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Theories of aging

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Title: Theories of aging


1
Theories of aging
  • AS300-002 Jim Lund

2
Mechanistic theory How animals age
  • OR, What biological process is responsible for
    aging?
  • Complexity of the aging phenotype has led to many
    theories that focus on particular aspects of the
    phenotype.
  • These theories dont necessarily compete with one
    another.

3
The challenge
  • Finding theories that account for the many
    aspects of the phenotype.
  • Needed theory that relates changes in one
    biological process to another--that incorporates
    many different aspects of the aging phenotype and
    relates them to common underlying mechanisms.

4
Mechanistic aging theory
  • Theories get evaluated on
  • Empirical validity (local evaluation)
  • Breadth of phenotypes explained by the theory.
  • Example replicative senescence model of aging.
  • Doesnt explain aging in post-reproductie tissues
    like the brain, or animals like the nematode worm

5
Mechanistic aging theories
  • There are a host of mechanistic theories, one
    review counted 200.
  • Typically researchers studying one aspect of
    aging would focus on an underlying aspect that
    seemed responsible for aging in that tissue, and
    then theorize that this process is responsible
    for other aspects of aging.
  • Most theories were soon discarded--they didnt
    have much explanatory power.

6
Overview of mechanistic theories
  • Somatic mutation
  • Genetic damage leads to progressive loss of
    potential to make necessary proteins.
  • DNA damage and DNA repair
  • Loss of repair effciency with age leads to
    somatic mutation with effects described above.
  • Error catastophe
  • Faulty transcription and/or translation decrease
    cellular capacity to a subvital level.
  • Altered proteins
  • Post-translational damage reduces cellular
    efficiency.

7
Overview of mechanistic theories
  • Dysdifferentiation
  • Faulty gene activation-repression results in a
    cell synthesizing unnecessary proteins, changing
    its differentiation state and disrupting cellular
    and tissue function.
  • Free radicals
  • Longevity is inversely proportional to the extent
    of oxidative damage directly proportional to
    antioxidant defense activity.
  • Waste accumulation
  • Waste products of metabolism (proteins, lipids,
    etc) accumulate d and depress cellular efficiency
    if not removed or diluted by cellular division.

8
Overview of mechanistic theories
  • Post-translational protien changes
  • Time-dependent chemical cross-linking of
    protein/lipids/sugars impairs cell and tissue
    function to a subvital level.
  • Wear and tear
  • Originally focused on ordinary insults and
    injuries of daily living. Damage builds up and
    decreases organisms functioning to a subvital
    level.
  • Minor role in aging.
  • Metabolic mechanisms
  • Longevity is inversely proportional to metabolic
    rate. Disproven as originally formulated, but
    evolved into the mitochondrial free radical
    theory.
  • Genetic mechanisms
  • Changes in gene expression cause senescent
    changes in cells. May be different in different
    cell types, sometime intra-cellular, sometimes
    intercellular.

9
Overview of mechanistic theories
  • Signaling mechanisms
  • Failure of intracellular signaling processes. A
    component of several of the other aging theories
    dysdifferentiation, neuroendocrine, and
    immunological especially.
  • Neuroendocrine
  • Failure of cells with integrative functions leads
    to loss of homeostasis, senescence, and death.
  • Immunological
  • Homeostasis depends on proper immune function.
    Immune functions are phagocytosis of foreign,
    infected, or damaged cells, and regulation of the
    neuroendocrine system. Excessive inflammation is
    also damaging.

10
Stochastic theories
  • Random processes lead to regular changes (aging).
    How?
  • Aging is due to accumulation of random changes.
  • Faulty macromolecules accumulate through
  • Failure to repair stochastic damage or stochastic
    error in macromolecular synthesis.
  • Progressive accumulation continues until cells
    and tissues are so crippled that systemic death
    results.

11
Stochastic theories
  • Assumptions
  • The cell or tissue or organism has certain types
    or classes of molecules particularly sensitive to
    certain types of damage.
  • Long-lived species are can better tolerate
    molecular damage than short-lived species.
  • Better repair systems.
  • and/or
  • Greater functional redundancy.

12
Wear and tear theory
  • Early theory, based on observation of the effects
    of everyday damage
  • Evidence against it
  • Animals raised in protected environments still
    age, have the same maximum lifespan.
  • Too vague
  • Outdated Aspects of this reformulated into more
    mechanistic theory that specifies what
    macromolecules, what cellular changes are
    involved and how they lead to aging.

13
Post-translation protein modifications
  • Several types of cross-links and modifications.
  • Protein-protein
  • Protein-lipid
  • Most common type
  • Advanced Glycosylation End Products (AGEs).

14
Details of AGE formation
15
Advanced Glycosylation End Products (AGEs).
  • Rate depends on oxygen, time, and glucose
    concentrations.
  • Collagen (1/3 of total mammalian protein).
  • Collagen is extracellular and has a low turnover
    rate.
  • Cross-link levels increase with age.
  • Affects joints, arteries, heart muscle, etc.
  • AGEs increase faster in shorter lived rodent
    strains than in longer lived strains (Harrison et
    al., 1978).
  • Extracellular AGE crosslinks are recognized and
    degraded by macrophages
  • AGEs affect intracellular proteins and DNA as
    well.
  • DNA repair occurs and protein turnover faster
    intracellularly.
  • More AGEs in Type I diabetics.
  • Cross-links slowed by caloric restriction and
    exercise (Masoro et al., 1989).

16
Altered protein theory
  • Changes to proteins impairs cellular process in a
    progressive manner until subvital levels.
  • Initial evidence observed
  • Catalytic activity of many enzymes decreases
    25-50 in older animals.

17
Altered protein theory
  • Reduced protein function due to several types of
    post-translational changes
  • Denaturation of proteins (can be heated/cooled to
    refold restore function).
  • Covalent modifications
  • protein carbonyl levels higher in old animals
  • Other protein modifications.
  • In an old animal, oxidized protein is 30-50 of
    total protein (Berlett and Stadtman, 1997).

18
Altered protein theory
  • Protein turnover slows down as animals age
  • Protein synthesis rate is reduced.
  • Cytoplasmic protein degradation pathway activity
    is reduced.
  • This increases protein half-life (the time
    proteins exist) and increases total protein
    damage levels.
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