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

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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 Granholmgranholm@musc.edugranholm@musc.eduwww.musc.edu/agingwww.musc.edu/aging