THE PATHOPHYSIOLOGY OF AGING.

DIAGNOSTICS AND TREATMENT THE ELDERLY PEOPLE

In the XXI century, the problem of increased of absolute and relative in the number of elderly people became actual for many countries around the world. Rapidly increased the numbers of these age groups: from 200 million in 1950 to 600 million in 2000 and up to 1 billion 100 million people in 2010.

The future of a human population is in large part predictable from analysis of its current age structure, the numbers of people in age classes. This is usually illustrated as a set of bar graphs for the size of the population, divided by sex, by age group. Here are the age distributions of Mexico and the United States, for example; this was the profile in approximately 1980. The relatively greater numbers of people in younger cohorts in Mexico was characteristic of a country which was experiencing rapid growth, with the number of births significantly exceeding deaths. In the United States, the post World War II “baby boom” generation produced a visible bulge, here (1980) visible in the 15-40 year age cohorts. The relatively smaller numbers of children, compared to older people, in the United States reflects a population whose growth was slowing.

Because the stability of various parts of the world is in part influenced by future population trends, even the US military views world demographics with interest. This slide comes from a 2008 US Joint Operating Environment military power point presentation.

The United States’s population is appears uniform until a closer look is taken.  Generally, the country produces a uniform citizenship at roughly 20 million citizens for every lustrum.  After the 60 years old benchmark the amounts of citizens is skewed right with not even a million above 90 years of age due to human life constraints.  In total there are roughly 309 million Americans.

American population is heavily marked by its history.  There are two notable bulges in the population, between the ages of 45 and 59 and between 15 and 29.  These differentiations are the baby boomers and their offspring.  Soldiers returning from World War Two founded large families and kicked off a population boom on an unprecedented scale.  The core of the veteran’s children were born between 1950 and 1965.   These children are in the 45-59 year of age in the chart.  The children of the baby boomers are born between 1981 and 1995.  They comprise of the younger age mean between the ages of 15 and 29.  It is little surprise that in the United States that the median age of births is roughly 30.5 in the United States, which is also the mean age difference between these two generations.

Here, the relative size of the populations and representative age distributions are apparent. Both India and China stand out as having huge populations, but the effect of China’s population policies (a decline in births is now apparent in the 0-25 year cohorts) contrasts dramatically with India’s youth-rich demographics. Smaller in absolute population, Nigeria reveals even more explosive population growth. Note that Mexico, which had undertaken a major government propaganda effort to persuade smaller family sizes, displays a less pyramidal structure than in the previous (1980) graph (above), indicating a population that is slowing its growth. Brazil, Germany, Russia, and Japan show age distributions that indicate current or near-future declines in population.

 

Growth in the number of older people requires studying the characteristics of the organism, diseases and their treatment.

 

Morbidity in the elderly (60-74 years) is 2 times higher and senile (75-89 years) age is 6 times higher than in younger individuals. This presents the greater need of this category of patients in medical care.

Polymorbidity characterized for the elderly and senile patients. Many chronic diseases are mutually aggravate each other and worsen the prognosis. The course of these diseases is atypical, often hidden against the background of general decrease the reactivity, peculiarities of inflammatory processes, of changes in the immune system, age-related changes.

Diagnosis in people of older age groups require other approaches, is more complex and time consuming. This is due to peculiarities of course of disease, age-related changes that limit the use of sophisticated instrumental methods.

Often people die not from old age, they die from a disease that appear with age. These diseases can and should be treated. Current concept of medicine is that people should be live a long time, while maintaining the health and creative activity. Today there is no doubt of the need for compulsory study of gerontology and geriatrics.

The aim of clinical gerontology (geriatrics) is the study of physiological and pathophysiological peculiarities an elderly person, of peculiarities of pathological processes and diseases, of peculiarities of the compensatory mechanisms which provide preservation the function of the affected organ, of their age-related peculiarities. They form the basis for the understanding of etiologic and pathogenetic principles of primary and secondary preventive maintenance, diagnosis and treatment of the elderly.

The modern classification of periods life of man (by WHO).

Young age in humans is defined as 20-34 years; mature age – 35-44 years, middle age – 45-59 years, “elderly” 60-75 years, and “aged” is the term applied to individuals greater than 75 years, 90 and more – centenarians

Geriatrics

Theories of Health and Disease:

1.      Humoral Theory

2.      Demonic Theory

3.      Religious Theory

4.      Magnetic Theory

5.      Miasmatic Theory

6.      Germ Theory

7.      Christian Science Theory

8.      Psychosomatic Theory

9.      Stress Theory

10.    Ecologic Theory

Life span refers to a theoretical limit on how long an organism might live under ideal circumstances. For humans, generally assumed to be 115 to 120 years.  This figure has not changed for centuries.

 

Compression of morbidity suggests the ideal aging process would keep disease and disability at a minimum until toward the end of life, after which one would die quickly.

 

Theories of Aging:

 

Three general categories of internal or external changes that contribute to the aging process:

·                   Secular changes – the result of natural wear and tear

·                   Senescent changes – due to aging of tissues & organs, especially those with low mitotic rate

·                   Pathological changes – resulting from disease processes

 

Heavy Labor Theory – Higher mortality rate among people who engage in overly strenuous work, especially if they are over age 55.  Death usually results from heart disease or cancer.

 

Overcrowded Conditions Theory – Rural versus urban living may be a key to longevity.  Physiological and psychological behavior varies, and people who live in cities and who have a faster-paced lifestyle seem to die younger than their country-dwelling counterparts.

 

Wear and Tear Theory – Regular stresses on body systems or organs reduces the life span of that particular area.  This might be associated with repeated ingestion of alcohol or other drugs.

 

Separation Theory – Aging and death are speeded up due to inability to adjust socially and/or psychologically after the death of a loved one.  Apathy is common.

 

Hypoxia Theory – Decrease in cerebral perfusion due to circulatory insufficiency related to a number of complications including illegible handwriting and decreasing memory and/or alertness.

 

Brain Size Theory – This theory that animals with larger brains live longer has been disproved.  The theory itself is not associated with the fact that brain weight diminishes to about 92% of its age-30 volume by the age of 75, or that nerve conduction velocity decreases to about 90%.

Enriched Environment Theory – Higher education and continuing educational experiences seem to provide psychological stimuli to enhance and lengthen life.

 

Bacteria and Virus Theory – The body succumbs to continual bombardment by micro-organisms.  Experimental rats in sterile environments had their life spans increased by 16 to 22 months.

 

Functional Theory – Lack of physical activity precipitates aging.  By maintaining some type of regular activity, individuals may experience better vascularization, increased stroke-volume and less vascular resistance, less heart disease, decrease in blood pressure, better collateral circulation, increased heart size, greater volume of blood capable of carrying more oxygen, more pliable vessels, better triglyceride removal resulting in less atherosclerosis.

 

Enzyme Theory – Vague notion that various enzymes may encourage or perhaps result from aging.

 

Nutritional Theory – Excess weight contributes to cardiovascular disease and early death.  The ratio of fat to muscle increases with age, and proper diet and exercise can help delay certain chronic and degenerative diseases, such as hypertension, coronary artery disease, and osteoporosis.  The life span of rats nearly doubled when their diet was reduced by two thirds.

 

Activity Theory – Family, work, social, and leisure activities helps to allay the effects of aging.

 

Free Radical Theory – Oxygen may interact with unsaturated fats in the tissues of an aging person and produce yellow-brown pigments.  This is similar to the reaction that causes varnish to harden and turn yellow as it dries and ages.  Anti-oxidants like vitamin E may neutralize the effects of free radicals.  Cell division increased from 50 to 120 in test-tube studies where vitamin E was added, along with a 30% increase in the lifespan of lab mice.

