Neurobiology of Aging

Neurobiology of Aging

Speaker: David F. Tang-Wai, MDCM, FRCPC, Assistant Professor (Neurology), University of Toronto; University Health Network Memory Clinic, Toronto, ON.

Dr. David Tang-Wai presented a review of the basic mechanisms of human aging and offered a detailed application of the theories of aging to neurodegenerative disorders, foremost Alzheimer’s disease (AD). He discussed the neuropathology of AD and its causative factors.

Dr. Tang-Wai, acknowledging the previous speakers, noted that aging comprises multiple rather than single mechanisms, and all of those factors concerned in neurological aging and its disorders—from genetics to oxidative stress to mitochondrial dysfunction and accumulation of senescent cells—are interacting and inextricable processes.

Enumerating some of the key changes to the nervous system with age, Dr. Tang-Wai mentioned the import of age-related physiological change, such as brain atrophy, decreased catecholaminergic and dopaminergic synthesis, decreased “righting” reflexes, and decreased stage 4 sleep. Clinically these manifest in altered/slowed gait, body sway and forgetfulness, along with sleep disturbances (e.g., insomnia). However, these changes should be distinguished from conditions suggestive of disease processes, such as dementia, depression, movement disorders such as Parkinson’s, falls, and sleep apnea, none of which are normal accompaniments to the aging process.

Recent studies confirm that some cognitive decline is universal with advancing age, a decline that begins in early adulthood. Mental efficiency and capacity peak by the late 20s and then decline.

Moving on to an overview of AD, Dr. Tang-Wai noted that age is the biggest risk factor for the disease, the risk for which doubles beyond age 65. Alzheimer’s is the most common form of adult-onset dementia, but he noted that it may soon be surpassed by mixed Alzheimer-vascular dementia. What happens to the brain pathologically in AD is global shrinkage, widened sulcal margins, narrowed gyri, and increased sylvian fissure (Figure 1). As AD progresses at the microscopic level, synaptic and neuronal loss follow. Finally, pathological hallmarks of AD appear, including Hirano bodies, neurofibrillary tangles, granulovacuolar degeneration, and senile plaques.

He briefly reviewed the formation of tangles, which are the result of hyperphosphorylated tau (tau has 6 isoforms that pair up and conglomerate, ultimately forming tangles), as well as senile plaques (extracellular deposits of amyloid). He detailed multiple types of senile plaque, including diffuse plaque of aging, which may be seen in the nondemented older adult; neuritic plaque with a dense amylytic core; and with time “burned out” plaque that leaves a prominent amyloid core. This process begins in the hippocampus; thus, memory is first affected.

Discussing distribution of plaques and tangles as well as Braak staging, Dr. Tang-Wai described AD’s initial impairments in memory, progressing through the association cortex, and affecting sensory and motor systems in late stages. A mention of the amyloid beta (Ab) hypothesis prompted review of the predominant risk factors for AD, including Apolipoprotein E allele (accelerates cognitive decline in cognitively normal older adults and is associated with decreased processing speed and learning as well as reduced glucose metabolism), hypertension, obesity, hypercholesterolemia, and diabetes. Dr. Tang-Wai gave particular consideration to diabetes as a risk factor whose importance is under new and increased scrutiny. He noted that insulin influences memory by modulation of synaptic structure and function, long-term potentiation, and alterations of CNS levels of neurotransmitters. Insulin’s effects on the brain are protective. Insulin-resistant states include hyperinsulinemia, which reduces insulin transport across the blood-brain barrier and lowers insulin levels and activity in the brain. Reduced brain insulin signaling is associated with increased tau phosphorylation and higher Ab levels, which are the direct pathological signs of AD.

Obesity and hypercholesterolemia involve the adverse effects of increased insulin resistance as well as increased free fatty acids (FFA). Elevated FFA involve cascading adverse effects. They inhibit insulin-degrading enzymes, thus decreasing Ab clearance, stimulating assembly of amyloid plaque and tau filaments. Free fatty acids may also induce inflammation, which indirectly stimulates amyloid formation and neurofibrillary tangles.

Other key risk factors for AD include midlife hypertension, also involving insulin resistance and the risk of elevated Ab deposition; and oxidative stress, to which the brain is distinctly vulnerable as it is largely composed of easily oxidized lipids, has a high oxygen consumption rate (one-quarter of the oxygen consumed goes directly to the brain), and lacks strong antioxidant defenses, Dr. Tang-Wai noted. The link between AD and oxidative stress relates primarily to the increase in oxidation in the brain with aging.

Mitochondrial dysfunction, or energy dysfunction, is also implicated in AD. Research shows that Ab can interact with mitochondria and cause mitochondrial dysfunction. Mitochondrial dysfunction accelerates adverse processes associated with neurodegeneration (altered calcium homeostasis, ROS generation, glycol-oxidation, which can accelerate Ab aggregation and enhance proliferation of microglia; DNA mutation; and alterations of tau and Ab processing). Further, the oxidative changes in AD are associated with neurofibrillary tangles (and it has been theorized that effects of oxidative damage affect the neuron itself) as supported by the evidence of the presence of protein carbonyls, products of lipid peroxidation, and advanced glycation end products.

Focus is increasingly trained on the role of inflammation in AD through the synergistic effects among three major elements: microglia, astrocytes, and neurons. Inflammatory components related to AD neuroinflammation include microglia and astrocytes, both of which indirectly generate Ab. Microglia surround the neuron, and can produce reactive oxygen species and nitric oxide, leading to neurodegeneration. Astrocytes can produce neurodegeneration through production of reactive oxygen species, degradation of Ab, and production of cytokines and chemokines leading to more involvement of microglia. Damaged neurons themselves can also produce cytokines and chemokines, and increase CRP and amyloid P, which then activate the complement system. Finally, Ab itself can be an inciting factor for the genesis of astrocyte and microglial activation. Because there is increased production of reactive oxygen species and production of cytokines and chemokines, the result is phagocytosis and degradation of Ab. The tau protein can influence activation of complement systems. Microglia if upregulated can lead to decreases in Ab degradation and decreased insulin, leading to glucose intolerance, which can lead to Ab secretion. The sum effect is loops upon loops of compounding forces.

