biological theories of aging winter 08 lecture 5 – chapter 5

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Biological Theories of Aging Winter 08 Lecture 5 – Chapter 5

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Biological Theories of AgingWinter 08

Lecture 5 – Chapter 5

Many Theories

•Wear & tear•Hayflick

• Telomere•Rate of Living

•Caloric Restriction•Free Radical•Autoimmune•Cross linkage

Non Genetic

•Genetic Cellular•Error Cascade

Genetic

1882

Wear & Tear Theory of Aging

Ordinary insults and injuries of daily living accumulate, and over time decrease the organism’s efficiency

• years of damage to cells, tissues and organs • preprogrammed process: biological clock• preprogrammed amount of energy used up

Human body like your car engine

Hans Selye: The Discovery of Stress (1936)

General Adaptation Syndrome (G.A.S.)

if the duration of stress is sufficiently long, the body eventually enters a stage of exhaustion, a sort of aging "due to wear and tear"

Alarm reactionResistance Exhaustion

childhoodadulthood senescence

1 week old fruit flies fly 110 minutes without landing

1 month-old fruit flies must land after 19 minutes

Theory is weak…

– Animals raised in a protective environment still age

– Wear and tear could easily be viewed as a result of aging and not a cause of it

– The theory is outdated because it does not deal with specific cellular and molecular mechanisms

Hayflick Theory of Aging – Cellular Theory (1960)

• there is a limit to the number of times cell can divide• cells reach a predefined limit (Hayflick Limit) replicative senescence causes a nondividing state• inability to divide represents aging

• cells from older organisms divide proportionately fewer times than cells from younger ones

Debunked Carrel (1940): cultured cells were immortal (HeLa Cells)

Hayflick’s experiments

In vitro cell culture

Finite # of passages:Hayflick Limit~50

tissue

trypsin

Medium, temp confluent

trypsin

Passage population doublingMedium, temp confluent

Hayflick Experiments: Male & Female Fetal Cells

40th PD 10th PD

Male con Male & Femalemix

Female con

youngold

20 PD

Male con

30 PD 30 PD

Only female cells remain Female

con

Rats: PD ~ 10 3.5

Humans PD ~ 50 122

Galapagos tortoises PD ~110 200

Fibroblasts

Cells in long-lived animals replicate longer in culture than animals with shorter life spans. Long-lived animals have a higher Hayflick Limit than short-lived ones.

Normal human fibroblasts (left) and fibroblasts showing a senescent morphology (right). Notice the common elongated morphology of senescent cells.

Extension of Wear & Tear: Why only 50 PDs?

Answer: The Telomere Hypothesis of Aging

• Telomeres are sequences of nucleic acid• End pieces of DNA (the tail of DNA)• Every time cells divides, telomeres shorten• Once the telomeres become too short, cell division slows and finally ceases and the cell will die

A.M. Olovnikov, 1996   

telomeres are lost with age in normal dividing cells, cancer cells escape mortality by activating the enzyme telomerase.

Telomere becomes too short& cannot replicate…Cell becomes “old”

Apoptosis:

The process by which a cell dies at a natural,

"pre-programmed" time

1. Erosion 2. Addition:

telomerase

Dolly had DNA in her cells that is typical of an older animal

Dolly was cloned from a mammary cell taken from a 6-year-old ewe

Cloned in 1996

Died Feb 14, 2003: euthanized progressive lung disease…died 6!!! years earlier

The energy an animal burns in an hour

Max Rubner (1908)discovered the relationship among metabolic rate, body size and survival rate

• Born with a limited amount of energy • If we use energy slowly rate of aging is slowed• If the energy is consumed quickly aging speeds up

nearly all mammals expire after anywhere from 1 billion to 2 billion heartbeats

Rate of Living Theory of Aging – (1908)

This theory explains why most larger animals live longer than most smaller animals

• rapid metabolism = shortest life spans• slower metabolic rates = tend to have longer life spans

70 yrs

50 yrs

12 yrs

3 yrs

Rate of Living Theory Updated & Refined: Caloric Restriction Theory of Longevity

1937 - Clive McCay, Cornell University - 33% CR (rats) 50% increase in max lifespan

•Yeast (increases by 25% when glucose level in culture reduced from 2% to 0.5%)•Mosquitoes•Flies•Protozoans•Roundworms•Spiders•fish

late 1980s - start three studies with monkeys NIA - Baltimore - 160 monkeys (squirrel monkeys and rhesus monkeys) Univ. Maryland - Baltimore - 27 monkeys Univ. Wisconsin - 76 monkeys approx. 30% CR + supplements

"To lengthen thy life, lessen thy meals." Benjamin Franklin

Mice: 1 mo. =2 yr old in human

Adult-onset CR extends animal life only when phased in gradually (over a period equivalent to 2.5 yrs in humans) & when given a nutrient-enriched diet.

