Transcript Biology of Aging - Medical University of South Carolina

Biology of Aging
Lotta Granholm
Center on Aging
MUSC
"Every man desires to live long;
but no man would be old."
Jonathan Swift (1667 - 1745)
Why should we study aging?
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35 million >65 yrs today (13% of pop)
This will double in 25 years
>85 yrs will increase 5-fold
1 of 5 get prescribed inappropriate
meds
• ½ physician time
• ½ prescription meds
• ½ hospital stays
The sad truth…
• Of 700,000 physicians 9,000 Geriatricians
• < 1% of nurses have adequate geriatric training
• Of 100,000 researchers, < 600 list Aging as main
interest!
• Of 144 med schools, 5 have Dept Geriatrics, and
< 30 have Aging Centers
Summary: < 0.5% of health professionals have
adequate geriatric training
Some age
gracefully...
Goldie Jean Studlendgehawn
born on November 21, 1945
http://www.gossip-celebrities.info/img/goldie-hawn-pictures
http://mercifulcrap.files.wordpress.com
http://www.szepseg.com/uploaded_images
http://www.morrisonhotelgallery.com/images
http://www.szepseg.com/uploaded_images
The Sydney Morning Herald
http://www.smh.com.au
What is Aging?
• The word senescence is
derived from the Latin word
senex, meaning "old man" or
"old age."
• The rate of Aging has
remained unchanged for
thousands of years.
• Life expectancy is different
from aging rate and reflects
many other factors
http://thebruceblog.files.wordpress.com
Terminology associated with
Aging:
• "Aging" = Gradual and spontaneous
change, resulting in maturation through
childhood and adolescence, and then
decline through middle and late age
• "Senescence" = The process by which the
capacity for cell division, growth, and
function is lost over time
Cont…
• Life expectancy = Lifespan: the period of
time in which the life events of a species
typically occur.
• Maximum lifespan (tmax): the maximum
period of time organisms of a given species
can live. Usually refers to the longest-lived
individual
• Ageism = stereotyping habits/characteristics
of older adults
Life expectancy in western society
•Average life span in the US
in 1900 was forty-nine; in
1998 it was seventy-seven.
•Social and medical
interventions reduced early
and late MORTALITY, but did
not alter the Rate of Aging
•Improvement of sanitation,
hygiene, and public health.
•In part genetically
determined. Studies of life
span in large families
Life expectancy:
• Life expectancy at birth is also a measure of
overall quality of life in a country and
summarizes the mortality at all ages
• Japan's : 82.12 average (number 3 in the world)
• US average: #49 in the world with 78.11 (2009)
• Macau: 84.6 (number 1 in the world)
• South Carolina Average: 74.8, and declining!
Physical signs of aging
• Wrinkles on the face and body.
• Sight, hearing, taste, and smell become less acute.
• Hair begins to thin and turn gray.
• Gain weight, particularly around the waist and hips.
• Loss of bone density over time (especially in women)
• Slower reflexes and altered gait; development of motor
dysfunction
• Less acute mental agility, and declining memory.
• Complex diseases associated with aging are caused by
the interaction of genetic and environmental factors.
Pathology that occurs with Age
Prevalence of selected chronic conditions, expressed in
percentages, as a function of age for the US population (20022003 dataset). Source: National Center for Health Statistics,
Data Warehouse on Trends in Health and Aging.
Successful Aging
• Percent individuals >65 has
increased, but proportion
residing in nursing homes
has decreased (5%)
• Percent of persons 75-84
with disabilities has
decreased (<30%)
• This suggests an increase
in Successful Aging
avoiding
disease and
disabilit y
Successf ul
social
Aging cognitive
net works
and physical
healt h
How to be a centenarian…
How long will you live?
Successful Aging
one trait that is
common to all
centenarians is
optimism
http://lenol66.files.wordpress.com
Life span lengthened in 3
ways:
• Increase early survival
• Increase late survival
• Delaying senescence
Increased early or late
survival affects mortality
but not the rate of aging
http://www.sciencemag.org
How to study aging
• Longitudinal studies - Same subjects over
period of time, assess changes. The main focus of
longitudinal cognitive aging studies is on intra-individual changes. Example:
Rotterdam Aging study
• Cross-sectional studies - Subjects of different
ages assessed on one occasion, comparative.
• Cross-sequential studies - Combines crosssectional and longitudinal techniques by
assessing subjects in a cross-sectional sample
more than once. The best design but time-consuming and costly
Animal Models in Aging
 Short lives, experimental results
collected quickly, or over many
generations;
Caenorhabditis
elegans
 Maintained easily and
inexpensively, present less complex
genetic or physiological systems
than humans.
Saccharomyces
cerevisiae
Genetically engineered animal
models for exploring the basic
mechanisms involved in the aging
Drosophila
melanogaster
Courtesy R. Moore
Mus musculus
Artificial selection for longevity
Mean life span: increased from 40 to 70 days
“Health span”: increased from 30 (blue) to 60 (pink) days
From Dr. Robert Arking
So what is it that makes
us age?