 

Metabolic Theory – Also known as the Energy Theory, this concept is that each person is born with a given amount of energy to be expended over a lifetime.  Sleeping in a cool room and lowering the temperature generally are thought to contribute to longevity.

 

Fixed Life Span Theory – Also known as the Genetic Theory, this concept is that each person is genetically programmed with an “aging clock” that determines when to begin aging and how fast.  Dr. Leonard Hayflick demonstrated that an infant’s cells divided about 50 times, compared to fewer divisions in older subjects.  He froze cells after a number of divisions, then thawed them later and noted that they “remembered” where they were and continued to divide until they reached 50 divisions.  Dr. Donner Denckle believed that the pituitary gland releases a hormone (DECO – “decreasing oxygen” – the “death hormone”) beginning at puberty that inhibits the body’s ability to utilize thyroxin, decreasing metabolism and contributing to the aging process.

 

Autoimmune Theory – Antibodies attack and destroy normal cells.

 

Stress Theory – Chronic transient stress as a factor in aging as well as in some disease processes.

 

Mutation / Radiation Theory – Overexposure to radiation causes more rapid aging and morbidity due to deleterious effects on RNA and DNA.

 

Cross-linkage Theory – Collagen molecules begin to cross-link during the aging process, increasing rigidity and reducing solubility.  This may be a result rather than a cause of aging.

 

Understanding human aging is a prerequisite to providing the best geriatric care. Age-related physiologic changes in different organ systems predispose older persons to specific diseases, or alter the presentation of disease. Strategies for disease treatment may need to be modified to accommodate for the age-related changes that occur in various organ systems.  Age-related physiologic changes may contribute to geriatric syndromes.

Fig. 1. Examples of age-related physiologic changes, and their clinical significance

Statement of the problem and program objectives

PROBLEMS: (1) Age-related physiological changes in organ systems and geriatric syndromes are ofteot accounted for in the assessment and treatment of hospitalized older patients. This may lead to under-diagnosis of geriatric syndromes, and/or inappropriate therapeutic interventions; (2) Faculty have heavy clinical responsibilities, where teaching becomes an added burden . 

OBJECTIVES: (1) enhance the geriatric assessment skills of medical residents, and improve their ability to recognize and document common age-related physiologic changes, and geriatric syndromes, and (2) reduce the time faculty physicians spend on teaching during in-patient clinical rounds.

Fig. 2. The residents should be able to recognize the kyphosis, the visual loss, and the use of a cane as risk factors for falls, and the edentulism as a risk factor for malnutrition

 

The decline in stem-cell functionality with age can be due to age-related changes at many levels. This figure illustrates several possibilities using a skeletal muscle fibre and an associated stem (satellite) cell as a model. In response to tissue injury, local signals induce satellite cells to begin proliferating in order to generate sufficient progeny for tissue repair. Age-related changes in satellite cells, in the satellite-cell niche or in the systemic milieu could all result in a diminished functionality of satellite cells in an aged organism, manifested as a decreased propensity to generate sufficient functional progeny for effective regeneration.[http://www.nature.com/nature/journal/v441/n7097/fig_tab/nature04958_F4.html]

 

Cardiovascular Aging

 

At early ages, the LV diastolic filling rate begins to decline, which is compensated for by increasing arterial contraction to sustain stroke volume and workload, maintaining sufficient ejection fraction. However, with age, the LV contractility and ejection fraction, as well as sympathetic modulation of heart rate, and response to β-adrenergic receptor activation all decrease. A reduction in cardiac output due to decline in function with age stimulates the myocardium to compensate by increasing muscle mass by undergoing cardiac hypertrophy; although this may provide short-term enhancement of cardiac output, the long-term effect of hypertrophy diminishes cardiac function. Ventricular hypertrophy is the result of an increase in size of individual cardiomyocytes and can be either physiological, which is reversible (eg, exercise-induced), or pathological which is irreversible (disease-based).

The third European guidelines on cardiovascular disease (CVD) prevention, launched at this year’s European Society of Cardiology (ESC) Congress, were influenced by the results of the second European Action on Secondary Prevention through Intervention to Reduce Events (EUROASPIRE II) survey, which was conducted in 15 European countries. EUROASPIRE was part of a major ESC initiative promulgated to update and replace the Framingham database with a data set that is based on current European population demographics. Examination of these new data revealed that the management of patients’ risk factors has not been effective in achieving the goals for CVD prevention set out in the joint European societies’ 1998 guidelines. As a result, the new guidelines differ in several major aspects from the previous ESC guidelines, which were largely based on data from the Framingham Heart Study.

The 2003 guidelines have abandoned the Framingham model and are based on this new, large European database of almost 3 million person-years of observation followed for almost 10 years with > 7000 fatal cardiovascular events as an endpoint. The guidelines are specifically intended to encourage the development of national guidance on cardiovascular disease prevention, acting as a framework that can be adapted to reflect different political, economic, social, and medical circumstances in the different regions of Europe.

The guidelines were prepared by Third Joint European Societies’ Task Force on Prevention of Cardiovascular Disease, chaired by Guy G De Backer, MD (Ghent University Hospital, Belgium). The task force was a partnership of 8 major societies:

·         European Society of Cardiology (ESC)

·         European Society of Atherosclerosis (EAS)

·         European Society of Hypertension (ESH)

·         European Society of General Practice/Family Medicine (ESGP/FM)

·         European Association for the Study of Diabetes (EASD)

·         European Heart Network (EHN)

·         International Society of Behavioural Medicine (ISBM)

·         International Diabetes Federation Europe (IDF-Europe)

plus representatives of the ESC Working Groups on Epidemiology and Prevention, Cardiac Rehabilitation & Exercise Physiology, and Cardiovascular Nursing. The guidelines are endorsed by the parent bodies.

A pocket version of the guidelines is also available in print. The full document will be published later this year in the European Journal of Cardiovascular Prevention & Rehabilitation as well as online.

The objectives of the guidelines are to reduce the incidence of first or recurrent clinical events due to coronary heart disease, ischemic stroke, and peripheral artery disease.

The focus is prevention of disability and early death. To this end, the guidelines address the role of lifestyle changes, the management of major cardiovascular risk factors, and the use of different prophylactic drug therapies.

New Aspects of the Guidelines

1.     The guidelines are concerned with the prevention of CVD rather than just coronary heart disease (CHD). The etiologies of myocardial infarction, ischemic stroke, and peripheral arterial disease are similar, and recent intervention trials have shown that several forms of therapy prevent not only coronary events and revascularizations, but also ischemic stroke and peripheral artery disease. Hence, initiation of specific preventive action is recommended based on estimation of risk of any vascular event.

2.     The risk assessment uses the Systemic COronary Risk Evaluation (SCORE) model and risk charts (see below), which can be adapted to different national conditions, resources, and priorities, and takes into account the heterogeneity in CVD mortality across European populations.

3.     Risk is defined in terms of the absolute 10-year probability of developing a fatal rather than any cardiovascular event.

4.     The threshold for high risk of a fatal cardiovascular event is now defined as ≥ 5% rather than ≥ 20% as previously.

5.     The first priorities in clinical practice are patients with established CVD, peripheral artery disease, or cerebrovascular lesions; asymptomatic individuals at high risk for developing atherosclerotic CVD; and close relatives of both groups.

6.     Updated recommendations are given regarding behavioral changes, risk factor management, and the prophylactic use of drugs. This includes a more professional management of behavioral risk factors, for which the goals remain similar: no smoking, making healthy food choices, and being physically active.