44% CR

CR starting at: 12.5 mo. = 30 yrs. In human

27% CR

13.5 mo. = 40 yrs in humans

George Roth, Ph.DLong-term studyBegan in 1987

"Until 1987, caloric restriction was never tried in a controlled way with animals that live longer than three years," says Roth. A decade later, we're finally accumulating information on how caloric restriction affects primates.

currently a Guest Scientist at NIA, President and CEO of Gerotech Inc.

Findings in NIA Primate CR Study Matches Rodent Data

 (-) Body weight yes

 (-) Fat and lean mass yes

 (-) Time to sexual maturation yes

 (-) Time to skeletal maturation yes

 (-) Fasting glucose/insulin yes

 (-) Metabolic rate (short-term) yes

 (*) Metabolic rate (long-term) yes

 (-) Body temperature yes

 (*) or (+) Locomotion yes

 (-) Triglycerides yes

 (+) IGF-1/growth hormone yes

 (*) Wound closure rate yes

 (*) B-gal senescent cells ?

(-) = decrease, (+) = increase, (*) = no change30% CR 10 yr study

• diabetes: greatly reduced • fewer signs of spinal arthritis • less decline in melatonin levels• increase in HDL

Compared to Americans, Okinawan elders  get 80% fewer breast and prostate cancers  get 50% fewer ovarian and colon cancers 

have 50% fewer hip fractures  have 80% fewer heart attacks 

40% fewer calories than Americans and 17% fewer calories than the Japanese average

http://www7.nationalgeographic.com/ngm/0511/sights_n_sounds/index.html

Okinawan Elders

Greatest # centenarians

CR

reduces the amount of fuel available for cells and the amount of oxygen needed by the mitochondria to convert the existing fuel into energy, and it makes the existing metabolic process more efficient

Free Radical Theory of Aging

(1954)

• Aging is a result of oxidative damage caused by free radicals generated by the metabolic system

• Free radicals are unstable organic molecules that appear as a by-product of oxygen metabolism in cells

• Free radicals are any number of chemical species that are highly reactive because they possess an odd number of electrons and seek to combine with other molecules to pair off their free electron

• Damage: lipids, protein, carbohydrates, nucleic acids, various other cell components

• Supported by caloric restriction studies: caloric restriction extends life expectancy by

Denham Harman, Ph.D, M.D,

ROSOxygen-derived radicals are generated constantly as part of normal aerobic life (1 – 5 % of 02)

• formed in mitochondria as oxygen is reduced along the electron transport chain

ROSs: are also formed as necessary intermediates in a variety of enzyme reactions

Table 1. Rates of Auto-Oxidationand Life Spans of Mammalian Species 14

SpeciesOxidation

RateLife Span (yrs)

Man 24 90

Orangutan 25 50

Baboon 35 37

Green monkey

41 34

Squirrel monkey

74 18

Rat 104 4

Mouse 182 3.5

•Melatonin

All found to decrease free radical damage

Induced overexpression of mitochondrial Mn-superoxide dismutase extends the life span of adult Drosophila melanogaster.

 Sun J; Folk D; Bradley TJ; Tower JMolecular and Computational Biology Program, Department of Biological Sciences, University of Southern California, University Park, Los Angeles, California 90089-1340, USA

Genetics.  2002; 161(2):661-72 (ISSN: 0016-6731)

•Superoxide dismutase

An enzyme that converts the superoxide ion (·O2¯) into hydrogen peroxide. This enzyme is part of the cellular antioxidant defense system.

Error Cascade Theory

Autoimmune Theory:

• immune system begins to decline after adolescence• vulnerability to disease and a sluggish response to some tumor cells • system so weakened that it can no longer distinguish between the body’s own and foreign tissues, i.e. the body may begin to attack itself.

Cross-Linkage Theory: • Connective tissue looses elasticity with age (wrinkles, cataracts) • Loss of elasticity results from accumulation of cross-linking compounds that cause the collagen to become stiff• Some of this cross-linking may be caused by free radicals