Transcript MCB 135K Mid-Term I Review

MCB 135K Section
February 13, 2005
GSI: Laura Epstein
Today
• Evolutionary Theory of Lifespan
• Oxidants and Anti-oxidants
• Neurodegeneration, Repair, Plasticity
Evolutionary Theory of Life
Span
- Huntington’s Disease, a dominant lethal mutation
How does Huntington’s stay in the population if it results in lethality?
*JBS Haldane
100
%
Natural
Selection
10
20
Age of onset for Huntington’s = ~35yr
30 40 50 60 70
age in years
80
Hypothesis: Aging results from a decline in the
force of natural selection.
Aging in Nature
Natural Selection
Aging Begins
100
%
Alive
Life Span in Nature
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3
Life Span in the Lab
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age in years
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- Most organisms do not age in a natural environment.
Lifespan is proportional to extrinsic mortality!
-If mortality is high an organism will die from
predation or other hazards before it grows old.
-Therefore, if extrinsic mortality limits survival
there is no reason to evolve a life span
that is longer than an organism would
normally survive in nature.
Evolutionary Theories of Aging
Disposable Soma - Somatic cells are maintained only to ensure
continued reproductive success, following reproduction
the soma is disposable. (life span theory)
Antagonistic Pleiotropy - Genes that are beneficial at younger
ages are deleterious at older ages.
(Pleiotropism = The control by a single gene of
several distinct
and seemingly unrelated phenotypic effects)
Mutation Accumulation - Mutations that affect health at older
ages are not selected against (no strong evidence).
Opossums and Life Span
- ultimate prey, ~ 80% die from predation
- typically reproduce once
- age very rapidly
-Hypothesis: The presence of predators limits life span, natural
selection favors somatic maintenance for only as long
as an average opossum can be expected to live.
-How could you test this hypothesis?
Steve Austad, U. of Idaho
Sapelo Island Opossums
- no predators (out in daytime)
- longer average life span
- reproduce twice (fewer offspring/litter)
-Are these changes due to a lack of predators, or a physiological
change that delays the aging process?
Physiological Change - Sapelo island opossums not only
live longer, they age slower than mainland animals.
-Sapelo Island opossums have less oxidative
damage than mainland opossums.
(collagen X-linking)
Selection at age of reproduction alters lifespan
Offspring of “old” flies are selected
% Surviving
- Reproductive period extended
- Stress resistant, -super flies
- Early adult fecundity reduced
*antagonistic pleiotropy
Normal
old flies selected
Age in Days
Evolution in the Laboratory
Offspring of “young” flies are selected
- Early adult fecundity increased
*antagonistic pleiotropy
% Surviving
old flies selected
Normal
young flies
selected
Age in Days
Summary of Drosophila Selection
1) Selection at age of reproduction can alter the lifespan of
Drosophila (lifespan has been doubled by this technique).
2) Increase in lifespan has a cost, reduced fecundity (reproduction).
- antagonistic pleiotropy -
3) Long-lived flies are stress resistant (heat shock, oxidants).
Exceptions to the Rule
Some organisms evolve unique adaptations that allow the
subsequent evolution of exceptional life span.
Rats and Bats: Rats live for ~3 years, Bats live for ~30 years
Bats evolved a mechanism (flight) that reduced extrinsic mortality
and allowed for the subsequent evolution of a long life span.
What other adaptations might lead to prolonged life span?
Exceptional Life Span in Eusocial Insects
Queen Bees and Queen Ants have exceptional life spans!
•Small size
•Many offspring
Why do they live so long?
- Protected from the environment, therefore extrinsic mortality is low!
What does this tell us about aging?
-Body size is correlated with lifespan, but is not
necessarily a determinant of lifespan.
-Reproduction / metabolism does not control life span.
•Some queen ants produce their body weight in offspring each day
-Life Span results from selective pressures.
The p53 Tumor Suppressor
Stress
Genome Stress
DNA damage
Oxidative Stress
p53
Apoptosis
Senescence
Growth Inhibition
- Loss of p53 function results in an increased incidence of cancer
- p53 is mutated in ~80% of all human tumors
p53 may promote aging…
p53
Cancer
Aging
Why did we evolve a system that
limits our lifespan?
-to protect against cancer!
(Antagonistic Pleiotropy again!)
Life Span versus Aging
Aging - can not be selected for, results from an absence
of natural selection.
Life Span - results from selection and extrinsic mortality
Environmental Selection - predators, natural hazards
Social Selection - parental investment, sexual behavior
Main Ideas
1. Life span results from selective pressure.
2. Life span is inversely proportional to extrinsic mortality.
3. Aging results from a lack of natural selection with age.
Questions
• What is the disposable soma theory?
• What is antagonistic pleiotropy?
• Is life span proportional to extrinsic
mortality?