Patients With Established CVD and High-Risk Individuals

The guidelines recommend that in patients at potentially high risk of CVD, the risk of total CVD should be assessed by the SCORE system (see below). Goals in these patients and those with established CVD should be:

Lifestyle:

·         Do not smoke

·         Make healthy food choices

·         Be physically active

Risk factors:

·         Blood pressure

o    < 140/90 mm Hg in most

o    < 130/80 mm Hg in some

·         Total cholesterol

o    < 5/0 mmol/L (150 mg/dL) in most

o    < 4.5 mmol/L (175 mg/dL) in some

·         LDL cholesterol

o    < 3.0 mmol/L (115 mg/dL) in most

o    < 2.5 mmol/L (100 mg/dL) in some

·         Good glycemic control in all persons with diabetes

Prophylactic drug therapy should be considered in particular groups. These parameters have been summarized as a mnemonic for the practitioner as the “European heart health telephone number”: 14090530 which is parsed out as:

·         140 (mm Hg) SBP

·         90 (mm Hg) DBP

·         5 (mmol/L) total cholesterol

·         3 (mmol/L) LDL cholesterol

·         0 NO SMOKING

Systemic COronary Risk Evaluation — SCORE

A new European risk prediction system, SCORE , has been developed to define the lifestyle, risk factor, and therapeutic targets for CVD prevention. SCORE is representative of typical European populations, and the risk score system has been optimized for coronary prevention in European clinical practice. Describing the development of the SCORE chart,

Troels F Thomsen, MD, PhD (University Hospital Glostrup, Copenhagen, Denmark), noted the problems with the chart used in the previous ESC guidelines:

1.     The Framingham function overpredicts in European populations with low or medium levels of disease incidence.

2.     It was derived from a relatively small data set with few or no events in some risk factor combinations.

3.     It was impossible to combine > 5 variables.

4.     It used endpoints that could not be reproduced from other data sets and were therefore hard to validate.

5.     It probably underestimated the importance of diabetes.

The SCORE system differs from the European task force chart used in previous guidelines in important ways (Table). SCORE was developed using data from 12 European cohort studies (N = 205,178), some with multiple component cohorts, mainly population studies covering a wide geographic spread of countries at different levels of cardiovascular risk. The SCORE data come from one quarter million persons and contain some 3 million person-years of observation and more than 7000 fatal cardiovascular events. It addresses fatal events rather than total events, total cardiovascular risk rather than just CHD, charts for cholesterol and cholesterol:HDL ratio, and includes more detail for the 50- to 65-year age range. No charts are included for individuals with established disease or diabetes.

Table. ESC Task Force Chart (1998) Compared With the SCORE System (2003)

Risk estimation is based on age, sex, smoking habits, systolic blood pressure (SBP), and either total cholesterol or cholesterol/HDL ratio.[7] Using the SCORE model, risk charts can be provided for all European countries. Total risk can be calculated from SCORE charts, such as those shown in Figures 1 and 2. The low-risk chart is for countries such as Belgium. France, Greece, Italy, Luxembourg, Portugal, Spain, and Switzerland. The high-risk chart is for use in all other European countries. Relative risk is calculated by comparing an individual’s risk category with that of a nonsmoking person of the same age and gender with blood pressure ≤ 140/90 mm Hg and total cholesterol < 5 mmol/L (< 190 mg/dL).

Figure 1. The new European Risk Chart based on SCORE data. For high CVD risk, regions are based on total cholesterol levels. Adapted from Conroy et al, Eur Heart J. 2003;24:987-1003. Copyright© 2003 European Society of Cardiology. All rights reserved.

Figure 2. The new European Risk Chart based on SCORE data. For low CVD risk, regions are based on total cholesterol levels. Adapted from Conroy et al, Eur Heart J. 2003,24:987-1003. Copyright © 2003 European Society of Cardiology. All rights reserved.

 

SCORECARD is the electronic counterpart to the SCORE risk chart, and will be launched in February 2004. It operates with the same risk factors, end points, colors, etc, but shows total risk as a bar chart and the distribution of modifiable risk factors as a pie chart. The expected effect of intervention is calculated from large randomized clinical trials in hypertension and hypercholesterolemia and is also shown in a bar chart. At the end of a consultation, the clinician may print an individual’s health advice based on their actual risk profile. This will be done in the national language, both on the screen and in print. The health promotion advice for the patient will be compiled from endorsed professional sources in each country. SCORECARD has been translated into 47 languages and calibrated to each country’s national mortality statistics. Clinicians will be able to download the nationally tailored version of the program from the ESC homepage

 

Aging of the vasculature results in increased arterial thickening and stiffness as well as dysfunctional endothelium. Clinically, these changes result in increased systolic pressure and present major risk factors for development of atherosclerosis, hypertension and stroke, and arterial fibrillation. Vascular dysfunction associated with aging leads to a variety of age-related pathologies, including loss of adequate tissue perfusion (resulting in ischemia), insufficient vascular growth or regression (resulting in hypertension), or excessive growth and remodeling (resulting in age-related macular degeneration). The vasculature undergoes structure and function alterations with age that are well documented, such as luminal enlargement with wall thickening and a decline in endothelial cell functioegatively affecting endothelium-dependent dilation and promoting vascular stiffness. In addition, endothelial cells lose their ability to proliferate and migrate after tissue injury. Furthermore, endothelial barriers become porous and vascular smooth muscle cells migrate into subendothelial spaces and deposit extracellular matrix proteins that result in intimal thickening. At the molecular level, as endothelial cells age, they exhibit a reduction in endothelial nitric oxide synthetase (eNOS) activity, reducing the abundance of NO. NO is a critical vasodilator produced by endothelial cells, regulating vascular tone, in addition to inhibiting vascular inflammation, thrombotic events, and aberrant cellular proliferation. Loss of NO also promotes endothelial cell senescence. Numerous mechanisms can modulate eNOS activity. However, hemodynamic shear stress, the frictional force acting on endothelial cell surface as a result of blood flow, is one of the most potent inducers of eNOS activity. As vessels age, they are exposed to less hemodynamic stress due to reduced blood flow caused by decline in heart function; in addition, endothelial cells become less responsive to shear stress, resulting in a decline in the protective NO. Therefore, measuring arterial thickness and stiffness in aged can lead to further understanding of the role various longevity genes influence vasculature aging. Elastic properties of arteries can be directly measured, as well as histological analysis of luminal enlargement, arterial thickness, and deposition of vascular smooth muscle cells. In addition, measuring eNOS activity in vessels, as well as endothelial senescence, can also serve as a marker of vascular aging.

 

The aged immune system, typically hyporesponsive to infection and vaccination, can be hyperresponsive in the context of inflammatory pathology. Here we review current work examining the mechanisms behind the amplified inflammatory profile of aged adaptive immunity, and the reciprocal relationship between chronic inflammation and immune aging. Aged hematopoietic stem cells are driven to differentiate following accumulated DNA damage, thus depleting the stem cell pool and increasing the number of damaged effector cells in the circulation. Chronic DNA damage responses in lymphocytes as well as senescent cells of other lineages initiate the production of inflammatory mediators. In addition, aged lymphocytes become less reliant on specific antigen for stimulation and more prone to activation through innate receptors. When these lymphocytes are exposed to inflammatory signals produced by senescent tissues, the bias toward inflammation exacerbates destruction without necessarily improving immunity.

► The aging immune system is more prone to inflammation but less protective. ► DNA damage reduces stem cell renewal, depleting lymphoid and promoting myeloid progenitors.

► Poor DNA repair perpetuates damage and alters mature lymphocyte function. ► Aged T and B lymphocytes are less antigen-dependent and more inflammatory.

► Cytokine production by senescent cells exacerbates inflammation.