Theories of Aging:
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Oxidative Damage
Telomeres
Genetic Alterations with aging
Mitochondrial Aging
Other processes involved:
• Inflammatory processes
• Hormonal changes
• Life style choices
Oxidative stress:
imbalance production/breakdown
• Free radicals are normal products of metabolism
• Predominant cellular free radicals are:
- superoxide (O2 -)
- hydroxyl (OH-)
- nitrogen dioxide (NO2)
superoxide
- hydrogen peroxide (H2O2)
Oxidative stress can lead to:
• Damage to mitochondria, DNA, protein
processing and cellular metabolism
- lipid peroxidation
- protein oxidation
- DNA oxidation
• This ultimately leads to:
- Loss of cellular phenotype
- Necrosis
- or Apoptosis
Endogenous defense mechanisms:
O2
H2O
Mitochondria
P450 oxidases
Catalase
O2-
SOD
H2O2
OH+
H2O
2 GSH
Aging↓
Glutathione
Reductase
Glutathione
Peroxidase
GSSG
H2O
Telomeres and Aging
• Repetitive DNA sequences
At the ends of all human
Chromosomes
From: Aditya Rana in Biotechnology
• In humans there are 46 chromosomes;
thus 92 telomeres (one per end)
• Telomere is about 10 to 15 kb in length,
composed of the tandem repeat
sequence: TTAGGG
• Without telomeres, ends
of chromosomes would
be “repaired”, leading to
chromosome fusion and
abnormal function
• Telomeres regulate how
many times a cell can
divide. Telomere
sequences shorten each
time DNA replicates
• Once telomeres shrink to
a certain level, cells can
no longer divide; hence
aging
From: National Institutes
on Aging (not protected by
copyright); official domain
Summary of Telomere theory:
Telomere length declines in dividing cells as we age
Telomere length in bp
(human blood cells)
8,000
3,000
1,500
0
35
Age in years
65
Genes that affect Aging:
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Stress resistance genes
Genes targeting inflammation
Genes that slow basic metabolism, like IGF
Overall genetic stability
The problem:
Altered gene expression resulting from quality
control defects allows errors to accumulate as
cells divide leads to cells with diminished
function
Many genes shown to influence life span are involved
in DNA damage repair and protection.
Progeria:
• Two forms in humans;
Werner's syndrome
(adult-onset progeria) and
Hutchinson-Gilford
syndrome (juvenile-onset
progeria).
• Most clinicians believe
that progeria is segmental
aging
• Mutation in Werner’s
codes for a DNA helicase
(DNA repair/unwind)
From: www.immortalhumans.com/982/
From:http://www.scripps.edu/~jjperry/research.html
Progeria
Werner’s syndrome:
- chromosome instability syndromes
-Inability to repair DNA
-Increased rate of cancer
-mutated helicase
-inherited as autosomal recessive
Hutchinson-Gilford:
-no helicase abnormality
-The pattern of inheritance is uncertain
-have shorter than normal telomeres
-undergo early cell senescence.
Mitochondrial
Aging
Mitochondrial
DNA is extra
sensitive to
damage, such as
oxidative stress
because it does
not have repair
mechanisms like
normal DNA
Summary of mitochondrial theory:
• Decreased activity of electron transport
chain complex with aging
• Increased release of ROS
• Alterations in mitochondrial apoptosis
pathways (Bax/Bcl-2 etc)
• Lack of repair mechanisms mtDNA
• Slower mitochondrial turnover
accumulates mtDNA mutations
Genomic Alterations with Aging:
Intact telomeric
DNA
Intact nuclear
DNA
Intact mtDNA
Endogenous
oxidative stress
DNA repair
Damaged/shorter
telomeric DNA
Cell cycle arrest
senescence
Damaged
nuclear DNA
Mutation
and
cancer
Apoptosis
Cell loss
Aging
Damaged
mtDNA
Diminished
energy
production
What can we do about it?
Caloric restriction
• 40% reduction in caloric intake
• Results in healthy, long-lived rats/mice
• Biomarkers of aging are altered with CR:
- lower body temperature
- reduced plasma insulin
• Gene expression more stable (sign of
senescence delay)
http://www.wired.com/wiredscience/2009/07/monkeylongevity
What else can we do to enhance
Healthy Aging?
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Nutritional antioxidants (food, supplements)
Anti inflammatory (Minocycline, NSAIDS)
Cholesterol lowering (Statins)
EAT LESS
Exercise
Diet and brain health
• US average 3,500 calories/day
• Normal intake for an adult is 2,000/day
• Antioxidant foods: blueberries, spinach,
strawberries, acai
• Oatmeal and muscadine grapes lower cholesterol
• Curcumin and ginseng affect brain activity
• Transfats and saturated fats bad for the brain
• Moderate exercise lowers risk for Alzheimer’s
disease with 50%
Methods for increasing
longevity
Artificial selection
for longevity
Caloric
restriction
pharmaceuticals
and life style
Increased activity of stress-resistance
genes
Decreased levels of
Reactive Oxygen species
Decreased tissue damage and
inflammation
Increased longevity
Genetic
engineering
SESSION 1: PHYSIOLOGY OF
AGING
due: March 26
• Goal: Student will have a better understanding of the normal
aging process.
• Session Competencies:
• Assess functional health status: Activities of Daily Living (ADL)
and Instrumental Activities of Daily Living (IADL).
• Describe what is meant by the statement, “normal aging is
heterogeneous” citing changes that affect different tissues and
organs in different individuals at different rates.
• Practice the skill of taking and reading a blood pressure.
Activities of Daily Living (ADL)
Activities of daily living are activities
related to personal care and include
bathing or showering, dressing, getting in
or out of bed or a chair, using the toilet,
and eating.
Instrumental Activities of Daily
Living (IADL)
• Instrumental activities of daily living are
activities related to independent living and
include preparing meals, managing
money, shopping for groceries or personal
items, performing light or heavy
housework, and using a telephone.
Lotta Granholm
[email protected]
www.musc.edu/aging