targets for therapeutic interventions in the fields of cancer and other age-related diseases.

References

1. Blasco MA. Telomere length, stem cells and aging. Nat Chem Biol 2007;3:640-9.
2. Bodnar AG, Ouellette M, Frolkis M, et al., Extension of life-span by introduction of telomerase into normal human cells. Science 1998;279:349-52.
3. Campisi J. Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell 2005;120:513-22.
4. Ithana K, Campisi J, Dimri GP. Mechanisms of cellular senescence in human and mouse cells. Biogerontol 2004;5:1-10.
5. Hasty P, Campisi J, Hoeijmakers J, et al. Aging and genome maintenance: lessons from the mouse? Science 2003;299:1355-9.
6. Kirwan M, Dokal I. Dyskeratosis congenita: a genetic disorder of many faces. Clin Genet 2008;73:103-12.
7. Marciniak R, Guarente L. Human genetics. Testing telomerase. Nature 2001;413:370-3.
8. Mitchell JR, Wood E, Collins K. A telomerase component is defective in the human disease dyskeratosis congenital. Nature 1999;402:551-5.
9. Dokal I, Vulliamy T. Dyskeratosis congenita: its link to telomerase and aplastic anaemia. Blood Rev 2003;17:217-25.
10. Blasco MA, Lee HW, Hande MP, et al. Telomere shortening and tumor formation by mouse cells lacking telomerase RNA. Cell 1997;91:25-34.
11. Rudolph KL, Chang S, Lee HW, et al. Longevity, stress response, and cancer in aging telomerase-deficient mice. Cell 1999;96:701-12.
12. Lee HW, Blasco MA, Gottlieb GJ, et al. Essential role of mouse telomerase in highly proliferative organs. Nature 1998;392:569-74.
13. Marciniak RA, Johnson FB, Guarente L. Dyskeratosis congenita, telomeres and human ageing. Trends Genet 2000;16:193-5.
14. Cawthon RM, Smith, KR, O’Brian E, et al. Association between telomere length in blood and mortality in people aged 60 years or older. Lancet 2003;361:393-5.
15. Panossian LA, Porter VR, Valenzuela HF, et al. Telomere shortening in T cells correlates with Alzheimer’s disease status. Neurobiol Aging 2003;24:77-84.
16. Nakamura K, Takubo K, Izumiyama-Shimomura N, et al. Telomeric DNA length in cerebral gray and white matter is associated with longevity in individuals aged 70 years or older. Experimental Gerontology 2007;42:944-50.

Dysphagia in Older Adults

Fred Saibil, MD, FRCPC, Staff Physician, Division of Gastroenterology, Sunnybrook and Women’s College Health Science Centre, Associate Professor of Medicine,
University of Toronto, Toronto, ON.

Dysphagia is frequently under-rated as a symptom by both patients and their physicians. This article highlights the common causes of dysphagia in older patients and discusses the potential contributing factors in this age group. Newer therapies are also mentioned.

Key words: dysphagia, presbyesophagus, swallowing, motility.

Results of Molecular Medicine Studies Coming Fast and Furious

Oral cancer is the most common neoplasm of the head and neck and the ninth most common cancer worldwide. A simple, novel genetic test may now help with early diagnosis of this disease. The most common premalignant lesion of the oral cavity is oral leukoplakia, the presence of white patches in the mouth. Leukoplakia is recognized as an increased risk for cancer but there are no reliable clinical or histologic features that can be used to predict whether it will progress to cancer.

Researchers measured the DNA content (ploidy) of 150 patients with oral leukplakia, classified as epithelial dysplasia. What they found was that ploidy could be used to predict outcome. Patients with leukoplakia containing the normal 46 chromosomes were unlikely to progress to cancer. However, a startling 84% of patients with aneuploid lesions developed squamous cell carcinoma. The test was 97% accurate in its ability to predict that a patient would not develop cancer, and 84% accurate in its ability to predict that one would.

Unfortunately, a single molecular marker or class of markers cannot be used to predict the outcome of every case of oral leukoplakia because oral cancers develop along complex molecular pathways. Further studies are needed to support these data.

Sources

1. Sudbo J, Kildal W, Risberg B, Koppang H, Danielsen HE, Reith A. New England Journal of Medicine. 2001;344:1270-8.

Lou Gehrig’s Disease: A Closer Look at the Genetic Basis of Amyotrophic Lateral Sclerosis

Nariman Malik, BSc
Contributing Author,
Geriatrics & Aging.

Lou Gehrig: A Brief History
Lou Gehrig was born June 19, 1903 in New York City. He played for the New York Yankees from 1923 to 1939 and was one of the most famous first basemen in the history of major league baseball.¹ The man known as the 'iron horse of baseball' and 'Columbia Lou' was originally recruited for only two games in 1923.² However, this durable athlete went on to play in 2,130 consecutive games.³ In fact, he never missed a game until he voluntarily benched himself on May 2, 1939.