 

 

 

Chronic inflammation and aging

Figure 1. DNA damage responses (DDR) are induced by many different age-associated DNA damage events and promote inflammation through different mechanisms. (a) Accumulated DNA damage in lymphoid hematopoietic stem cells (HSCs) induces differentiation into mature lymphocytes and leads to an imbalance in the stem cell pool, which becomes dominated by myeloid precursors. The reduction in lymphoid HSCs, combined with thymic involution and reduced bone marrow output, leads to a reliance on innate immunity favoring broad inflammatory responses. (b) The lymphocytes differentiating from damaged HSCs may harbor unfavorable mutations that then integrate into the adaptive repertoire. In addition, DDR induced by age-associated nontelomeric DNA damage or telomeric erosions can contribute to the activation of T effector cell populations and production of inflammatory mediators. (c) Cellular senescence induced by DNA damage has also been shown to induce the production of inflammatory cytokines by a variety of cell lineages not directly related to the immune system, a process coined as senescence-associated secretory pattern (SASP). In addition to directly causing pathology, this inflammatory tissue environment can attract and activate lymphocytes in a bystander fashion, even in the absence of specific antigen stimulation.

Figure 2. Age-associated changes to B and T lymphocytes. Aging of the immune system is associated with changes to B and T lymphocytes. These changes have different underlying mechanisms but related downstream consequences. T and B cells experience reduced selection pressure, owing to changes in primary lymphoid tissues and changes in survival requirements. Both cell types become less reliant on exposure to specific antigen through the BCR and TCR for activation, and more responsive to innate/antigen-independent signals, such as TLR ligands and cytokines. Additionally, there is cross talk between populations. Aged B cells are effective antigen presenters, and preferentially induce Th1 and Th17 responses in T cells. In parallel, aged regulatory T cells fail to suppress Th17 responses, with the effect that proinflammatory responses are promoted. [http://www.sciencedirect.com/science/article/pii/S0952791512000623

]

 

Coping with Age-Related Physical Changes

Attention has been paid to some of the physical changes that occur with age. Now we want to focus on how the elderly can cope with some of those changes. “Age-related physical changes may have psychological and social implications. Biological changes can affect the individual’s attitudes, behaviors, and identity as self-perception is affected by one’s appearance and competence”.

 The following chart gives specific changes and coping strategies for them.

 The ability to adapt to everyday life may be influenced by the effects of aging on mental abilities. Cognitive abilities may also affect self-respect and how individuals view their own aging process. However, normal age-related changes are not all negative, in spite of some losses in speed and memory in later years. Elderly people can compensate for memory changes by devising a balanced attitude in their self-concept

 

 

Factors that Influence Longevity:

Heredity – Proven through twin studies (higher correlation among identical than fraternal) and parental longevity (related to both genetics and parenting style).

 

Gender – Females in almost every country and among all racial groups live longer than males, most likely due to environmental, behavioral, and biological factors.

 

Race and ethnicity – Blacks die on average five years earlier than whites.  American Indians die on average six years earlier than the general population.

 

Smoking – The single most important thing one can do to increase life expectancy is not to smoke.

 

Disease – Likely to shorten the life span, whether genetic or acquired.

 

Body weight and height – Overweight people are more likely to experience chronic illness that reduces life expectancy.  Shorter people have lower death rates and fewer diet-related chronic diseases and live longer than taller people.

 

Physical activity – Higher levels of physical activity are associated with lower death rates from cardiovascular disease and other morbidities.

 

Alcohol use – It is still unclear whether alcohol itself has an effect.  Protective influence from plant estrogens?  Also, moderate drinkers tend to have other lifestyle characteristics that predispose to longer life, e.g., higher socioeconomic status, less rigid personalities.

 

Marital status – Married people live longer than those who are divorced or widowed.  Never-married people have the highest death rates; research supports the correlation between fewer social relationships and increased illnesses.  Also, single, divorced, and widowed individuals are more likely to smoke and drink heavily.

 

Psychological factors – Resilience to effects of stress & disease more demonstrable in some people.

 

Social class – Higher educational levels, more prestigious occupations, and above-average income all contribute to higher longevity.

 

Cultural factors – Multi-factorial influence includes sanitation, prevalence of infectious diseases, diet, and access to health care.

 

Physical environment – Radiation, air pollution, and water pollution are known to be associated with variations in life expectancy.

 

THE AGEING PROCESS

Many of us grew up with the idea that ageing is a biological programme shaped by natural selection to ensure turnover of the generations.  Most gerontologists now think this is wrong.

In the wild, old animals are lost to accidents or predators, disease or cold, dying long before they show any signs of damage from ageing.  So, ageing as a means of culling the old makes little sense; yet genes certainly exert a powerful influence over the length of life, hence the tendency for longevity to run in families.  What are these genes that regulate length of life, if not evolved to direct our death?

Because wild animals die young, natural selection is relatively powerless to eliminate mutations that have their adverse effects in later life, especially if they have a positive impact in a youngster.  For example, a high testosterone level may aid the reproductive drive of a young male, but it predisposes to later health problems.  For natural selection, early advantage counts much more than trouble which might follow later.  This is important when we consider the impact of natural selection on our body’s mechanisms for maintenance and repair.

Maintenance is essential if the body is to retain its health functions.  But, maintenance is metabolically expensive and it may be too costly to build a body that could last forever.  The ‘disposable soma’ theory suggests that our genes, under pressure from natural selection, settled on a solution ‘good enough’ to see us through the 30 years of ‘nasty brutish and short’ life available to our distant ancestors.

This arrangement is less suited to today’s safer living conditions, so we now age and die because of the limitations of our maintenance and repair.  Ageing appears to be a lifelong accumulation of faults at the cellular and molecular level, each a random occurrence insignificant in itself, combining to overwhelm the body’s ability to keep its systems running.  The random nature of these faults is what makes us each age so individually, and it is this individuality and the underlying complexity, which makes the ageing process such an intriguing scientific challenge.

 

Age Related Conditions

Ageing does not only affect older people or those approaching old age. From birth, and possibly before, the cells that make up our bodies are accumulating damage. The impact of this damage is highly variable, influenced heavily by our genes, by chance, and by our choice of behaviours.

Eventually, though this progressive degradation of our tissues results in the impairment of our senses and reductions in the performance of our bodies, such that older people are considerably more likely to suffer from a range of diseases and impairments. Indeed for many of these, age is the single biggest risk factor.

Research of the causes and mechanisms of ageing offers hope that what we learn will help us not only address the symptoms of individual conditions, but reduce the risk of or delay, for all of us, development these conditions in future.

Circulatory Conditions

o        Coronary Heart Disease

o        Stroke

·                    Respiratory Diseases

·                    Cancer

·                    Neurological and cognitive conditions

o        Dementia

o        Alzheimer’s Disease

o        Dementia with Lewy Bodies

o        Parkinson’s Disease

·                    Sight and Hearing Degradation

o        Long-sightedness

o        Glaucoma

o        Deafness

·                    Muscular Skeletal Degradation

o        Osteoporosis

o        Osteoarthritis

 

Major Geriatric Concerns

Several conditions compromise independence and quality of life in older persons. These conditions result in increased suffering, service utilization, and health-related costs. Research will be expanded to address the following geriatric concerns:

                 

 

                  Weakness and falls result in approximately 1.5 million fractures in the US each year, including debilitating fractures of the hip and spine. Muscle weakness, bone loss, dizziness, and impaired mobility contribute to falls and other injuries. New strategies are needed to reduce the risk of falls through health promotion and patient education, safety measures, environmental modifications, and improved therapies.

                 

 

                  Delirium, also known as acute confusional state, is a serious and preventable cause of suffering and service use among elderly people. A recent study showed that hospitals may be able to reduce the number and duration of episodes of delirium in at-risk older patients by addressing specific risk factors. Research is aimed at preventing delirium by understanding and reducing these risk factors, which include: (1) cognitive impairment, (2) sleep deprivation, (3) medication error, (4) immobility, (5) visual and hearing impairment, and (6) dehydration.