• Does natural selection cause aging?
Oxidants and Anti-Oxidants
Free Radicals
• Free radicals are unstable
• React quickly with other compounds,
doing cell and body damage
• Once produced, they multiply unless
neutralized by anti-oxidants or other
free-radical scavengers.
• Free radicals rarely occur in nature
• Oxygen can have several unpaired
electron “pairs”
The Free Radical Theory of Aging
“Aging results from the deleterious
effects of free radicals produced in
the course of cellular metabolism”
Harman D., Aging: A theory based on free radical
and radiation chemistry, J. Gerontol. 11: 298,
1956
Free Radical
Chemistry
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Reactive radicals attack indiscriminately
Can add to unsaturated bonds
Can abstract electrons or hydrogen atoms
Propagate chain reactions
Can cause bond scission
Can cause crosslinking
– Crosslinking - Formation of bonds among polymeric chains
• Produce secondary toxic agents
Implications for Aging
• Some free radical-induced chemical
modifications may have unique impacts
• Crosslinked products may not be degradable
• Scission of bonds in DNA, particularly
multiple events may erase vital information
What are the Major Oxidants?
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Hydroxyl radical (OH )
Hypochlorite (HOCl)
Singlet oxygen 1O2
Peroxynitrite (OONO-)
Hydrogen peroxide (H2O2)
Free or loosely-bound iron, copper or heme
.
Superoxide radical (O2 -)
.
• Nitric oxide (NO )
Lipid Peroxidation
• PUFAs* contain weakly bonded hydrogen
atoms between double bonds
• Chain reactions are probable because of
high local concentrations of double bonds
*PUFAs means polyunsaturated fatty acids
Oxidant Sources
Table 5.1
Regulated
Unregulated
• Enzymes involved •in “Leaky” electron transport
• Damaged proteins and lipids
cell signaling
• Toxins (food, water)
• Immune cells
• Smoke
• Irradiation (UV)
Major Antioxidants
Table 5.2
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Vitamins E and C
Thiols, particularly glutathione
Uric acid
Superoxide dismutases (Cu/Zn or Mn SOD)
Catalase and glutathione peroxidase
Heme oxygenases
Protein surface groups (Msr)
Glucose and Oxidants
• In cell culture models high glucose correlates
with oxidant production
• Diabetes implications
Are Oxidants the Cause of Aging? (Table 5.8)
Pro
Con
•Caloric restriction may reduce
oxidative stress
•Life span extension in mutants may
be associated with stress resistance
•Knockout mice lacking MnSOD
have restricted survival
•Enzyme mimetics extend life span
in some aging models.
•Some drugs, probably acting as
antioxidants, have been claimed to
extend lifespan.
•Vitamin C, a superb free radical
scavenger, is not synthesized by long-lived
primates.
•Chronic radiation in low doses does not
shorten life span (may increase it).
•Dietary supplementation with Vitamin E
and C does not extend life span.
•Tissue comparison (brain vs. muscle)
seems incompatible with
oxidant/antioxidant models of aging.
•Exercise, that increases oxidant stress,
improves life span.
Questions
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Name 3 oxidants and 3 antioxidants
What are sources of oxidants?
How do free radicals cause damage?
What does high levels of glucose have to do
with oxidants?
Neurodegeneration, Repair, and
Plasticity
• Neuroendocrine theory of aging:
Alterations in either the number or the
sensitivity of various neuroendocrine
receptors gives rise to homeostatic or
homeodynamic changes that result in
senescence.
Neuron regeneration?
How is that possible?
• While until the 1990s we thought neurons
couldn’t regenerate, now we’ve seen that
certain neurons have the potential to
regenerate under specific circumstances.
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Neurons in lining of cerebral ventricles
Hippocampus
Neuroglia (astrocytes and oligodendrocytes)
Microglia (“macrophages” of nervous system)
What conditions favor regeneration?
• Whole body:
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Exercise
Nutrition
Some stress
Education
Good circulation
• Neural
microenvironment
– Brain metabolism
– Hormonal changes
Education and death rates
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Higher education, lower death rates
Higher education, lower disability
Higher income, lower death rates
Comments?
Why would education decrease
death rates?
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Access to medical care
Access to exercise
Better nutrition
Higher income
Responsibility to health behaviors
Lower rates of smoking and alcohol
Brain reserve capacity
• When these things (listed in previous slide)
happen in young life, brain reserve capacity built
• This means more neuronal branches and more
axonal/dendritic connections, better brain blood
supply
• Evidence: a person with more education has
longer dendritic branching length and more
connections
• With old age there is denudation of neurons—less
branching
Questions
• What is the neuroendocrine theory of
aging?
• What is the relationship between education
and death rates? And why is it hypothesized
to be this way?
• What is brain reserve capacity? How might
it help you in old age?