Theories of Biological Aging by KL19o9

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									Theories of Biological
       Aging
            Dave Morgan
    Alzheimer Research Laboratory
        Dept of Pharmacology
  AGING

 Successful
  Typical
Unsuccessful
               Is Aging Universal?
   Senescence is the age when an organism’s viability is
    reduced dramatically due to impaired physiology
   Gradual Senescence
       Humans, most mammals
   Negligible Senescence
       Redwoods, Bristlecone pines, Tortoises, Rockfish, Lobsters
   Rapid, Obligate Senescence
       Many insects, Annual plants, Salmon, Some mice
   Single Celled Organisms
       Fission produces two daughters of equal seniority
    Survival Curves Indicate the Effects
           of Aging on Mortality
   100 % surviving at
    birth (age 0)
   Early infant mortality
   Age-independent
    mortality rate (10-50)
   Age-dependent
    mortality rate (60+)
   50% = median (~avg)
   0% = maximum
    Lifespan Effects of Slowing Aging
   Eliminating Disease increases median longevity;
    rectangularizes the survival curve (1-3).
   Slowing Aging increases both median and maximum
    longevity (curve 4).
Senescence Occurs Rarely in the Wild

    In the wild,
     organisms rarely
     reach the age of
     senescence.
    Age-associated
     degenerative diseases
     are recent causes of
     death
  Average Longevity has Increased
over Time. Maximum Appears Fixed
    POPULATION                  Mean       Maximum
                                Lifespan   Lifespan

    Wurm (30,000 B.C.)          29          75
    Paleolithic (12,000 B.C)    32         110
    Mesolithic (8,000 B.C)      31         110
    Neolithic (6,000 B.C.)      38         110
    Classic Greece (500 B.C.)   35         110
    Classic Rome (0 B.C.)       32         110
    England (1200 A.D.)         48         110
    England (1376)              38         110
    United States (1900)        45         110
    United States (1950)        70         110
    United States (1985)        75         110
    Most Infants do not Reach Puberty
   Infant Mortality
    was the norm
   Evolution
    operates until the
    age of
    reproductive
    success
   Prehistoric
    gravesites contain
    primarily children
Longevity Increased Dramatically in
         the 20th Century
   Major gain is
    reduced
    childhood
    mortality
   Likely Causes
      Sanitation

      Nutrition

      Medical Care
        Leading Causes of Death
                         1900                                     1984

RANK        Cause of Death           Percent           Cause of Death     Percent
                                     Mortality                            Mortality
1           Pneumonia and            11.8               Heart Disease     37.5
            Influenza
2           Tuberculosis             11.3              Cancer             22.2
3           Diarrhea and              8.3              Cerebrovascular     7.6
            Enteritis                                   Disease
4           Heart Disease             8.0              Accidents           4.6

5           Cerebrovascular           6.2              C. O. P. D. *       3.4
             Disease
6           Nephritis                 5.2              Pneumonia and       2.9
                                                       Influenza

7           Accidents                 4.2              Diabetes            1.8
8           Cancer                    3.7              Suicide             1.4
9           Diptheria                 2.3              Liver Disease       1.3
10          Meningitis                2.0              Atherosclerosis     1.2
    * C.O.P.D. = Chronic Obstructive Pulmonary Disease and Allied Conditions
     Do Women Outlive Men Because
          They Are Shorter?
   Height is inversely related
    to longevity in many
    populations with widely
    divergent overall
    longevities
   Women are 8% smaller
    than men (on average) and
    live 7.9% longer).
   The line relating height
    and longevity is identical
    for men and women
The J Curve. Humanity Dominates
Wear and Tear Theories of Aging
   Extrinsic Causes
   Stochastic (not determined)
   Proceeds much like aging in your automobile
    Biological Clock Theories of Aging
   Aging is
    programmed
   Intrinsic;
    generated from
    within
   Determinant
   Clocks may exist
    as a master clock
    and/or cellular
    clocks
   Different species have
    different maximum
    longevities even in
    captive environments
   Genetics must be the
    cause of the differences
   Wear and tear theories
    claim the genes work by
    preventing aging
   Biological clock theories
    claim the genes directly
    cause aging (regulate
    clock rate)
Programmed Aging: Limited Cell
     Proliferation Potential
The Hayflick Limit
Population Doublings Correlate with
            Longevity
   Longer lived species
    have more population
    doublings
   Cells from young
    individuals have more
    population doublings
   Cells from individuals
    with progerias
    (accelerated aging
    syndromes) have fewer
    population doublings
    Biological Clock may be Telomeres
   Caps on the ends of chromosomes get shorter each cell
    division
   When telomeres get too short, cells stop dividing
    Telomerase extends telomeres
   If telomeres disappeared
    each generation, the next
    generation may run out
   Telomerase permits
    separation of a mortal
    somatic cell lineage and
    an immortal germ line
    lineage.
   Multicelled creatures
    permitted the soma to
    become disposable
Transformed cells activate telomerase
     Limitations of the Cell Division
               Hypothesis
   Tissues (bone marrow) can be serially
    transplanted to give lifespans far exceeding that
    of original donor
   Most of your body mass is post-mitotic cells
   Telomerase knockouts have normal offspring
    for several generations
    Wear and Tear: DNA Mutations
   Damage to most
    molecules overcome by
    replacement (turnover of
    lipids and proteins).
   Damage to DNA, the
    blueprint, if permanent,
    leads to accumulation of
    errors.
   Causes are heat, oxygen,
    mutagens
     DNA Repair May Slow Aging
   Cells have multiple
    DNA repair systems
   Accumulated
    mutations should
    lead to impaired cell
    function, even in
    new cells if damaged
    DNA is copied
Regulation of Inflammation in Transgenic Mice
     Biological Energy Partitioning
   As a species, organisms may exchange energy between
    repair and reproduction.
If too little repair, individuals die before they reproduce. Natural
selection chooses enough repair to maximize reproductive effort.
Theoretically, enough repair leads to negligible senescence
(human median longevity of 1000 years).
         Caenorhabditus Elegans
   Microscopic
    nematodes
   Hermaphroditic, easy
    to clone
   About 1000 cells,
    developmental fate
    mapped
   Easy to mutate
   Several mutations
    that extend lifespan,
    also reduce fecundity
Radiation extends mouse lifespan
        Humans may benefit also
   Survivors of atomic
    bomb attacks have
    reduced rates of cancer
   Hormesis- small
    amounts of damaging
    agents toughens the body
   Tanning, strength
    training, calluses are
    examples
           The Aristotelian Mean
   “All things in moderation”
   Longevity maximized by
    avoidance of excess
   Longevity may also be
    maximized by avoidance
    of abstinence
   Jeanne Calment. Lived to
    123. Died several years
    ago. Smoked cigars to 110.
    Drank champagne until
    she died.
                    Conclusions
   Aging likely results as an accident. So few organisms
    reached advanced age there was no evolutionary
    advantage to avoid aging
   Pleiotropy. The idea that something could benefit an
    organism during development, but be detrimental as
    the organism aged
   Both biological clock and wear and tear theories have
    support. Aging, like many diseases is likely to be
    multifactorial. Theories are not mutually exclusive.

								
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