                 

 

                  Urinary incontinence (UI), a significant medical problem with physical and psychosocial ramifications, affects up to one-third of women over age 65. Studies have shown that medications, surgery, and behavioral approaches can be effective in treating some women with UI. The need remains for additional research on the underlying causes of UI, on development of new, safe treatment methods, and on educating elders and health professionals about the condition.

                 

 

                  Studies suggest that sleep disturbances afflict a majority of the older population in the United States, contributing to personal discomfort and illness and caregiver burden. Contrary to a commonly held belief, however, chronic insomnia, which occurs in about one-third of our elderly population, is not a normal consequence of aging. To reduce the burden of sleep disturbances, scientists are studying: (1) the mechanisms underlying sleep-wakefulness cycles, (2) normal and abnormal biorhythmicity of the aging nervous system, and (3) the effects of concurrent disease states on sleep. Planned research should contribute to developing new and more effective therapeutic methods that will correct the underlying pathology of sleep disorders to improve quality and duration of sleep in older persons.

                 

 

                  Serious depression is an important public health problem in older people that may occur along with other common medical conditions. Often overlooked or misdiagnosed, clinical depression can affect cognition and exacerbate physical, mental, and emotional problems. In collaboration with the National Institute of Mental Health, research will continue to refine and develop diagnostic screening tests for depression in older adults and to develop more effective medications with fewer side effects.

                 

 

                  Comorbidities and their influence on function, health, and treatment must be better understood. The risk of multiple diagnoses increases with advancing age, leading to concerns regarding interactions among diseases, interactions between a drug given for one disease and a coexisting disease or condition, and drug-drug interactions as diseases are treated. Efforts also are underway to improve strategies for including in clinical trials persons with comorbidities so that the effects are better understood for the types of drugs most likely to be prescribed for the elderly.

 

Cardiovascular Disease

 

Diseases of the heart and blood vessels are the leading cause of hospitalization and death in older people. Congestive heart failure is the most common diagnosis in hospitalized patients aged 65 and older. NIA is pursuing a broad program of basic and clinical cardiovascular research, often in collaboration with the National Heart, Lung, and Blood Institute. Recent findings have demonstrated the effectiveness of both pharmacologic and lifestyle approaches in reducing hypertension and preventing heart disease and stroke. Characterization of age-associated changes in both the structure and function of the heart and blood vessels is vital to the development of newer, more effective treatment and prevention interventions. Research priorities include genetic and environmental risk factors for hypertension, heart disease, and stroke. Studies are ongoing to determine the causes of age-associated increases in vascular stiffness, a potential risk factor for cardiovascular disease.

Other research will focus on age-related changes in the structure and function of the heart’s conduction system that can increase the risk of cardiac arrhythmias, especially atrial fibrillation; if uncorrected, this condition can lead to strokes. Additional priorities include determining the reasons for gender and racial differences in the aging cardiovascular system, delineating the relationship of cardiac enlargement to aging and disease development, and reducing the progression of early atherosclerotic disease.

 

Cancer

The second leading cause of death among the elderly is cancer, with individuals age 65 and over accounting for 70 percent of cancer mortality in the United States. In collaboration with NCI, NIA is expanding basic and clinical research on breast, prostate, and colon cancers, common in older people, and launching a new initiative to expand participation of older cancer patients in clinical trials. This research focuses on:

                  Age-related changes that contribute to increased cancer incidence and mortality in older persons

                  Aggressive tumor behavior in the aged patient

                  The impact of previous or concurrent conditions and disabilities on the cancer experience of older patients.

Specific research topics include: (1) dose adjustment for antitumor agents and radiation therapy, (2) diagnostic cancer imaging, (3) how coexisting diseases affect cancer treatment and survival outcome, and (4) survival advantages or disadvantages of minority or ethnic populations.

 

Diabetes

Type 2 diabetes, which results from insulin resistance and abnormal insulin action, is most prevalent in the older population. Diabetes complications, such as heart disease and loss of sight, increase dramatically when blood sugar is poorly controlled and often develop before diabetes is diagnosed. Working with the National Institute of Diabetes and Digestive and Kidney Diseases, NIA is exploring strategies to prevent type 2 diabetes and to expand knowledge on usual age-related increases in insulin resistance and glucose tolerance. Studies also are focusing on how changes caused by type 2 diabetes affect responses to treatment and prevention strategies in older persons. Other studies will develop critical resources to study genetic susceptibility and gene/environment interaction in type 2 diabetes.

 

Bone, Muscle, Skin, Joint, and Movement Disorders

Osteoporosis (loss of mass and quality of bones), osteoarthritis (inflammation and deterioration of joints), and sarcopenia (age-related loss of skeletal muscle mass and strength) contribute to frailty and injury in millions of older people. Several initiatives, some in collaboration with the National Institute of Arthritis and Musculoskeletal and Skin Diseases, are unraveling the underlying mechanisms of aging in bone, muscle, skin, and joints with the goal of conserving or enhancing their function and preventing pathologies. For example, factors are being explored to define the influences that can predispose older people to fractures and develop effective prevention and intervention strategies for age-related musculoskeletal decline.

 

 

Also contributing to loss of mobility and independence are changes in the central nervous system that control movement. Cells may die or become dysfunctional with age, as in Parkinson’s disease. Therefore, older people may have difficulty with gross motor behavior, such as moving around in the environment, or with fine motor skills, such as writing. Research is being conducted to understand the underlying age-related changes that occur in the motor control areas of the brain with the aim of developing therapeutic interventions. One such approach—deep brain stimulation—is being pursued as a collaborative effort with the National Institute of Neurological Disorders and Stroke.

Vision, Hearing, and Other Sensory Disorders

Age-associated changes in sensory function, including vision, hearing, taste, smell, proprioception, and vestibular function, can lead to significant loss in function and decrease the quality of life for many older persons. In collaboration with the National Institute of Deafness and Other Communication Disorders and the National Eye Institute, progress is being made in discovering risk factors for age-related hearing loss and vision decline. Increased emphasis is being given to research on multiple sensory deficits in older people, which increases their risk for mortality and loss of independence. Ongoing research is redesigning products and developing new technologies for older people to make reading easier and more understandable, enhance hearing and other sensory abilities, and otherwise contribute to functional independence.

Age-related declines in taste and smell may have an impact on both the enjoyment and nutritional choices of the elderly. Studies on flavor enhancement are aimed at maintaining healthful eating habits, especially in sick and otherwise debilitated elderly. Understanding the mechanisms involved in decreased sensory function also is expected to lead to interventions to maintain optimal function into the later years.

 

Benign Prostatic Hyperplasia (BPH)

It is common for the prostate gland, part of the male reproductive system, to enlarge with age. More than one-half of men in their sixties and as many as 90 percent in their seventies and eighties have some symptoms of this condition, known as BPH. Symptoms stem from obstruction of the urethra (the canal through which urine passes out of the body) by the adjacent prostate gland. Severe BPH can lead to:

                  Urinary tract infections

                  Bladder or kidney damage

                  Bladder stones

                  Incontinence.

Although some researchers believe that factors related to aging may spur development of BPH, the cause is not well understood. NIA stimulates research on the causes of the high incidence of prostate growth in older men and on issues related to treatment and potential regimens to minimize prostate growth.

