Theories of aging II

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Theories of aging II
We die because our cells die. -William R. Clark

• AS300-003 Jim Lund

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DNA damage aging theory

• Somatic mutation
• Genetic damage leads to progressive loss of
  potential to make necessary proteins.
• DNA damage and DNA repair
• Loss of repair efficiency with age leads to
  somatic mutation with effects described above.
• Error catastophe
• Faulty transcription and/or translation decrease
  cellular capacity to a subvital level.

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Somatic mutation theory of aging

• Proposed by Szilard, 1959.
• Genetic damage leads to progressive loss of
  potential to make necessary proteins.
• DNA damage.
• Sometimes damage is repaired.
• Sometimes damage leads to mutations or
  chromosomal abnormalities.

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Evidence for somatic mutation

• Chromosomal abnormalities more frequent in old
  animals cells, i.e. old lymphocytes.
• Chromosomes from old humans more fragile rate of
  aminopterin-induced breakage higher than in young
  samples.
• X-rays produce mutations, leads to death in a
  dose-dependent manner.
• Effects of aneuploidy can be similar to aging.
  Example Down syndrome, trisomy 21.
• However, not all cell/tissues show chromosomal
  abnormalities.

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Evidence for somatic mutation

• Most mutations will knock out single genes.
• Drosophila P-element experiments. Use P-elements
  to introduce mutations-gtlead to shorter
  lifespans, 22 over 16 generations. (Woodruff and
  Nitikin, 1995).
• Cancer evidence of mutations. Increasing
  mutation levels, increasing mutation rates as
  animals age.

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Evidence against somatic mutation

• DNA damage at measured rates will only lead to a
  few somatic mutations per cell over a lifetime.
• This total damage is likely not enough to account
  for the observed age-related changes in cells.

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DNA damage and repair

• DNA mutation rate determined by balance between
  DNA damage and DNA repair.
• DNA damage leads to errors in protein synthesis,
  loss of proteins, and this decreases cellular
  efficiency in a progressive manner that leads to
  loss of cell vitality.

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DNA damage model
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DNA damage types
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DNA damage

• Sources of DNA damage
• Oxidative damage, free radicals.
• Environmental toxins, smoking.
• UV irradiation.
• Errors in DNA synthesis and repair
• Multiple different types of DNA damage, each with
  its own cellular repair mechanism.

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DNA damage

• DNA damage stops DNA replication, the cell cycle
  checkpoint.
• Unrepaired damage can slow/stall cell division
  (the p53 dependent checkpoint).
• Extensive DNA damage can trigger apoptosis.
• Prevents neoplasm (cancer), but reduces
  replacement of cells.
• In non-dividing cell populations, cell death
  reduces function redundancy.

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DNA damage and repair theory

• Prediction of the theory
• Positive correlation between DNA repair ability
  and lifespan.
• Age-related decrease in repair capability leads
  to aging phenotypes.

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1. Positive correlation between DNA repair
ability and lifespan.

• DNA damage rates are proportional to species
  oxygen consumption rate.
• DNA damage can be assayed for tymine glycol and
  thymidine glycol in urine. (Ames et al., 1994).
• Mice have high rate of damage, humans have a low
  rate.
• DNA repair
• Higher rates measured in long-lived organims.

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DNA repair ability
Hart and Setlow, 1974
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DNA repair ability
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2. Age-related decrease in repair capability
leads to aging phenotypes.

• Assays show higher repair rates in young
  fibroblasts compared to old fibroblasts.
• Mouse 3-fold increase in frequency of point
  mutations in liver between infancy and old age,
  2-fold increase in brain (Dolle et al., 1997).
• Fly Copy number of DNA repair gene mei-41
  affects lifespan. No copies short lifespan.
  Extra copy extended lifespan (Symphorien and
  Woodruff, 2003).
• Human Werners syndrome (DNA helicase).

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DNA damage and repair theory

• Hormesis
• Mild DNA damage agents can induce the repair
  systems, and if the inducing damage is mild
  enough, the net effect is postive.
• Sonneborn (1997) showed that the clonal lifespan
  of the paramecium is
• Shortened by UV irradiation
• Causes thymidine dimerization of DNA and induces
  DNA repair systems.
• Lengthened if UV irradiation is followed by
  photoreactivation (reverses dimer formation).

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Mouse DNA repair mutation phenotypes
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DNA damage and repair theory

• Genetic diseases of DNA repair, Werners syndrome
  and others produce some but not all aging
  phenotypes.
• Chemical antioxidants generally have little
  effect on lifespan.
• Genetic manipulations that increase free radical
  scavenging rarely increase lifespan.
• Hard to untangle nuclear DNA damage from
  mitochondrial DNA damage.

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DNA damage and repair theory

• Still questions to be addressed
• Is the level of DNA damage enough to produce
  senescence? (100 or less mutations / old cell in
  most tissues)
• Mechanisms by which DNA mutation leads to aging
  cells? Gene expression changes, chromatin
  changes, reduction of repair efficiency?
• DNA damage and repair likely contributes to aging
  but by itself is not sufficient explanation of
  aging.