Biology of Aging Lotta Granholm Center on Aging MUSC.
-
Upload
lynette-caldwell -
Category
Documents
-
view
226 -
download
3
Transcript of Biology of Aging Lotta Granholm Center on Aging MUSC.
Biology of AgingBiology of AgingLotta GranholmCenter on Aging
MUSC
"Every man desires to live long; but no man would be old."
Jonathan Swift (1667 - 1745)
Why should we study aging?Why should we study aging?
• 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…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
Goldie Jean Studlendgehawnborn on November 21, 1945
Some agegracefully...
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?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 Terminology associated with Aging: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…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:• 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 agingPhysical 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 AgePathology that occurs with Age
Prevalence of selected chronic conditions, expressed in percentages, as a function of age for the US population (2002-2003 dataset). Source: National Center for Health Statistics, Data Warehouse on Trends in Health and Aging.
Successful AgingSuccessful 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
social networks cognitive
and physical health
avoiding disease and disability
Successful Successful AgingAgingsocial
networks cognitive and physical
health
avoiding disease and disability
Successful Successful AgingAging
How to be a centenarian…How to be a centenarian…
How long will you live?How long will you live?
Successful AgingSuccessful 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 agingHow 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 cross-sectional 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 AgingAnimal Models in Aging
Saccharomyces cerevisiae
Caenorhabditis elegans
Drosophila melanogaster Mus musculusCourtesy R. Moore
Short lives, experimental results collected quickly, or over many generations;
Maintained easily and inexpensively, present less complex genetic or physiological systems than humans.
Genetically engineered animal models for exploring the basic mechanisms involved in the aging
Artificial selection for longevity
From Dr. Robert Arking
Mean life span: increased from 40 to 70 days“Health span”: increased from 30 (blue) to 60 (pink) days
So what is it that makes So what is it that makes us age?us age?
Theories of Aging:Theories of Aging:
• Oxidative Damage• Telomeres• Genetic Alterations with aging• Mitochondrial Aging
Other processes involved:• Inflammatory processes• Hormonal changes• Life style choices
Oxidative stress: Oxidative stress: imbalance production/breakdownimbalance production/breakdown
• Free radicals are normal products of metabolism• Predominant cellular free radicals are:
- superoxide (O2 -)
- hydroxyl (OH-)
- nitrogen dioxide (NO2)
- hydrogen peroxide (H2O2) superoxide
Oxidative stress can lead to: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:Endogenous defense mechanisms:
O2- H2OOH+H2O2
MitochondriaP450 oxidases
O2
SODSOD
GSSGGSSG
2 GSH2 GSH
CatalaseCatalase
GlutathioneGlutathionePeroxidasePeroxidase
H2O
GlutathioneGlutathioneReductaseReductase
H2O
Aging↓
Telomeres and AgingTelomeres and Aging
• Repetitive DNA sequences
At the ends of all human
Chromosomes
• 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
From: Aditya Rana in Biotechnology
• 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:
Tel
om
ere
len
gth
in
bp
(h
um
an b
loo
d c
ells
)
Telomere length declines in dividing cells as we age
8,000
1,500
3,000
0 35 65Age in years
Genes that affect Aging:Genes that affect Aging:• 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: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:http://www.scripps.edu/~jjperry/research.html
From: www.immortalhumans.com/982/
ProgeriaProgeriaWerner’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 Mitochondrial AgingAging
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: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:Genomic Alterations with Aging:
Intact telomeric DNA
Damaged/shorter telomeric DNA
Intact nuclear DNA
Damaged nuclear DNA
Intact mtDNA
Damaged mtDNA
Endogenous oxidative stress
Aging
Cell cycle arrestsenescence
ApoptosisCell lossMutation
and cancerDiminished
energy production
DNA repair
What can we do about it?What can we do about it?
Caloric restriction 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 What else can we do to enhance Healthy Aging?Healthy Aging?
• Nutritional antioxidants (food, supplements)
• Anti inflammatory (Minocycline, NSAIDS)
• Cholesterol lowering (Statins)
• EAT LESS
• Exercise
Diet and brain healthDiet 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 Methods for increasing longevitylongevity
Increased activity of stress-resistancegenes
Decreased levels of Reactive Oxygen species
Decreased tissue damage and inflammation
Increased longevity
Artificial selectionfor longevity
Caloricrestriction
pharmaceuticalsand life style
Geneticengineering
SESSION 1: PHYSIOLOGY OF SESSION 1: PHYSIOLOGY OF AGINGAGING
due: March 26due: 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 (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 Instrumental Activities of Daily Living (IADL)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 GranholmLotta [email protected]@musc.eduwww.musc.edu/agingwww.musc.edu/aging