In order to produce the end result of AD pathology, key risk factors and genetic factors must be in place. Inflammation and oxidative injury are multisystemic. The processes he detailed in connection with AD pathology, Dr. Tang-Wai observed, apply to all neurodegenerative processes; these protein conformations/aggregations and inflammation are present in Parkinson’s disease and Creutzfeldt Jakob, as well as familial amyotrophic lateral sclerosis.

Measurement of Protection: How Do We Determine How||Well the Vaccine Works?

Advances in Influenza Vaccination

Measurement of Protection: How Do We Determine How Well the Vaccine Works?

Speaker: Allison McGeer, MSc, MD, FRCPC, Professor, Public Health Sciences, University of Toronto; Director, Infection Control, Mount Sinai Hospital, Toronto, ON.

Dr. Allison McGeer discussed the efficacy of current vaccines, referencing North American and international study data, and considered future avenues for improvement in vaccination practices and outcomes.

Most evidence-based data drawn from the North American experience with vaccination are taken from observational studies as the major U.S. and Canadian regulatory bodies called for a halt to placebo-controlled trials, given the evidentiary weight for the benefit of vaccination programs.

Despite the clear ethical benefit to the injunction, information about vaccine utility is still required from randomized controlled trials. Questions continue to be raised as to how well current vaccines protect against infection due to factors such as antigenic drift. Placebo-controlled studies are still conducted internationally and can serve as a valued source of information. Dr. McGeer described several such trials.

First she detailed a Dutch study that aimed to determine the efficacy of influenza vaccination in older adults. The randomized double-blind placebo-controlled trial involved fifteen family practices and a total of 1,838 healthy subjects age 60 years or older. The researchers found that among those study participants age 60–69 the vaccine was 57% effective in preventing influenza; among those individuals over age 70, efficacy dropped to 23%.¹ A similar study in Thailand that sought to determine the efficacy and cost-effectiveness of influenza vaccination in older Thai adults living in an urban community found that in individuals age 60–69 efficacy was 67%; at age 70 and over efficacy dropped to 34 %.² A third trial from Malaysia looking at vaccine efficacy in long-term care facilities supported influenza vaccination of persons with chronic diseases and >50 years of age living in institutions.³ They found that vaccination was 75% effective in preventing influenza-like illness.

Because the success rates sound modest, Dr. McGeer acknowledged that scepticism about vaccination persists. She advised that as or more important than efficacy rates are the numbers of individuals protected from disability and death, as well as the cost-effectiveness of the vaccine and vaccination programs. She cited a Swiss study focused on influenza-attributable mortality in which investigators found that vaccination led to very substantial decreases in mortality.⁴ She pointed out that the benefits of increasing vaccination have been documented by the Public Health Agency of Canada. In the 1980s, an average of approximately 7,500 deaths was attributed to influenza each year. With increasing vaccination rates, the estimated annual number of deaths dropped to 4,500 in the late 1990s. While further improvements are necessary, Dr. McGeer emphasized the direct benefits related to that drop. For those over 65 years of age, vaccination saves lives, prevents hospitalization, and saves $17/person in direct health care costs.⁵

Dr. McGeer described three potential avenues for decreasing the continuing burden of influenza in Canada: increasing influenza vaccination rates, improving case management, and developing more effective vaccines.

First, there is clearly substantial gain to be achieved from improving vaccination rates. Currently, Ontario has the highest overall influenza vaccination rates in Canada, but even in Ontario, vaccination rates among older adults are still no more than 80%. Vaccination rates among health care workers and children remain low.⁶ She pointed out that herd immunity from pediatric vaccination has led to dramatic reductions in adult disease due to Haemophilus influenzae and Streptococcus pneumoniae, and that vaccination of children against influenza is likely to confer substantial protection for adults (Figure 1). More importantly she described several studies that demonstrate unequivocally that vaccinating health care workers in chronic hospitals and long-term care facilities for older adults reduces all-cause mortality during the influenza season by 45%.⁷ Data show that the number of health care workers that must be vaccinated in order to prevent one resident/patient death in this setting is eight.

Dr. McGeer pointed out that some gains could also accompany improved diagnosis and treatment. During the peak of influenza season, more than 20% of patients presenting to the emergency department with fever and any cardiac or respiratory diagnosis have influenza. Since treating severely ill influenza patients with antivirals reduces the risk of mortality by 70%,⁸ improved diagnosis and therapy may improve outcomes, and reduce morbidity and mortality.

Finally, Dr. McGeer emphasized that, while improving vaccination rates with existing vaccines, and improving diagnosis and management will have an impact on the burden of influenza, the true benefits lie with the development of new vaccines that would offer improved efficacy in older adults. She referred discussion of new vaccines to the final symposium speaker, Dr. David Greenberg.

References:

1. Govaert TM, Thijs CT, Masurel N, et al. The efficacy of influenza vaccination in elderly individuals: a randomized double-blind placebo-controlled trial. JAMA 1994;272:1661–5.
2. Praditsuwan R, Assantachai P, Wasi C, et al. The efficacy and effectiveness of influenza vaccination among Thai elderly persons living in the community. J Med Assoc Thai 2005:88:256–64.
3. Isahak I, Mahayiddin AA, Ismail R. Effectiveness of influenza vaccination in prevention of influenza-like illness among inhabitants of old folk homes. Southeast Asian J Trop Med Public Health 2007;38:841–8.
4. Brinkhof MW, Spoerri A, Birrer A, et al. Influenza-attributable mortality among the elderly in Switzerland. Swiss Med Wkly 2006;136:302–9.
5. Maciosek MV, Solberg LI, Coffield AB, et al. Influenza vaccination health impact and cost effectiveness among adults aged 50 to 64 and 65 and older. Am J Prev Med 2006;31:72–9.
6. Kwong JC, Rosella LC, Johansen H. Trends in influenza vaccination in Canada, 1996/1997 to 2005. Health Rep 2007;18:9–19.
7. Hayward AC, Harling R, Wetten S, et al. Effectiveness of an influenza vaccine programme for care home staff to prevent death, morbidity, and health service use among residents: cluster randomised controlled trial. BMJ 2006; 333:1241.
8. Toronto Invasive Bacterial Diseases Network. Risk Factors for Macrolide-Resistance in Pneumococcal Bacteremia. The 48th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy, October 25, 2008, Washington, DC.