Gehrig had an impressive career. He had a lifetime batting average of .340, hit 493 home runs and was a four-time winner of the Most Valuable Player award.³ He was also inducted into the Baseball Hall of Fame. The 1938 season had proven to be a bad one for Gehrig as he was not playing up to his usual standard. During spring training for the 1939 season, he began having trouble getting power behind the ball and had difficulty with his movements.² Unhappy with his performance, Gehrig voluntarily benched himself.

Six weeks later, Gehrig was referred to the renowned Mayo Clinic where he was diagnosed with amyotrophic lateral sclerosis (ALS). Gehrig was never told his true diagnosis and was unaware that the outcome was fatal. Only his wife and a few of her confidantes knew the true nature of Gehrig's illness.

New Model for Neuronal Cell Death in Inherited Neurodegerative Diseases

There appear to be different biochemical mechanisms that underlie neuro-degeneration in a variety of different diseases including Alzheimer's (AD), Parkinson's (PD), Huntington's (HD) and amyotrophic lateral sclerosis (ALS). AD, PD and HD, are all characterized by the accumulation of protein aggregates, although the genes that produce the offending proteins are different, whereas in ALS there are alterations in the morphology of neuronal axons and in the expression of genes that encode neurofilaments.

A study that was recently published in the journal Nature suggests that although the essential biochemistry of these diseases may be different, they may have a common mechanism of neuronal cell death. Previously it was postulated that this common mechanism may be the process known as the 'cumulative-damage' hypothesis, which holds that the accumulation of damage to macromolecules, or toxic substances, eventually leads to the demise of the affected neuronal population. Over time, this would lead to an increase in the probability that a cell will die. If this theory were incorrect, one would expect that the probability of cell death would either remain constant, or would decline.

Clarke et al. investigated the kinetics of neuronal death in several neuro-degenerative diseases, in an effort to test the cumulative-damage hypothesis. Twelve different models of photoreceptor degeneration, hippocampal neurons undergoing excitotoxic cell death, and mouse models of cerebellar degeneration and Parkinson's and Huntington's disease, all showed patterns of death that are more consistent with a mathematical model in which the risk of cell death remains constant, or decreases exponentially with age. The authors propose that affected neurons are in an abnormal state, which they refer to as a 'mutant steady state', in which there is an increase in the probability that a single, rare catastrophic event will lead to cell death.

Particularly important is the fact that this study has implications for therapeutic intervention. The fact that a cell is not necessarily more likely to die with increasing age suggests that it may still be rescued by pharmaceutical intervention, even at a late stage in the disease process.

Source

1. Clarke G. et al. Nature 2000, 406:195-199.

Aging Research--Thoughts on the Present, Future, and Cellular Markers

An Interview with Dr. Tomas Prolla

Dr. Tomas A. Prolla, an Assistant Professor at the Departments of Genetics & Medical Genetics of the University of Wisconsin (Madison, USA), shares his thoughts on the field of "cellular markers for aging" and the implications of this research on the future of medicine and our society. Dr. Prolla's research focuses on the age-related changes in gene expression and the extent to which caloric restriction can offset these changes. Last year, Dr. Prolla and Dr. Richard Weindruch published a study identifying several genes involved in aging of mouse skeletal muscle.¹ Last March, Dr. Richard Lerner and Dr. Peter Schultz of The Scripps Research Institute (La Jolla, USA) published a study identifying genes involved in aging of human fibroblasts.²

Q: A recent batch of studies has used microarrays to provide a snapshot of the gene changes that occur with aging. These have included your study using mouse skeletal muscle and the recent Scripps study using aging fibroblasts. What is the significance of this work? Have we finally found the much sought after cellular markers for aging? Has this not been one of the Holly Grails of Aging research?

A: "Our findings suggest that DNA microarrays can be used to identify hundreds of biomarkers of aging on a tissue-specific basis.

The Fly That Would Live Forever

Investigations into Free Radical Effects on Cells: Interview with Dr. John Phillips at the University of Guelph

Kimby N. Barton, MSc

The contributions that Dr. John Phillips has made to the field of aging research have been mostly serendipitous. Dr. Phillips' major research interest has actually been in the field of what he terms 'oxygen toxicity', which just happens to tie into the free radical theory of aging. The free radical theory of aging states that reactive oxygen species (ROS) cause cellular damage, and that this cellular damage accumulates with time, eventually leading to cellular disease and death.

Dr. Phillips did not always think of oxygen as toxic. In fact, as an undergraduate he shared the popular misconception that oxygen was quite a good thing. It wasn't until he was a graduate student that he attended a seminar in which a researcher announced that he had found a protein called superoxide dismutase or SOD. SOD is an enzyme that helps convert oxygen radicals, into its less toxic form, hydrogen peroxide, which is then, with the help of a second enzyme, catalase, converted into molecular oxygen and water. Phillips was stunned to realize that oxygen was in fact so toxic that an entire system was required to try and prevent the damage it can wreak.

He obtained a faculty position at Guelph, where he began a research program that focussed on the fruit fly, Drosophila melanogaster--a model organism for studying genetic disease.

Genetics of Drug Metabolism: The Beginnings of Individualized Medicine for the Elderly

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.

Unravelling the Genetics of Early and Late-onset Alzheimer’s

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.