Transcript Theories of Aging - Molecular and Cell Biology

Theories of Aging
January 26, 2007
PS Timiras
Classification and brief description
of main theories of aging
Molecular
Cellular
Codon restriction
Wear-and-tear
Somatic mutation
Free radical accumulation
Error catastrophe
Apoptosis
Gene regulation.
Dysdifferentiation
Evolutionary
Disposable Soma
Antagonistic Pleiotropy
Mutation Accumulation
System
Rate-of-living
Neuroendocrine
Immunologic
Evolutionary Theory
Disposable Soma - Somatic cells are maintained only to
ensure continued reproductive success, following
reproduction the soma is disposable. (life span theory)
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)
Evolution in the Laboratory
Michael Rose, U.C. Irvine
% Surviving
Drosophila Survival Curve
Average life span = ~40d
Age in Days
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).
What about Humans?
-Unlike most animals, humans and some related primates age in
a natural environment.
-Menopause is also unique to humans. How can nature select for
a process that limits reproduction?
-How does parental care influence the evolution of human life span?
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).
Molecular Theories of Aging
Codon restriction
Fidelity and/or accuracy of mRNA message translation is impaired
with aging due to cell inability to decode the triple codons
(bases) in mRNA molecules
Somatic mutation
Type of stochastic* theory of aging that assumes that an
accumulation of environmental insults eventually reaches a level
incompatible with life, primarily because of genetic damage.
* Involving Random Chance
Molecular Theories of Aging, Con’t
Error catastrophe
Errors in information transfer due to alterations in RNA polymerase
and tRNA synthetase may increase with age resulting in
increased production of abnormal proteins
Gene regulation
Aging is caused by changes in the expression of genes regulating
both development and aging
Dysdifferentiation
Gradual accumulation of random molecular damage impairs
regulation of gene expression
Cellular Theories of Aging
Wear-and-tear
Intrinsic and extrinsic factors influence life span
Free radical accumulation
Oxidative metabolism produces free radicals which are highly
reactive and thus damages DNA and/or proteins and thus
degrades the system structure and function.
Apoptosis
Process of systematically dismantling key cellular components as
the outcome of a programmed intracellular cascade of
genetically determined steps.
System Theories of Aging
Rate-of-living
An old theory that assumes that there is a certain number of calories or
heart beats allotted to an individuals and the faster these are used the
shorter the life.
Neuroendocrine
Alterations in either the number or the sensitivity of various neuroendocrine
receptors gives rise to homeostatic or homeodynamcis changes that
results in senescence.
Immunologic
Immune system reduces its defenses against antigens and thus results in
an increasing incidence of infections and autoimmune diseases.
The Free Radical Theory of
Aging
“Aging results from the deleterious effects of
free radicals produced in the course of cellular
metabolism”
It is a molecule having unpaired electrons
Therefore, free radicals are unstable
Oxygen can be converted to reactive singlet oxygen
– For example: Reactive oxygen molecule
produced by respiratory burst in immune cells,
phagocytes, are toxic to microbial cells
Harman D., Aging: A theory based on free radical and radiation chemistry, J. Gerontol.
11: 298, 1956
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
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Superoxide radical (O2 -)
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• Nitric oxide (NO )
Major Antioxidants
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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)
For More Information about Oxidants
and Antioxidants
Read Chapter 5