Sponsored by an unrestricted educational grant from sanofi pasteur.

The Need for an Improved Influenza Vaccine

Advances in Influenza Vaccination

Chair: Allison McGeer, MSc, MD, FRCPC, Professor, Public Health Sciences, University of Toronto; Director, Infection Control, Mount Sinai Hospital, Toronto, ON.

The Need for an Improved Influenza Vaccine

Speaker: Janet E. McElhaney, MD, FRCPC, FACP, Professor and Allan McGavin Chair in Geriatrics Research, Department of Medicine, University of British Columbia, Vancouver, BC; and Center for Immunotherapy of Cancer and Infectious Diseases, Department of Immunology, University of Connecticut School of Medicine, Farmington, CT, USA.

Prior to addressing needed improvements in influenza vaccinations, Dr. Janet E. McElhaney reviewed the pathophysiology of influenza illness in older adults, highlighting the importance of cell-mediated immunity and how it might be improved through vaccination. In a younger adult with adequate antibody protection, the influenza virus is likely to be neutralized on the mucosal surfaces. These surfaces lose functional proficiency as individuals age, and the antibodies needed to fight infection may be of insufficient quality. Under these conditions the virus can replicate and spread quickly, invading the lungs, and pneumonia is a common outcome.

The age-associated decline in cell-mediated immunity correlates with a tremendous increase in late-life morbidity from influenza infections. The immune response to influenza is triggered when the virus is inhaled and proceeds to infect the epithelial cells lining the respiratory tract. In order to defend against the spread of infection, the T-cell response must be activated along with the interferons produced by cells in the respiratory endothelium in order to shut down viral replication.

Dr. McElhaney cautioned that the atypical presentation of illness, particularly in frail older adults, often leads to a missed diagnosis of influenza. She advised that fever and/or confusion might be the presenting symptoms, whereas cough may not be apparent at the time of examination or hospital admission. Pneumonia is a serious complication occurring in ~30% of influenza illnesses in older adults.
To further highlight the impact of influenza-related complications in older adults, Dr. McElhaney described profound disability and serious decrements in functional status as a consequence of infection. Of particularly adverse impact are the long-lasting constitutional symptoms that occur with flu. An individual with malaise lasting in excess of three weeks may experience a profound change in functional status. Periods of prolonged bed rest can translate to a loss of up to 5% of functional muscular strength per day. A single bout of prolonged influenza-related illness in an older individual can lead to a state of frailty.

Influenza vaccination is a cost-saving medical intervention as it reduces hospitalization and death rates due to pneumonia, exacerbations of heart failure, heart attacks, and strokes. A recently published study by Reichert et al. of predictors of excess mortality associated with influenza cycles found that peak months of mortality among older adults for ischemic heart disease, cerebrovascular disease, and diabetes mellitus coincided appropriately with peaks in pneumonia and influenza.¹

A serious consequence of influenza has been termed by Ferucci et al. as catastrophic disability, defined as a loss of independence in three or more activities of daily living (Figure 1). Approximately 72% of individuals who experience catastrophic disability have been hospitalized. Preventing morbidity resulting from influenza illness is of high importance: pneumonia and influenza are among the top three leading causes of catastrophic disability, along with strokes and congestive heart failure.²

New influenza vaccines are needed in order to prevent this morbidity. There are real challenges to this objective, however. Dr. McElhaney acknowledged that, currently, the content of split-virus vaccines can vary significantly from one manufacturer to another. This may affect the T-cell responses that can be stimulated to these vaccines.

Killed vaccines offer effective antigen presentation to T-helper cells that activate an antibody response but cytotoxic T-lymphocytes (CTLs) are poorly stimulated by these vaccines, and in current vaccine development efforts, research is aimed at stimulating both helper T-cells and CTLs. Helper T-cells produce cytokines that play an important role in the activation of CTLs, which combat influenza viral infections by recognizing and destroying virus-infected host cells that have become sites of viral replication. It is necessary to supply antibodies that come and bind the extracellular virus. In older adults, stimulation of T-helper cells in the local lymph nodes tends to stimulate TH2 cytokine responses, with interleukin-10 being produced. Research has simulated this kind of environment and shown that in cell culture systems the addition of inflammatory cytokines that increase with aging can promote this response. Other cells go on to become infected as it is a challenge to eliminate virus-infected cells. Current efforts aim to develop a vaccine with greater TH1 and interferon gamma production.

Where those same inflammatory cytokines have been turned on, instead of adding them directly to the culture the research she has been involved in has orchestrated their production using toll-like receptor agonists. They are on the antigen presenting cells, making them more effective. The stimulation with those TLR agonists in the culture with the vaccine will promote this such that the CTLs will kill those virus-infected cells by this granule-mediated process.

Dr. McElhaney described ongoing work to develop assays for granzyme B that have been correlated with protection. Granzyme B is produced in cytotoxic T-lymphocytes and is a key mediator of cytolytic activity against virus-infected cells. Through validation of the assay they have shown that this a sensitive measure of the CTL response to vaccination as well as the interferon gamma to IL-10 ratio.
Influenza is a serious illness and is an often missed diagnosis in older individuals due to age-related changes in the immune response to influenza. Complications of influenza go beyond pneumonia and include cardiovascular morbidity, iatrogenic complications, and risk for catastrophic disability resulting in frailty. The true impact of the disease is not totally known, and efforts must continue toward improving current vaccines as treatment strategies for influenza cannot ensure a positive health outcome.

References:

1. Reichert TA, Simonsen L, Sharma A, et al. Influenza and the winter increase in mortality in the United States, 1959–1999. Am J Epidemiol 2004;160:492–502.
2. Ferrucci L, Guralnik JM, Pahor M, et al. Hospital diagnoses, Medicare charges, and nursing home admissions in the year when older persons become severely disabled. JAMA 1997;277:728-34.

