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1. Theories of Biological Aging
Alzheimer Research Laboratory
Dept of Pharmacology
2. AGING Successful Typical Unsuccessful
3. Is Aging Universal? Senescence is the age when an organism’s viability is reduced dramatically due to impaired physiology
Humans, most mammals
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
4. 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
5. 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).
7. 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
8. Average Longevity has Increased over Time. Maximum Appears Fixed
9. Most Infants do not Reach Puberty Infant Mortality was the norm
Evolution operates until the age of reproductive success
Prehistoric gravesites contain primarily children
10. Longevity Increased Dramatically in the 20th Century Major gain is reduced childhood mortality
11. Leading Causes of Death
12. 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
13. The J Curve. Humanity Dominates
14. Wear and Tear Theories of Aging Extrinsic Causes
Stochastic (not determined)
Proceeds much like aging in your automobile
15. Biological Clock Theories of Aging Aging is programmed
Intrinsic; generated from within
Clocks may exist as a master clock and/or cellular clocks
16. 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)
17. Programmed Aging: Limited Cell Proliferation Potential
18. The Hayflick Limit
19. 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
20. Biological Clock may be Telomeres Caps on the ends of chromosomes get shorter each cell division
When telomeres get too short, cells stop dividing
21. 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
22. Transformed cells activate telomerase
23. 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
24. 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
25. 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
27. Biological Energy Partitioning As a species, organisms may exchange energy between repair and reproduction.
29. 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
30. Radiation extends mouse lifespan
31. 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
32. 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.
33. 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.