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Chapter 27 – Aging and Associated Diseases
Outline:
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Theories behind aging and longevity
Experimental models
Diseases associated with aging
Alzheimer’s disease
Werner Syndrome
Huntington’s disease
Introduction:
The study of aging is not what it used to be. Gerontology was a young science when
Congress created the National Institute on Aging (NIA) in 1974 as part of the National
Institutes of Health (NIH). At that time, theories of aging abounded, but data was scant.
Gerontology lacked, or was just in the early stages of developing, ways to explore the
fundamentals of the aging process. Now, nearly 30 years later, the science base has
grown in depth, breadth, and detail. And, with this growth have come new insights into
the processes and experience of aging. Where gerontologists once looked for a single,
all-encompassing theory to explain aging - a single gene, for instance, or the decline of
the immune system - they are now finding multiple processes, combining and interacting
on many levels. Cells, proteins, tissues, and organ systems are all involved, and
gerontologists are now able to discern many more of the mechanisms by which these
components cause or react to aging (1).
FIGURE 1: US POPULATION OVER THE PERIOD OF TIME FROM THE NATIONAL INSTITUTE
ON AGING (2)
Improved understanding of the mechanisms of longevity can be used to fight age-related
diseases and disabilities and to ensure a healthy, active, and independent life well into a
very old age.
The dream of extending life span has shifted from legend to laboratory. As
gerontologists explore the genes, cells, and organs involved in aging, they are
uncovering more and more of the secrets of longevity. As a result, life extension may
now be more than the stuff of myth and the retardation of disease and disability, realistic
goals.
Gerontologists talk about two kinds of life span:
1. Maximum life span (MLS), the greatest age reached by any member of a
species. In humans this is 120 years.
2. Average life span (ALS), the average age reached by members of a population.
Life expectancy, the number of years an individual can expect to live, is based on
average life spans.
Average life span and life expectancy in the United States have grown dramatically in
this century, from about 47 years in 1900 to about 75 years in 1990. This advance is
mostly due to improvements in sanitation, the discovery of antibiotics, and medical care.
Now, as scientists make headway against chronic diseases like cancer and heart
disease, some think it can be extended even further.
Maximum human life span seems to be another matter. There is no evidence that it has
changed for thousands of years despite fabled fountains of youth and biblical tales of
long-lived patriarchs. However, very recently, the dream of extending life span has
shifted from legend to laboratory. As gerontologists explore the genes, cells, and organs
involved in aging, they are uncovering more and more of the secrets of longevity. As a
result, life extension may now be more than the stuff of myth and the retardation of
disease and disability, realistic goals.
Theories on Aging:
1. Molecular Gene Theories
 Codon restriction: translation fidelity impaired due to inability to decode mRNA.
 Error catastrophe: fidelity declines with increase in abnormal protein.
 Somatic mutation: accumulation of DNA damage.
 Gene regulation: changes in gene expression regulating both aging and development.
2. Cellular Theories
 Free radical: mitochondria ROS, protein DNA damage.
 Wear and tear:
1. Glycoxidation theory (AGE, advanced glycation end-products)
2. Inflammation theory
 Senescence: accumulation of senescent cells due to replicative senescence (e.g.
telomere shortening) or cellular senescence (e.g. stress)
3. System Theories
 Rate-of-living: assuming a fixed amount of metabolic potential for every living organism
 Neuroendocrine: alterations in neuroendocrine control of homeostasis
Results in age related physiological changes
 Immunologic: decline in immune function with age results in increased disease
4. Evolutionary Theories
 Disposable soma: (Life span theory) soma is disposable following reproduction
 Antagonistic pleiotropy: genes beneficial at young age are deleterious at old age
 Mutation accumulation: mutations that affect health at old age
Genetic connection and longevity genes:
Drosophila melanogaster or fruit flies that routinely live for 70 or 80 days, nearly twice
the average of Drosophila life span. Evolutionary biologist Michael Rose has bred the
long-lived stocks by selecting and mating flies late in life.
FIGURE 2: CALORIE RESTRICTION MODEL OF YEAST
To begin the process of genetic selection, Rose first collected eggs lay by middle-aged
fruit flies and let them hatch in isolation. The progeny were then transferred to a
communal Plexiglas cage to eat, grow, and breed under conditions ideal for mating.
Once they had reached advanced ages, the eggs laid by older females (and fertilized by
older males) were again collected and removed to individual hatching vials. The cycle
was repeated, but with succeeding generations, the day on which the eggs were
collected was progressively postponed. After two years and 15 generations, the
laboratory had stocks of Drosophila with longer life spans. Rose has bred longer life
spans into fruit flies by selecting for other characteristics, such as ability to resist
starvation, so the flies' long life spans are not necessarily tied to their fertility late in life.
One possibility is that the anti-oxidant enzyme, superoxide dismutase (SOD), is involved.
In another laboratory at Irvine, the late Robert Tyler discovered that the longer-lived flies
had a somewhat different form of the SOD gene, which was more active than its
counterpart in the flies with average life spans. This finding has given a boost to the
hypothesis that anti-oxidant enzymes like SOD are linked to aging or longevity.
LAG-1 is short for longevity assurance gene.
FIGURE 3: XENOHORMESIS HYPOTHESIS
In the Xenohormesis hypothesis, Sirtuins enzyme is evolved early in life's history to
increase somatic maintenance and survival during times of adversity. The Xenohormesis
hypothesis of Howitz and Sinclair proposes that primordial species synthesized
polyphenolic molecules to stimulate sirtuins during times of stress. Plants have retained
this ability. Survival pathways in fungi and animals have retained the ability to respond to
plant stress signaling molecules because they provide useful prediction about the state
of the environment and/or food supply. This ability would allow organisms to prepare for
and survive adversity when they might otherwise perish (Howitz et al., 2003).