Sponsored by an unrestricted educational grant from sanofi pasteur.

Cellular Senescence

Cellular Senescence

Speaker: Sharon Marr, BSc, MD, FRCP(C), MEd, McMaster University & Hamilton Health Sciences Centre, Division of Geriatrics and General Internal Medicine, Hamilton, ON.

In her address to geriatrics trainees, Dr. Sharon Marr aimed to promote a clearer understanding of the cellular changes accompanying aging, to clarify basic concepts relevant to DNA and gene expression that affect senescence, to detail cellular defense mechanisms, and to review the clinical implications of cellular senescence.

Given projected increases in the population of older adults, and the burden of age-associated disease on the health care system, a better understanding of the biology of aging is of value to clinicians. Dr. Marr distinguished between the concepts of lifespan, defined as a constant, maximum length of life for a member of a species under optimum living conditions (e.g., 120 years), and life expectancy, which is the statistically calculated estimate of the number of years of life one is expected to live at any given age.

Lifespan factors relevant to cellular changes with aging include genetic and environmental factors (e.g., impact on lifespan of caloric restriction, DNA damage/mutations, ionizing radiation, oxidative stress within or outside the cell), as well as psychological and metabolic stress, such as diabetes.

Cellular senescence (derived from the Latin senex, or old age) is fundamentally understood as a process induced by evolution into an organism’s genetic make-up. The concept encompasses all of the biological processes of a living organism as it ages. Senescence induces functional changes in cells with “full replicative potential” and in those in the post-mitotic phase.

She discussed the relevance of the Hayflick phenomenon to cellular senescence. The limit refers to the finding that human cells derived from embryonic tissues can only divide a finite number of times in culture. Dr. Hayflick and colleagues, working with human diploid fibroblasts (a cell type found in connective tissue) found that they cease to grow in vitro after a limited number of population doublings (~50 replications), a phenomenon named “replicative senescence,” which serves as a model to understand human aging.

Dr. Marr then discussed the relevance of telomere shortening. Telomeres are noncoding regions at the tips of chromosomes; this capping prevents chromosome fusions. In vertebrates, they are composed of repeated sequences of TTAGGG. With each replication our DNA starts to shorten a bit.

Telomere shortening is now considered the main causal mechanism of replicative senescence.¹ Also key were James Watson’s findings that DNA polymerase could not fully synthesize the 3’ end of linear DNA. Building on the insight into incomplete replications of chromosome ends, Alexey Olovnikov observed that human somatic cells could not fully repair chromosome shortening during DNA replication, and that damage occurs each time. Olovnikov proposed that the end-replication problem would result in telomere shortening with each round of replication and that this mechanism could be the cause of replicative senescence. However, further research has shown that telomerase activity can also elongate telomeres and correct the normal telomere erosion.

Research in genetics has also provided insight into human aging and cell senescence. Accelerated aging syndromes have highlighted the role of genes, such as in Werner’s syndrome, a defect on the WRN gene, located on the short arm of the 8th chromosome. The disorder is directly caused by shorter-than-normal length telomere maintenance and impairs DNA replication.

Animal studies into telomere erosion and shortening have suggested that this shortening is correlated with aging, and that chronological age is not a predictor of life expectancy.²

In general, Dr. Marr summarized, replicative senescence is associated with progressive loss of telomeric DNA strand replication of the ends of DNA molecules and telomeres become shorter with each cell division. Certain proteins (e.g., b-Galactosidase and tumour suppressor proteins) have been found to be protective against certain cancers (p53, p21, and p16) are up-regulated. Genetic and oxidative damage also contributes to telomere shortening by direct damage to DNA.

Dr. Marr then spoke to aging’s effects on organs, which age at different rates, and then turned to age-related decrements in the immune system. The innate immune system, the first line of defense against infection, comprises neutrophils, macrophages, natural killer cells, and cytokines and chemokines. For example, neutrophils experience age-related decreases in phagocytosis, oxidative burst, and bactericidal activity, while macrophages with age lose efficiency in phagocytosis, oxidative burst, and MHC class II expression. Other key changes include promotion of a pro-inflammatory state with increased cytokines. Such a state may increase or stimulate the development of diseases such as osteoporosis, neurodegeneration, and atherosclerotic heart disease, and such a state produces degradation products that are difficult to eliminate.

In terms of altered adaptive immunity, in T-cells, thymic involution hastens progressive loss of naïve T-cells, and there is decreased ability to process new pathogens, among other deleterious effects. Key B-cell changes include reduced naïve B cells, decreased immunoglobulin generation (IgM>IgG), increased autoantibodies, and reduced antibody binding affinity
Despite reduced immunogenicity, evidence for certain vaccinations in older adults is clear. For example, the new varicella zoster vaccine found that herpes zoster was reduced by 61% and post-herpetic neuralgia by 66%.³

Regarding the implications of cell senescence on cardiovascular disease and treatment, Dr. Marr noted that coronary endothelial cells and smooth muscle cells age as we age, citing work with stains on protein deposition that were positive for b-Galactosidase (associated with senescence). Other studies investigating telomere knock out have cited an increase in cardiac myocyte proliferation, myocyte hypertrophy and heart failure, suggesting that telomere shortening with age could also contribute to cardiac failure in humans.⁴

Skeletal muscle aging is also of concern, and she reminded listeners that aging is associated with gradual loss of muscle mass and strength, a decline that begins as early as age 25 (Figure 1). There is more infiltration of fat into cells, and fast-twitch muscle fibres age at an accelerated pace compared to slow-twitch.⁵ Factors that contribute to skeletal muscle aging include the decreased proliferative ability of muscle cells and the adverse effects of oxidative stress, which can cause premature muscle aging. In addition, there are well-known effects of aging bone, with decreased bone formation and decreased cartilage maintenance and repair.

 

Closing with a consideration of the clinical implications of cellular aging, Dr. Marr cited increased risk of infection, and increased burden of illness with poorer immunogenicity; however, hope lies in new research into preventing many forms of late-life cancer (e.g., via repressing ectopic telomerase or inhibition of telomerase), and the increasingly recognized importance of avoiding environmental stresses and promoting good lifestyle habits.

