Biological Theories of Aging

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Biological Theories of Aging Winter 08 Lecture 5
Chapter 5
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Many Theories
Non Genetic

• Wear tear
• Hayflick
• Telomere
• Rate of Living
• Caloric Restriction
• Free Radical
• Autoimmune
• Cross linkage

Genetic

• Genetic Cellular
• Error Cascade

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1882
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Wear Tear Theory of Aging

• Ordinary insults and injuries of daily
• living accumulate, and over time decrease
• the organisms 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
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Hans Selye The Discovery of Stress (1936)
General Adaptation Syndrome (G.A.S.)
Alarm reaction
Exhaustion
Resistance
childhood
senescence
adulthood
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"
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1 week old fruit flies fly 110 minutes without
landing 1 month-old fruit flies must land after
19 minutes
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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• The theory is outdated because it does not deal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

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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)
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Hayflicks experiments In vitro cell
culture Finite of passages Hayflick Limit50
tissue
trypsin
Medium, temp? confluent
trypsin
population doubling
Passage
Medium, temp? confluent
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Hayflick Experiments Male Female Fetal Cells
young
old
40th PD
10th PD
Female con
Male con
Male Female mix
20 PD
30 PD
30 PD
Only female cells remain
Male con
Female con
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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.
Rats PD 10
3.5
Humans PD 50
122 Galapagos tortoises PD 110
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Fibroblasts
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Normal human fibroblasts (left) and fibroblasts
showing a senescent morphology (right). Notice
the common elongated morphology of senescent
cells.
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Extension of Wear Tear Why only 50
PDs?Answer The Telomere Hypothesis of Aging
A.M. Olovnikov, 1996   

• 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

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

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Cloned in 1996
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
Died Feb 14, 2003 euthanized? progressive lung
diseasedied 6!!! years earlier
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Rate of Living Theory of Aging (1908)
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
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70 yrs
50 yrs
12 yrs
3 yrs

• 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

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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

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"To lengthen thy life, lessen thy meals."
Benjamin Franklin
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Mice 1 mo. 2 yr old in human
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CR starting at 12.5 mo. 30 yrs. In human
13.5 mo. 40 yrs in humans
44 CR
27 CR
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.
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"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.
George Roth, Ph.D Long-term study Began in 1987
currently a Guest Scientist at NIA, President
and CEO of Gerotech Inc.
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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 ?

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

(-) decrease, () increase, () no
change 30 CR 10 yr study
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Okinawan Elders
Greatest centenarians
40 fewer calories than Americans and 17 fewer
calories than the Japanese average
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 
http//www7.nationalgeographic.com/ngm/0511/sights
_n_sounds/index.html
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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
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Free Radical Theory of Aging (1954)
Denham Harman, Ph.D, M.D,

• 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

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• ROS
• Oxygen-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

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Table 02 Leading Causes of Death in the U.S.
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Table 1. Rates of Auto-Oxidationand Life Spans of Mammalian Species 14 Table 1. Rates of Auto-Oxidationand Life Spans of Mammalian Species 14 Table 1. Rates of Auto-Oxidationand Life Spans of Mammalian Species 14
Species Oxidation Rate Life 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
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• Melatonin

All found to decrease free radical damage
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• Superoxide dismutase
• An enzyme that converts the superoxide ion (O2)
  into hydrogen peroxide. This enzyme is part of
  the cellular antioxidant defense system.

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)
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Error Cascade Theory
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• 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 bodys 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

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