FIGURE 4: THE ACTIVITY OF TELOMERE
Telomeres cap the ends of chromosomes to protect them from inappropriate “repair”
mechanism. Each time a cell divides, the telomeres shed a number of bases, so
telomere length gives some indication of how many divisions the cell has already
undergone and how many remain before it becomes senescent.
Biochemistry and Aging:
1. ROS: Demolishing proteins and damaging nucleic acids, ROS are thought to be the
villains in cells. The free radical theory of aging, proposed by Denham Harman at the
University of Nebraska, holds that damage caused by ROS is responsible for many of
the bodily changes that come with aging. Free radicals have been implicated not only in
aging but also in degenerative disorders, including cancer, atherosclerosis, cataracts,
and neurodegeneration.
2. AGEs: Glucose attaches to proteins, setting in motion a chain of chemical reactions
that ends in the proteins binding together or crosslinking, a process called nonenzymatic glycosylation or glycation, thus altering their biological and structural roles.
The process is slow but increases with time. Crosslinks, which have been termed
advanced glycosylation end products (AGEs), seem to toughen tissues and may cause
some of the deterioration associated with aging. AGEs have been linked to stiffening
connective tissue (collagen), hardened arteries, clouded eyes, loss of nerve function,
and less efficient kidneys.
Diseases associated with Aging:
1. Alzheimer’s Disease
Dr. Alois Alzheimer observed and autopsied brain of patient with dementia.
Dementia=means out of one’s mind. Clinical diagnosis usually made if three symptoms
are present: impairments in short-term memory, in other areas of cognition (e.g.,
language), and in social or daily functioning. It is the most common form of dementia, a
general term for memory loss and other intellectual abilities serious enough to interfere
with daily life. Alzheimer’s disease accounts for 50 to 80 percent of dementia cases.
Alzheimer autopsied brain of AD patient has shrunken cerebral cortex, with damaged
and dead cells. A normal, healthy female brain usually weighs between 1100 and 1400
grams. AD brains shrink below 1000, as the disease destroys brain tissue. Tightly
packed ruts & grooves of cortex also change.
FIGURE 5: ALZHEIMER’S BRAIN
2. Werner’s Syndrome
Thirty years later, Oppenheimer and Kugel (USA) described a similar case of what they
termed "Werner's syndrome", an inherited disease in which patients develop symptoms
post-puberty that resemble rapid aging. Clinical features of Werner's syndome are now
known to include: short stature, thin extremities, graying and loss of hair in their teens,
cataracts in their 20's , a change of voice osteoporosis, bone deformities, wrinked, dry
skin, diabetes, atherosclerosis, ankle ulcers, malignancies
Werner syndrome is a premature aging disease that begins in adolescence or early
adulthood and results in the appearance of old age by 30-40 years of age. Its physical
characteristics may include short stature (common from childhood on) and other features
usually developing during adulthood: wrinkled skin, baldness, cataracts, muscular
atrophy and a tendency to diabetes mellitus, among others.
The disorder is inherited and transmitted as an autosomal recessive trait. Cells from WS
patients have a shorter lifespan in culture than do normal cells. The gene for Werner
disease (WRN) was mapped to chromosome 8 and cloned by comparing its sequence to
existing sequences in GenBank. However, it has yet to be shown to have real helicase
activity (as a DNA unwinds important for DNA replication). The molecular role of WRN in
Werner syndrome therefore remains to be proven; as does any role it might have in the
aging process in general (3).
FIGURE 6: WERNER’S SYNDROME (4)
The picture shows Japanese-American Werner patient as a teenager, and at age 48
(Case #1 Epstein et al, 1966, Medicine 45:177). She had eight children, two of whom
were also affected. At 48, she had hair loss and graying, thin extremities, chronic
ulcerations of the ankles, atrophy of the skin and her right eye had been enucleated
several years earlier due to acute glaucoma resulting from bilateral cataract extraction at
the age of 27. She lived longer than many Werner patients and died as age 57.
The gene responsible for Werner syndrome: The WRN gene encodes a DNA helicase of
the RecQ family, in-vivo function unknown. In-vitro, WRN protein unwinds doublestranded DNA and has a high affinity for "G-DNA", a structure that may form at
telomeres, ribosomal DNA (rDNA) and other GC-rich sequences.
3. Huntington’s Disease
FIGURE 7: HUNTINGTON’ S DISEASE (5)
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It is a progressive neurodegenerative genetic disorder becoming noticeable in
middle age
The disease is caused by an autosomal dominant mutation on either of an
individual's two copies of a gene called “Huntingtin”
The Huntingtin gene normally provides the genetic information for a protein that
is also called “huntingtin”
The mutation of the Huntingtin gene codes for a different form of the protein,
whose presence results in gradual damage to specific areas of the brain
References:
1. http://www.nia.nih.gov/HealthInformation/Publications/AgingUndertheMicroscope/
2. Looking for the fountain of youth, Scientists unlock the secrets of aging
(Magazine)
3. http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gnd&part=wernersyndrome
4. http://monnatlab.gs.washington.edu/images/wrn_patient_pedigree.jpg
5. http://en.wikipedia.org/wiki/File:Neuron_with_mHtt_inclusion.jpg