References:

1. Shawi M, Autexier C. Telomerase, senescence and ageing. Mech Age Devel 2008;129:3–10.
2. Bize P, Criscuolo F, Metcalfe NB, et al. Telomere dynamics rather than age predict life expectancy in the wild. Proc Biol Sci 2009;276:1679–83.
3. Oxman MN, Levin MJ, Johnson GR, et al. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med 2005;352:2271–84.
4. Leri A, Franco S, Zacheo A, et al. Ablation of telomerase and telomere loss leads to cardiac dilatation and heart failure associated with p53 upregulation. EMBO J 2003;22:131–9.
5. Lexell J. Human aging, muscle mass, and fiber type composition. J Gerontol A Biol Sci Med Sci 1995;50 Spec No:11–6.

New Technology in Influenza Vaccination

Advances in Influenza Vaccination

New Technology in Influenza Vaccination

Speaker: David P. Greenberg, MD, Senior Director, Scientific and Medical Affairs, US, Sanofi Pasteur; Adjunct Associate Professor of Pediatrics, University of Pittsburgh School of Medicine; Pediatric Infectious Diseases, Children’s Hospital of Pittsburgh, Pittsburgh, PA, USA.

Dr. David Greenberg’s discussion focused on novel technologies that could improve the immunogenicity achieved with influenza vaccines as well as increase vaccination rates among both older and younger adults.

Dr. Greenberg initially focused on results of studies with a high-dose intramuscular vaccine tested on older adults. Older adults’ declining humoral and cellular immunity, due to immunosenescence, increases their susceptibility to infection and decreases their immunologic responses to vaccines. As a result, older adults’ response to vaccination may be poor, yielding fewer protective antibodies. Higher-dose vaccines are being pursued to overcome this limitation.

Dr. Greenberg detailed a Phase 3 clinical trial of a high-dose influenza vaccine (60µg hemagglutinin [HA]/strain [H1N1, H3N2, and B]) that found value to the approach.¹ This randomized multicentre trial of 3,876 individuals, all ≥65 years of age and medically stable, compared high-dose vaccine versus standard-dose vaccine (Fluzone®, sanofi pasteur; 15µg HA/strain). The high-dose trivalent, inactivated influenza vaccine offered a fourfold higher antigen content compared with standard dose vaccine. Researchers reported significantly higher seroconversion and seroprotection rates and significantly higher hemagglutination inhibition (HAI) geometric mean antibody titres (GMTs) 28 days after vaccination among subjects who received high-dose vaccine compared with those who received standard-dose vaccine. Using strict U.S. Food and Drug Administration criteria, the high-dose vaccine demonstrated statistically superior immunogenicity compared with standard-dose vaccine (immunologic superiority for both A strains [H1N1 and H3N2] and noninferiority for the B strain). Local injection site reactions occurred more frequently in individuals who received the high-dose vaccine, but the reactions were generally mild to moderate.

Influenza-associated morbidity and mortality remains substantial among older adults, Dr. Greenberg emphasized, and the improved immunogenicity response elicited by the high-dose vaccine is likely to provide improved protective benefits for this population.
The next development in immunization research Dr. Greenberg discussed concerned seasonal influenza vaccination by intradermal microinjection (Figure 1). This is another approach to address the reduced immunogenicity of influenza vaccines among older adults that results from immunosenescence. Additionally, in healthy younger adults, vaccine uptake remains low. An intradermal delivery system offers an alternative that may improve vaccination rates and extend protection to people who might not otherwise receive annual influenza vaccination.

The physiologic principle of intradermal vaccination takes advantage of dendritic cells, which are the antigen presenting cells in the dermal layer. The dermal layer is also rich in lymphatic and blood supply, making it a robust arm of the immune system.
Dr. Greenberg reviewed results of two relevant Phase 2 clinical studies of intradermal vaccines.

The first was a multicentre, randomized study of 1,107 volunteers ≥60 years of age.² Participants received intradermal trivalent inactivated influenza vaccine containing 15 or 21mg of HA per strain or intramuscular control vaccine (Vaxigrip®, sanofi pasteur, 15 mg HA/strain). The primary endpoints of the study were the strain-specific HAI GMTs 21 days after vaccination. The authors of the study reported that, for each strain, the GMTs noted in association with each intradermal vaccine were superior to those noted with the intramuscular control.

The second was a Phase 2, multicentre, randomized open-label study of 978 healthy adults under age 60, which evaluated the immunogenicity and safety of intradermal trivalent inactivated influenza vaccine.³ Participants were randomized to either 0.1 ml intradermal vaccine with reduced antigen (9mg HA per strain) or conventional 0.5 ml intramuscular vaccine (Vaxigrip vaccine). Intradermal vaccination induced noninferior humoral immune responses against all three strains compared with intramuscular vaccine. Dr. Greenberg noted that conventional intramuscular vaccination induces strong immune responses in younger adults, but immunization rates need to be improved in this population. One means of achieving higher rates is through the alternative of this intradermal microinjection delivery system.

The intradermal needle used in these studies consisted of a very fine 30-gauge needle that protrudes only 1.5 milimetres (BD microinjection system [Becton Dickinson]). In addition to the advantages offered by this direct and potentially more efficient access to the immune system (via specialized dendritic cells and draining lymphatic vessels in the dermis), a needle shielding system protects the user against needle stick injuries.

Dr. Greenberg concluded that the studies offered sound evidence that intradermal vaccination can be used to elicit higher immune responses against seasonal influenza among older adults at a dosage of 15µg HA/strain, and is a promising alternative to intramuscular vaccination for adults <60 years of age, at a dosage of 9µg HA/strain.

The safety profile of intradermal influenza vaccination is comparable with conventional intramuscular vaccination but with higher rates of minor injection site reactions.