Infectious Diseases

The mechanisms that underlie the decline of immune function often accompany advancing age, leaving older people more vulnerable to conditions such as influenza and pneumonia. Success in understanding changes with age in immune competence and the underlying mechanisms of these changes have broad implications for vaccine development and reduction in infectious illness, which often leads to hospitalization and death in older people. An emerging research focus involves prevention of HIV/AIDS in older people, a growing health problem. NIA research on these issues is coordinated with the National Institute of Allergy and Infectious Diseases and the NIH Office of AIDS Research.

Remarkable progress is being made through basic, clinical, and epidemiologic research toward developing innovative, safe, and effective approaches to prevention and therapy for the population over age 65. These studies seek to:

                  Improve vaccine and drug development

                  Lessen the disabling effects of disease

                  Delay onset or progression of disease

                  Enhance pain management.

Aging research targets diseases and conditions that contribute significantly to mortality or disability in old age. A major focus of NIA research is Alzheimer’s disease, a devastating neurodegenerative disease that robs people of memory and other intellectual abilities, leading to loss of social and occupational function and ultimately to complete dependence on others. Additional important causes of disease and disability include: (1) cardiovascular disease and cancer, the two leading causes of death in older people; (2) bone, muscle, and joint disorders such as osteoporosis and osteoarthritis that contribute to pain and loss of mobility; (3) vision, hearing, and other sensory disorders that can isolate older people; and (4) numerous other age-related conditions, such as diabetes and incontinence, that deprive individuals of their independence.

Researchers in Aging Capitalize on New Findings To Reduce the Burden of Illness and Disability in Older People

Accelerate Discovery of Causes and Risk Factors and Improve Early Detection and Diagnosis of Disabling Illnesses

Genes associated with aging processes, longevity, and age-related diseases are providing insight into disease pathologies and individuals’ vulnerability to disease. Defining the underlying changes in biologic functions controlled by the genes can lead to possible targets for treatment and may help in early detection and diagnosis of disease. These findings are derived in part from studies of populations or families known to be at high risk for a disease. Population studies also uncover other potential risk factors, such as:

                  Environmental exposures across the lifespan

                  Health behaviors

                  The influence of coexisting conditions on the progression of a disease.

In addition, remarkable progress is being made through advances in imaging technology, a noninvasive means of observing the body’s biological activity. For example, these techniques can provide images of nerve cells as they communicate, can accurately measure cerebral blood flow, and can gauge the production of particular gene products. Plans are being developed to improve the resolution of this technology to assist in early detection and diagnosis.

Discover New Treatment and Prevention Strategies

New information on the underlying causes of and risk factors for diseases and disabilities are helping researchers develop interventions to delay onset, slow progression, and reduce the severity of disease and disability. Insights have emerged from: (1) studies on alterations in genes or gene products, (2) effects of hormones or other factors external to the cell, and (3) changes in how the body coordinates and integrates its complex activities. These studies have produced promising targets to prevent death or inappropriate proliferation of cells and to reduce inflammation and damage to tissues. Researchers are actively translating new knowledge on genetics, biochemistry, and physiology to develop new preventive strategies and medications. Studies are being considered for tissue repair and cell replacement using stem cells, immature cells that can differentiate into specialized cells to replace those lost due to normal cell turnover or injury. Clinical trials are needed to identify more effective strategies for rehabilitation to improve function and quality of life and to overcome barriers to optimum function. Behavioral and social science findings also are being applied to develop strategies that promote health and prevent disease.

Improve Health Behaviors and Medication Use

Exercise, proper diet, and other healthy behaviors can help prevent and reduce symptoms of disease. These benefits often rely on an individual’s willingness to make and sustain changes in lifestyle. Researchers are exploring strategies that can help motivate elders to adopt changes that promote health and adherence to medical recommendations.

 

Several pharmacological aspects need to be considered in managing antithrombotic therapies in elderly people. These include age-related changes in absorption, distribution, metabolism, and clearance of antithrombotic drugs (Fig. 1). Since polypharmacy is common in elderly patients, this exposes them to a greater risk of adverse drug–drug interactions. In addition to pharmacokinetics, age-related changes in pharmacodynamics may also occur, leading to a reduction of homeostatic mechanisms. This implies that drug reactions may be stronger or drug effects may be less attenuated. Overall, these pharmacokinetic and pharmacodynamic considerations may, therefore, impact the safety and

efficacy of antithrombotic treatment in the elderly, as described in the following text.

 

Figure 1. Mechanisms Leading to Pharmacokinetic Variations of Antithrombotic Drug Effects in the ElderlyEffects of antithrombotic drugs are subjects to age-related pharmacokinetic changes. These may occur at 1 or multiple levels: drug absorption, distribution, metabolism, and clearance.

 

Managing medications can be complex for older people, who may take several drugs for multiple health problems. Complications may occur because of interactions between two drugs or between a drug and dietary supplements, or because of physiological and functional changes associated with aging or age-related diseases. Planned research will provide new knowledge about medications to maximize their effectiveness and will develop new technical aids to assist physicians in monitoring drug use. New technologies and information will enable patients to better manage drugs and avoid adverse reactions.

Launch Clinical Studies To Improve Health and Reduce Burden of Disease

New clinical studies are being developed to: (1) improve the treatment of Alzheimer’s disease, cardiovascular disease, cancer, osteoporosis, and diabetes; and (2) test the effects of hormone replacement, dietary supplementation, and exercise and fitness. As pathways and processes of disease are defined, basic research findings can be translated expeditiously to clinical applications. These studies will test new drugs and compounds, strategies for improving physical and mental fitness, or approaches for preventing falls and other injuries. Several novel approaches are being applied to make these studies as efficient and cost-effective as possible. Every effort is being made to ensure participation of diverse populations. In addition to efforts to prevent disability among healthy older persons, studies also will focus on reducing disability and/or preventing or slowing additional decline among persons with disability as they continue to age.

Strengthen Infrastructure and Resources Required for Clinical Trials and Other Clinical Studies

Until recently, elders have been markedly underrepresented in clinical trials—even in some of the disorders most prevalent in older men and women. An invigorated program of clinical studies in older people is designed to produce:

 

                  Innovative changes in the design, planning, and implementation of clinical trials. For example, a special effort will be made through the Alzheimer’s Disease Prevention Initiative, which will be discussed later in this section.

                  New drug testing facilities and resources, such as an intramural Interventional Trials Unit to translate laboratory research findings to human findings in several age-related diseases and in immunology and endocrinology.

                  An expanded collaboration with the Veterans Administration Cooperative Studies Program to study osteoporosis and hormone replacement therapy in older men, nutritional interventions in vulnerable geriatric populations, multifactorial interventions to prevent fall-related fractures, and other topics.

                  New efforts with the National Cancer Institute (NCI) to improve cancer therapy in older people, including the effects of aging and coexisting conditions on responses to and side effects of surgery, chemotherapy, and radiation therapy.

 

Alzheimer’s Disease

NIA is the lead Federal agency for studying Alzheimer’s disease. As many as four million Americans suffer from the disease, the most common form of dementia. This brain disorder gradually progresses from mild memory loss to disturbing changes in behavior and personality, decline in the ability to think or recognize people, and profound memory loss. Gradually and inexorably, Alzheimer’s disease consumes and destroys normal brain function. Patients eventually are unable to care for themselves and sometimes are agitated to the point of causing harm to themselves or others. Both patients and the millions of family members and other loved ones who care for them are devastated by Alzheimer’s disease. These profound losses are related to abnormal changes in the brain that begin many years before memory loss or other clinical symptoms become apparent.

