Theories of Biological Aging

1. Theories of Biological Aging Dave Morgan Alzheimer Research Laboratory Dept of Pharmacology

2. AGINGSuccessfulTypicalUnsuccessful

3. 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

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 • Likely Causes • Sanitation • Nutrition • Medical Care

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 • Determinant • 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

26. Regulation of Inflammation in Transgenic Mice

27. Biological Energy Partitioning • As a species, organisms may exchange energy between repair and reproduction.

28. 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).

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.