The final approach Dr. Greenberg discussed was adjuvanted vaccines. He provided details of a Phase 1 clinical study of adjuvanted low-dose H5N1 (avian strain) vaccine conducted among participants age 18-40 years.⁴ Groups of 50 participants received 2 doses, 21 days apart, of influenza A/Vietnam/1194/2004 NIBRG-14 (H5N1) vaccine containing 1.9, 3.8, 7.5, or 15µg of HA mixed with an oil-in-water emulsion adjuvant or 7.5µg of HA without adjuvant. Homologous HAI and microneutralization titres were determined after each vaccination. Cross-reactivity against A/Indonesia/05/2005 RG2 was tested after the second vaccination. Dr. Greenberg described robust seroconversion rates with adjuvanted vaccine (72–89%) compared with unadjuvanted vaccine (34%). The adjuvanted H5N1 vaccine was well-tolerated, and adequate immune responses were observed with as little as 1.9µg HA. Further, antibodies induced by adjuvanted vaccine were crossreactive to another strain of avian influenza, clade 2 Indonesia/5/05 RG2 strain, not observed with unadjuvated vaccine. All strengths of the adjuvanted vaccine met European Committee for Medicinal Products for Human Use immunogenicity criteria.

The fundamental benefit of adding an adjuvant to H5N1 vaccine, Dr. Greenberg emphasized, is that it is dose-sparing. An emulsion-adjuvanted pandemic influenza vaccine could have a major, positive effect on pandemic vaccination strategies due to limited vaccine stockpiles and limited worldwide manufacturing capacity.

In closing, Dr. Greenberg highlighted that the morbidity and mortality of influenza remains substantial across all age groups, particularly among older individuals. The novel vaccination strategies he discussed could help improve immunologic responses among older persons, overcome suboptimal immunization rates among high-risk and healthy younger adults, and better prepare health professionals to meet an influenza pandemic.

References:

1. Falsey AR, Treanor JJ, Tornieporth N, et al. Randomized, double-blind controlled Phase 3 trial comparing the immunogenicity of high-dose and standard-dose influenza vaccine in adults 65 years of age and older. J Infect Dis 2009;200:172–80.
2. Holland D, Booy R, De Looze F, et al. Intradermal influenza vaccine administered using a new microinjection system produces superior immunogenicity in elderly adults: a randomized controlled trial. J Infect Dis 2008;198:650–8.
3. Leroux-Roels I, Vets E, Freese R, et al. Seasonal influenza vaccine delivered by intradermal microinjection: A randomised controlled safety and immunogenicity trial in adults. Vaccine 2008;26:6614–9.
4. Levie K, Leroux-Roels I, Hoppenbrouwers K, et al. An adjuvanted, low-dose, pandemic influenza A (H5N1) vaccine candidate is safe, immunogenic, and induces cross-reactive immune responses in healthy adults. J Infect Dis 2008;198:642–9.

Sponsored by an unrestricted educational grant from sanofi pasteur.

Normal Aging Part 1: Cardiovascular, Respiratory, Gastrointestinal

Normal Aging Part 1: Cardiovascular, Respiratory, Gastrointestinal

Speaker: Karen Fruetel, M.Ed, MD, FRCPC, Division of Geriatric Medicine, University of Calgary, Calgary, AB.

Dr. Karen Fruetel emphasized in her review of the physiological changes accompanying aging that attributes of “normal aging” have been derived from clinical studies. The studies are either cross-sectional, meaning that health markers are derived from comparisons between predefined aging cohorts, or are longitudinal studies that follow the same individuals over a number of years. Both types have their biases. Cross-sectional studies may falsely overlook confounders (e.g., comparing 20-year-old and 80-year-old study participants may overlook the fact that the latter were more likely to have smoked than today’s youth). Data from longitudinal studies are generally thought to be more robust, but such data may reveal selection biases (e.g., higher educational and/or socioeconomic status). Obtaining information on the true physiological consequences of aging is a challenge.

Dr. Fruetel commenced with a review of aging’s effects on the cardiovascular system. Autopsy studies suggest that advanced age is associated with increased left ventricular (LV) mass. Studies also show increased myocyte size and decreased number, and focal proliferation of the matrix in which myocytes reside. There is increased collagen cross-linking. As for systolic function, there is little change when at rest. However, there is decreased beta adrenergic stimulation. Exercise elicits altered effects: there is decreased exercise-related increase in heart rate and contractility, and peak cardiac output is blunted by 20–30% in response to maximal effort.
Maximal ejection fraction (EF) decreases during exhaustive upright exercise. Fundamentally, with age, systolic volume is preserved over a range of physical demand.

By contrast, Dr. Fruetel noted, the diastolic does change, and with age there is decreased early diastolic filling. Increased late diastolic filling is due to increased atrial contraction, and there is increased atrial size. Dr. Fruetel summarized the key age-related physiological changes to the heart as increased LV wall thickening, alterations in diastolic filling, and impaired EF and heart rate response to exercise.

Dr. Fruetel then reviewed age-related qualitative change to the arteries (Figure 1). Structural alterations occur such that irregularities appear in the size and shape of endothelial cells. There is fragmentation of elastin and the arteries become longer, wider, thicker, and stiffer. Data from the Baltimore Longitudinal Study of Aging (BLSA) found a 20% increase in the size of the aortic root. Further, BLSA figures show carotid wall intimal medial thickness increases 2–3 fold.

Looking at biochemical changes in the cardiovascular system, there is decreased production and release of nitric oxide. When nitric oxide enters a cell, it relaxes blood vessels, curbs abnormal growth of vascular muscle, prevents platelets and white blood cells from adhering to vessel walls, and binds to free radicals. Dr. Fruetel noted that some researchers consider decreased availability of nitric oxide in the endothelium as one of the earliest signs of arterial aging and a pathological sign of atherosclerosis. Other key biochemical changes include increased angiotensin II with age, and an increase in inflammatory markers.

Moving from altered biochemical structure to arterial functions, she noted the effects of these changes (such as increased IM thickness, disruption of elastin, increased collagen, reduced nitric oxide, more angiotensin II) as collectively resulting in increased arterial thickness. The resultant changes manifest as increased systolic BP and decreased diastolic BP, changing pulse waves, and increasing afterload. Pulse wave velocity is thus altered: the greater the arterial elasticity, the slower the pulse wave velocity should be. Increased velocity has consequences as vessels have both a conduit and cushioning function. Greater pulsatile flow translates to increased risk of damage to organs such as the brain and kidneys due to increased afterload. Such physiological changes, along with the effects of diabetes, hypertension, smoking, and hyperlipidemia, lead to increased prevalence of cardiovascular disease among older adults.