Major breakthroughs in genetic, molecular, and epidemiologic research are rapidly expanding our understanding of these pathologic changes. Researchers are precisely characterizing the regions of the brain, such as the hippocampus, that are involved in memory and other cognitive abilities. In Alzheimer’s disease, brain cells in these regions die in unusual numbers. Efforts are being made to inhibit loss of neurons, for example, by increasing protective growth factors in the brain. Communication among brain cells in patients with Alzheimer’s disease begins to break down as synapses—the communication points between neurons—are lost. Scientists are exploring ways to prevent this loss. Investigators are also tracking the formation and potential interaction between the two major lesions—amyloid plaques and neurofibrillary tangles—that proliferate in the brains of patients with Alzheimer’s disease, with the aim of finding ways to stop their formation, reduce their numbers, and minimize deleterious downstream effects.

Remarkable progress has been made toward a more complete understanding of the agents that damage cells and the subtle changes in cellular function that can trigger cell death in the brain. Alzheimer’s disease also can interact with other diseases, such as cardiovascular disease and stroke, to make symptoms worse. These findings suggest targets for new diagnostic, preventive, and therapeutic strategies for Alzheimer’s disease. In addition, these advances will certainly lead to insights about other diseases in which nerve cells die, including Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis and non-Alzheimer’s disease dementias.

 

Alzheimer’s Disease Prevention Initiative

The Alzheimer’s Disease Prevention Initiative strives to prevent Alzheimer’s disease and to slow disease progression once it is diagnosed. This initiative will intensify collaborative efforts to conquer Alzheimer’s disease between:

                  NIA and other NIH Institutes

                  Several government agencies

                  Organizations such as the Alzheimer’s Association

                  Pharmaceutical companies

                  Private foundations.

Goals are to:

                  Accelerate discovery of new risk and protective factors and identify promising targets for preventing disease through basic research.

                 

Potential targets for slowing or stopping the course of Alzheimer’s disease have multiplied as knowledge of the causes and early predictors of the disease increase. Several genes have been discovered that can cause Alzheimer’s disease and other dementias in certain families that develop these diseases in early to middle age. Progress in understanding the function of these genes has led to a surge in knowledge about the development of Alzheimer’s disease pathology—including proliferation of senile plaques and neurofibrillary tangles—and has stimulated efforts to block or even reverse the progression of these pathologies.

                 
Investigators are now better able to detect persons at high risk for developing Alzheimer’s disease. Powerful genetic tools have helped reveal genes, such as APOE e4, that influence susceptibility and disease progression in late-onset Alzheimer’s disease. These discoveries not only improve ability to identify persons who have a greater chance of developing Alzheimer’s disease before the disease causes damage to the brain, but also lead to new avenues of drug development as the basic mechanisms underlying disease progression are revealed.

                 

 

                  Developments in brain imaging and in cognitive testing are enabling researchers to identify people at ever earlier stages of the disease and to characterize brain and behavioral changes that precede clinically diagnosed dementia. For example, a brain imaging study of the size of the hippocampus in older individuals with mild cognitive impairment (a memory deficit beyond that expected for age and education) found that the smaller the hippocampus at the beginning of the study the greater the risk of later conversion to Alzheimer’s disease. These diagnostic advances will opeew opportunities for early interventions to prevent brain changes before clinical deterioration occurs. Research also is producing several candidates for diagnostic markers; appropriate markers would enable physicians to accurately distinguish Alzheimer’s disease from other dementing illnesses and from age-related loss of function.

Molecular and epidemiologic research has made progress in identifying possible new targets for drug therapy. These targets include inflammation and toxic oxidative agents known as free radicals. Another possible problem that could be corrected is loss of protective factors, such as estrogen or natural growth factors. 

                  Speed drug discovery and movement of promising new treatments and prevention strategies into clinical trials.

                 
To invigorate drug development, novel proposals are being solicited to target crucial pathways involved in thedevelopment of Alzheimer’s disease. Research has led to the threshold of discovery of effective agents targeting Alzheimer’s disease pathology. For example, researchers have succeeded in developing agents that retard deposition of brain plaques in animal models. Another promising research area is development of estrogen-like compounds that retain estrogen’s beneficial effects on the brain, while minimizing its negative effects on other organs. Yet another research area is the development of molecular compounds that prevent brain cells from dying or stimulate the generation of new brain cells. Ultimately, as a long-term goal, methods may be developed to introduce cells into the brain that could either protect brain cells from Alzheimer’s disease damage or even replace dysfunctional cells. 

                  Launch clinical trials to prevent Alzheimer’s disease.

Unlike trials that focused on reducing symptoms and slowing the progress of Alzheimer’s disease, many future trials will emphasize prevention of the disease. Advances in basic research and drug development are likely to include: (1) more effective anti-inflammatory compounds and antioxidants, (2) agents to prevent cell death, and (3) substances designed to stop the deposition of plaques and tangles in the brain. Such progress will enable more effective intervention at earlier stages in pathogenesis. The first NIH prevention trial—comparing the effects of vitamin E and Aricept—was recently initiated at more than 70 sites in persons diagnosed with mild cognitive impairment but not clinical Alzheimer’s disease. Aricept helps prevent the degradation of acetylcholine, a brain cell communication chemical important for attention and memory. Vitamin E is thought to have antioxidant properties that counteract damage from molecules called oxygen-free radicals. The goal is to stop the development of Alzheimer’s disease symptoms in these individuals, who are at high risk of developing the disease. Other trials involve estrogen; nonsteroidal anti-inflammatory drugs; cerebrovascular interventions; and a folate, vitamin B6, and vitamin B12 combination. Efforts also are being made to develop sensitive tests and techniques that can quickly and accurately track a drug’s effectiveness in slowing or arresting brain changes that precede or accompany the progression of Alzheimer’s disease. During the next several years, not only will trials be conducted among persons with mild cognitive impairment, but they also will be conducted in persons with completely normal cognition to prevent Alzheimer’s disease prior to emergence of any symptoms.

                  Expand strategies for improving patient care and alleviating caregiver burdens.

                  There is a critical need to develop more effective methods to treat and manage behavioral symptoms in persons who have Alzheimer’s disease and to significantly reduce caregiver burdens. Focused initiatives will develop and test new ways of managing the daily activities and stresses of caring for people with Alzheimer’s disease, with focus on behavioral symptoms most distressing to Alzheimer’s disease patients and their families: wandering, aggression, agitation, sleep problems, and incontinence. Clinical studies of behavior management strategies, both pharmaceutical and behavioral, also will be launched. Successful treatment of Alzheimer’s disease will help to: (1) prevent hospitalizations, (2) decrease unscheduled visits to care providers, (3) delay nursing home admission, (4) avoid preventable illnesses unrelated to Alzheimer’s disease, and (5) prevent caregiver burnout.

 

PHARMACOTHERAPY IN ELDERLY

Aging brings with it quite a few changes, some of which have implications for treatment.

• polymorbidity – greater number of diseases requiring greater number of drugs

• polypharmacy – the use of large quantities of drugs (4 or more), incorrect combinations of drugs or prescriptioon indicated drugs

• underprescription – nonprescription drugs that have a demonstrable effect on the disease and survival (typically statins, β-blockers after AMI, cholinesterase inhibitors in Alzheimer’s dementia, sufficient analgoterapie in cancer patients, antidepressants)

• decreased compliance – due to dementia or just due to excessive amounts of drugs

Changes in Pharmacokinetics

Absorption Decrease

There is pH increase in stomach, atrophy of villi and mucous in gut (decrease resorptive area), decrease in blood flow and motility in the GI tract. Overall, this leads to a slower onset of action of drugs administered orally. Muscle atrophy and reduced blood flow to the periphery is involved in the delayed onset of action of medications given intramuscularly.

Distribution

There is physiological decrease of total body water, it can be enhanced by dehydration (typical for the elderly). Dehydration affects the drugs that are water-soluble. Their concentration in plasma is increased and toxic.

On the contrary, the concentration of drug fat-soluble increases due to higher total body fat (drugs are stored in adipose tissue) → benzodiazepines.