Dr. Fruetel then detailed some changes to the gastrointestinal system with age. She discussed physiological anorexia of aging, a state in which consumption and caloric requirements drop with age. This state is multifactorial in origin: older adults’ smell is decreased; they experience more rapid satiety with reduced leptin levels (especially in males); their prevalence of dysphagia rises, partly due to decreased salivation but more generally due to medical illness and medications; and they experience more esophogeal problems as well as altered gastric emptying with advanced age, associated with gastrin and pepsinogen. Older individuals are more prone to gastric damage due to increased susceptibility owing to lower gastric prostaglandin levels, and thinner mucosal gel. There is no change in gastric emptying below a certain caloric level, nor change in colonic transit times. Gastrointestinal absorption is slightly changed, with reduced absorption of key vitamins and nutrients such as folate, B12, vitamin D, and calcium.

As for the liver, its size is reduced by one-third due to decreased hepatic cell regeneration and reduced blood flow, and while there is less mitochondria, activity is unchanged. In terms of function, there is no change in bilirubin or liver enzymes, and albumin levels are normal or only slightly decreased. Drug handling by the aging liver is slightly altered due to declines in hepatic metabolism, associated with decreased liver mass and decreased hepatic blood flow. Animal studies have shown reduced hepatic content of cytochrome P450; one human study found progressive decline in P450 levels with a 30% decline by age 70. Unlike the liver, the pancreas shows no change in size, but the volumes of duodenal secretion decline, as does insulin production, leading to issues of glucose intolerance.

Finally, Dr. Fruetel described age-related change to the human respiratory system. While Dr. Fruetel acknowledged the need for further investigation, some reliable data are available. Studies show that change occurs in the epithelial lining based on bronchial alveolar lavage cell populations, with a higher percentage of polymorphonuclear leukocytes but lower macrophages. There is an increased ratio of elastin to collagen, leading to increased lung compliance; further, there is decreased chest wall compliance due to calcification of cartilaginous articulations around the ribs, sternum, and spine. Airspace size increases but there is loss of surface area and an overall decline in the number of capillaries per alveolus.

Spirometry shows that FEV1 declines 0.3 l per decade; FVC declines are somewhat less. Residual volume increases, but the total lung capacity remains the same. Generally, studies show that peak expiratory flow changes; most age-related changes are in expiration and not the inspiration phase.

There is evidence of reduced muscular strength, with diaphragmatic strength reduced ~25%. Due to changes in the rib cage, older adults experience reduced respiratory strength. There is an increase in so-called dead space ventilation. Studies of aerobic capacity in fit vs. sedentary older individuals have found decreases in VO2 max, a drop experienced universally but at greater degrees in the nonfit. However, researchers have been able to produce improvements (up to 15%) in VO2 max in response to exercise training.

As for altered pulmonary defences, Dr. Fruetel described decreased mucociliary clearance with age as well as depression of the cough reflex among older adults when exposed to a noxious substance, compared to a younger cohort. Studies of older adults who inhaled noxious substance found that older individuals require a higher stimulus level to cough and may experience altered central nervous system perception of bronchoconstriction.

Theories of Aging

Theories of Aging

Speaker: Neal S. Fedarko, PhD, Division of Geriatric Medicine & Gerontology, Johns Hopkins University, Baltimore, MD, USA.

Dr. Neal Fedarko presented an overview of two theoretical categories that encompass explanations of human aging. They include evolutionary theories, which examine why humans age, and physiological theories, which examine how aging occurs.

The evolutionary theories predominantly focus on why aging exists and how aging has evolved as a process. Physiological theories, Dr. Fedarko explained by contrast, attempt to account for how aging occurs in humans and explicate structural and functional changes associated with aging, often focusing on specific aspects or structures that relate to advancing age (e.g., genetic programs, or genes involved in senescence; molecules and their chemical reactions such as free radicals; the activities of cell organelles; the signaling among cells and whole body systems maintaining homeostasis). Physiological theories are often subdivided into program theories, which posit aging as occurring due to intrinsic mechanisms, or may encompass random or stochastic explanations, namely, seeing aging as occurring by chance. Other accounts mix programmatic and stochastic theses.

Dr. Fedarko noted that aging theories generally touch upon one another, such that evolutionary theories often incorporate aspects of genetics and behaviour.

Evolutionary theories of aging reach back toward Charles Darwin, who stated nothing explicitly about aging. His successors suggested aging was a mechanism of natural selection that would weed out competitors for finite resources. A contemporary (1950s) evolutionary theory offered by P.B. Medawar known as the mutation accumulation theory (1952) described aging not as adaptive but as a byproduct of physiological events. Mutations, he held, are not screened out but accumulate over time, and they cause aging.

Another contemporary evolutionary theory is the antagonistic pleiotropic theory (1957) offered by G.C. Williams. He hypothesized that genes can have several traits, known as pleiotropy. These can have positive as well as negative effects, which would affect fitness in antagonistic ways. Pleiotropic mutations offer beneficial effects on the young (improved reproductive fitness) but harmful effects on the aged (reduced maintenance of the body). Aging is a product of the pressure of natural selection on these pleiotropic genes.

The trend in the evolutionary theory of aging is to combine the three and state that with increasing age, mortality rises, health and function decline, and that reproductive fitness declines over time. Natural selection is seen as exerting weak effects on mortality.
Dr. Fedarko then reviewed the physiological theories of aging that explore how we age. This question has interested physicians and philosophers as early as Galen (AD 129–c. 199), who saw aging as due to changes in bodily humours.

Posing the question of how we age invites the converse formulation, How do we live as long as we do? This is the approach of gerontology, Dr. Fedarko explained. Every physiological theory of aging identifies a maintaining or homeostatic structure as well as a corresponding theory of that system’s malfunction.

Dr. Fedarko offered numerous examples of maintenance or homeostatic systems (e.g., DNA repair, synthesis fidelity, clearance of defective RNA/proteins) that suggest factors in longevity and their corresponding theories of damage or malfunction (e.g., DNA damage, protein errors, and protein modifications) that account for mechanisms of aging.

For example, DNA repair is a target theory of genetic damage. Genes and chromosomes are susceptible to inactivating insults from radiation or other damaging agents. The evidence for the DNA damage theory gives rise to an aging phenotype. There is a demonstrated correlation between the amount of whole body irradiation and a shortened lifespan. There will be a consequent degree of somatic mutations in human T-lymphocytes with increasing age. Premature aging syndromes (e.g., Werner’s, Hutchinson-Gilford, ataxia telangiectasia, Cockayne’s) also offer compelling evidence. These accelerated aging syndromes share genes that are involved in DNA repair or metabolism, suggesting that if DNA cannot be maintained or repaired there is aging.

All physiological theories of aging have evidence against their explanatory power. Evidence against the DNA theory of aging addresses the theory’s implication that longevity should correlate with ploidy—namely, a benefit to more chromosome copies. The more copies, the longer you would live. But the theory is incorrect. The other inherent aspect is that mutations must occur over time, but mutations in DNA are not thought to occur at a high enough rate to give rise to aging phenotypes. It is proven that DNA damage, mutations, and chromosome abnormalities increase during aging, but it is not clear whether they are they contributory or merely associated with aging.

Among the other physiological theories described was the free radical theory of aging, which Dr. Fedarko named the most prominent theory of aging at present (Figure 1). Defense against oxygen free radicals is the homeostatic mechanism, and oxidative damage is theorized as a major contributor to aging. Free radicals can attack DNA and cause DNA base adducts, and modify DNA structure. Free radicals can also attack lipids, causing lipid peroxidation that builds over time. Oxidative damage can have an effect on long-lived cells such as neurons. Dr. Fedarko described the theory as important because of the causative role oxidation is perceived to have on other mechanisms of aging, namely, that is causes a cascade of further damage. It is seen as a causative agent in theories such as error catastrophe and protein modification theory.

Evidence for the theory includes proven damage to DNA, lipids, and protein; noted increases in abnormal mitochondria with age; proven acceleration of age with ionizing radiation; and superoxide dismutase in trisomy 21. However, counterevidence shows that antioxidant therapy does not increase lifespan (although some argue that the right therapeutic formulations have not been found) and that human cells already have effective defenses against radicals; others doubt the causative role of oxidation and see free radical damage as a secondary consequence of other processes.

Several theories once offered as causative theories of aging are now seen as stochastic agents that potentiate other aging mechanisms. Here Dr. Fedarko included the once-prominent toxic theory of aging that held that we accumulate toxic products in our bowel. The idea of toxic insults now contributes to other theories, such as the notion that UV exposure, smoking, and other environmental insults lead to phenotypic changes.

Dr. Fedarko detailed several other theories of aging, including the immunological and endocrine theories of aging, offering positive and negative evidence for each. On balance, he noted that most theories offer themselves as a sole account for human aging, but most embody aspects that synergize with other aging mechanisms. Dr. Fedarko suggested that one not view the many theories of aging as competing or mutually exclusive. Overall the varying accounts of aging reflect current understanding of the multiple maintenance and homeostasis mechanisms that allow for human longevity.

Community-Based Health Care for Frail Seniors: Development and Evaluation of a Program

Douglas C. Duke, MD, CCFP, Seniors Health, Northeast Community Health Centre, Edmonton, AB.
Teresa Genge, MN, Nurse Practitioner, Seniors Health, Northeast Community Health Centre, Edmonton, AB.

The delivery of relevant and coordinated health care to community-dwelling frail older adults is challenging. The community-based program described in this article applies a collaborative and flexible approach to the management and coordination of care of frail older adults. Although a feature of the program is its small size, its connection with professionals and services within a comprehensive health care system creates a much larger “virtual team.” Effectiveness of care is maintained through ongoing communication with care providers and the development of connections within the larger team.
Key words: frail older adults, geriatric evaluation and management, community-based care.

Nutrition Guidelines for Cancer Prevention: More Than Just Food for Thought

Kristen L. Currie, MA, CCRP, Department of Surgical Oncology, Division of Urology, Princess Margaret Hospital, University Health Network (UHN), Toronto, ON.
Sheri Stillman, RD, Clinical Nutrition, Allied Health, Princess Margaret Hospital, UHN, Toronto, ON.
Susan Haines, RD, Clinical Nutrition, Allied Health, Princess Margaret Hospital, UHN, Toronto, ON.
John Trachtenberg, MD, FRCSC, FACS, Department of Surgical Oncology, Division of Urology, Princess Margaret Hospital, UHN, Toronto, ON.

Older adults represent the highest percentage of new cancer diagnoses each year. This, combined with the increasing age of the population, underscores the importance of identifying methods for risk reduction. The World Cancer Research Fund, together with the American Institute for Cancer Research, has published recommendations for cancer prevention through diet and physical activity. These guidelines should be considered when counselling patients in cancer prevention. In this article, colorectal, breast, and prostate cancers are highlighted, and nutritional recommendations for these cancers are presented.
Key words: nutrition, prevention, colorectal cancer, breast cancer, prostate cancer.

Clinician’s Role in the Documentation of Elder Mistreatment

Elizabeth Pham, MD, Resident Physician, Department of Medicine, University of California, Irvine Medical Center, Orange, CA, USA.
Solomon Liao, MD, Associate Clinical Professor, Department of Medicine, University of California, Irvine Medical Center, Orange, CA, USA.

As the population ages, elder mistreatment is a growing concern in North America, and it includes physical and financial abuse and neglect. Careful documentation of the history, physical examination, and diagnostic data help achieve a clinical assessment that may be crucial to the outcome of a legal case and the protection of a patient. Good medical documentation ultimately saves clinicians time and demonstrates competency. This article discusses the items clinicians need to document in suspected cases of elder mistreatment. The emphasis is on issues that are above or beyond those performed in a routine clinical encounter.
Key words: elder mistreatment, elder neglect, elder abuse, financial exploitation, forensic documentation.