Malnutrition contributes to decrease in serum albumin – by increasing the plasma free fraction of drugs that bind to albumin → PAD, antidepressants, beta blockers.

Decreased Metabolization and Excretion

·                    Due to the decrease in total liver weight and liver perfusion, reduced function of some enzymes (CYP, glucuronyltranspherase → benzodiazepines).

·                    Decreased glomerular filtration, renal clearance, tubular secretion, renal hypoperfusion → aminoglycosides, lithium, digoxin, cimetidine, allopurinol, a contrast agent.

Changes in Pharmacodynamics

• increased number of receptors or sensitivity to drugs (warfarin, heparin).

• increased sensitivity to adverse effects of digoxin.

• increased CNS sensitivity to benzodiazepines, morphine, which cause sedation, delirium, depression, or even at therapeutic doses.^[

• numbness receptor beta – reduced effectiveness of β-blockers.

Adverse Effects and Drug Interactions

Side effects of drugs occur up to 20% of deaths in the elderly.

Typical side effects in the elderly are:

• orthostatic hypotension (syncope, falls)

• diarrhea, constipation

• sedation, delirium, confusion

Often drug interactions:

• warfarin + sulfonamides → displacement of drug from binding to binding protein → higher free fraction of warfarin and the risk of bleeding

Unsuitable/less Suitable Drugs in the Elderly

• tricyclic antidepressants – anticholinergic effect

• antispasmodics – the risk of urinary retention, delirium

• barbiturates, benzodiazepines – the risk of sedation, addiction

• methyldopa – depression, sedation, bradycardia

• digoxin – possible high risk of adverse effects

Medical drugs which need smaller doses (evidence based):

• atorvastatin (standard 10 mg/day, in elderly 5 mg/day)

• ibuprofen (standard 400-800 mg/3-4x day, in elderly 200 mg/3-4x day)

• metoprolol (standard 100 mg/day, in elderly 50 mg/day)

• omeprazole (standard 20 mg/day, in elderly 10 mg/day)

• and more …

 

 

PROGERIA

What is Progeria?

Hutchinson-Gilford Progeria Syndrome (“Progeria”, or “HGPS”) is a rare, fatal genetic condition characterized by an appearance of accelerated aging in children. Its name is derived from the Greek and means “prematurely old.” While there are different forms of Progeria^*, the classic type is Hutchinson-Gilford Progeria Syndrome, which was named after the doctors who first described it in England; in 1886 by Dr. Jonathan Hutchinson and in 1897 by Dr. Hastings Gilford.

How common is Progeria?

Progeria has a reported incidence of about 1 in 4 – 8 millioewborns. It affects both sexes equally and all races. In the past 15 years, children with Progeria have been reported all over the world, including in Algeria, Argentina, Australia, Austria, Belgium, Brazil, Canada, China, Columbia, Cuba, Denmark, Dominican Republic, Egypt, England, France, Germany, India, Ireland, Israel, Italy, Japan, Libya, Mexico, Morocco, Netherlands, Pakistan, Peru, Philippines, Poland, Portugal, Puerto Rico, Romania, South Africa, South Korea, Spain, Sweden, Switzerland, Turkey, United States, Venezuela, Vietnam, and Yugoslavia.

For a map of where living children reside, please go to our Meet the Kids page.

What are the features of Progeria?

Although they are born looking healthy, children with Progeria begin to display many characteristics of accelerated aging at around 18-24 months of age. Progeria signs include growth failure, loss of body fat and hair, aged-looking skin, stiffness of joints, hip dislocation, generalized atherosclerosis, cardiovascular (heart) disease and stroke. The children have a remarkably similar appearance, despite differing ethnic backgrounds. Children with Progeria die of atherosclerosis (heart disease) at an average age of thirteen years (with a range of about 8 – 21 years).

What does Progeria have to do with aging?

Children with Progeria are genetically predisposed to premature, progressive heart disease. Death occurs almost exclusively due to widespread heart disease, one of the leading causes of death worldwide.⁺ As with any person suffering from heart disease, the common events for Progeria children are high blood pressure, strokes, angina (chest pain due to poor blood flow to the heart itself), enlarged heart, and heart failure, all conditions associated with aging. Thus, there is clearly a tremendous need for research in Progeria. Finding a cure for Progeria will not only help these children, but may provide keys for treating millions of adults with heart disease and stroke associated with the natural aging process.

What is the cause of Progeria?

HGPS is caused by a mutation in the gene called LMNA (pronounced, lamin – a). The LMNA gene produces the Lamin A protein, which is the structural scaffolding that holds the nucleus of a cell together. Researchers now believe that the defective Lamin A protein makes the nucleus unstable. That cellular instability appears to lead to the process of premature aging in Progeria. PRF was the driving force behind finding the gene responsible for Progeria. A group of leading scientists from The Progeria Research Foundation’s Genetics Consortium was able to isolate the Progeria gene in October 2002, and in April 2003, PRF led the announcement that Progeria is caused by a mutation of the gene LMNA, or Lamin A.

This gene discovery was reported in the leading scientific journal Nature. The Progeria gene finding involved intensive collaboration between scientists including Dr. Leslie Gordon, PRF’s Medical Director, Dr. W. Ted Brown, a world expert on Progeria and Chairman of New York’s Institute of Basic Research in Developmental Disabilities’ Department of Human Genetics, Dr. Tom Glover, a PRF grantee and Professor at University of Michigan’s Department of Human Genetics, Dr. Francis Collins, Director of the National Human Genome Research Institute (responsible for mapping the human genome) and the senior author on the report, and first author Dr. Maria Eriksson, a postdoctoral fellow with Dr. Collins. “Isolating the Progeria gene is a major achievement for the medical research community,” said Dr. Collins, “The discovery not only gives hope to children and families affected by Progeria, but also may shed light on the phenomenon of aging and cardiovascular disease.”

Is Progeria passed down from parent to child?

HGPS is not usually passed down in families. The gene change is almost always a chance occurrence that is extremely rare. Children with other types of “progeroid” syndromes which are not HGPS may have diseases that are passed down in families. However, HGPS is a “sporadic autosomal dominant” mutation. This means that, for a family with one child with HGPS, non-twin siblings have the same chance of having HGPS as any other child in any other family – approximately one in 4-8 million. In very rare instances, about once every 100 cases of HGPS (or frequency of about 1 in 400 million births), HGPS can be passed down within a family.

How is Progeria diagnosed?

Now that the gene mutation has been identified, The Progeria Research Foundation has created a Diagnostics Testing Program. We caow look at the specific genetic change, or mutation, in the Progeria gene that leads to HGPS. After an initial clinical evaluation (looking at the child’s appearance and medical records), a sample of the child’s blood will be tested for the Progeria gene. For the first time ever, there is a definitive, scientific way to diagnose the children. This will lead to more accurate and earlier diagnoses so that the children can receive proper care. “Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford Progeria Syndrome”, Vol. 423, May 15, 2003.

What is PRF doing to help children with Progeria?

The Progeria Research Foundation funds medical research aimed at developing treatments and a cure for Progeria. PRF also has its own Cell & Tissue Bank that provides the biological materials researchers need to conduct their experiments. The PRF Cell & Tissue Bank was instrumental in the recent discovery of the Progeria gene. Cell lines from the PRF Cell Bank were essential to the experiments that led to the Progeria gene discovery. These same cells and tissues will be essential to finding treatments and a cure for Progeria. Additionally, PRF has established a Medical & Research Database to supply physicians and families with medical recommendations for cardiac care, nutrition and other medical issues to help the children have a better quality of life. We continue to analyze medical records of children with Progeria so that we can provide information on how best to medically help children with Progeria, and provide clues towards potential new treatments.