Theories of Aging

1. Theories of Aging January 26, 2007 PS Timiras

3. Classification and brief description of main theories of aging • Cellular • Wear-and-tear • Free radical accumulation • Apoptosis • System • Rate-of-living • Neuroendocrine • Immunologic Molecular Codon restriction Somatic mutation Error catastrophe Gene regulation. Dysdifferentiation Evolutionary Disposable Soma Antagonistic Pleiotropy Mutation Accumulation

4. Evolutionary Theory Disposable Soma - Somatic cells are maintained only to ensure continued reproductive success, following reproduction the soma is disposable. (life span theory) • Opossums and Life Span • - ultimate prey, ~ 80% die from predation • - typically reproduce once • - age very rapidly • Hypothesis: The presence of predators limits life span, natural • selection favors somatic maintenance for only as long • as an average opossum can be expected to live. Steve Austad, U. of Idaho -How could you test this hypothesis?

5. Physiological Change - Sapelo island opossums not only live longer, they age slower than mainland animals. -Sapelo Island opossums have less oxidative damage than mainland opossums. (collagen X-linking) • Sapelo Island Opossums • - no predators (out in daytime) • - longer average life span • - reproduce twice (fewer offspring/litter) • -Are these changes due to a lack of predators, or a physiological • change that delays the aging process?

6. Evolution in the Laboratory Michael Rose, U.C. Irvine Drosophila Survival Curve % Surviving Average life span = ~40d Age in Days

7. Selection at age of reproduction alters lifespan Offspring of “old” flies are selected - Reproductive period extended - Stress resistant, -super flies - Early adult fecundity reduced *antagonistic pleiotropy Normal % Surviving old flies selected Age in Days

8. Evolution in the Laboratory Offspring of “young” flies are selected - Early adult fecundity increased *antagonistic pleiotropy old flies selected Normal % Surviving young flies selected Age in Days

9. Summary of Drosophila Selection 1) Selection at age of reproduction can alter the lifespan of Drosophila (lifespan has been doubled by this technique). 2) Increase in lifespan has a cost, reduced fecundity (reproduction). - antagonistic pleiotropy - 3) Long-lived flies are stress resistant (heat shock, oxidants).

10. What about Humans? -Unlike most animals, humans and some related primates age in a natural environment. -Menopause is also unique to humans. How can nature select for a process that limits reproduction? -How does parental care influence the evolution of human life span?

11. Evolutionary Theories of Aging Disposable Soma - Somatic cells are maintained only to ensure continued reproductive success, following reproduction the soma is disposable. (life span theory) Antagonistic Pleiotropy - Genes that are beneficial at younger ages are deleterious at older ages. (Pleiotropism = The control by a single gene of several distinct and seemingly unrelated phenotypic effects) Mutation Accumulation - Mutations that affect health at older ages are not selected against (no strong evidence).

12. Molecular Theories of Aging Codon restriction Fidelity and/or accuracy of mRNA message translation is impaired with aging due to cell inability to decode the triple codons (bases) in mRNA molecules Somatic mutation Type of stochastic* theory of aging that assumes that an accumulation of environmental insults eventually reaches a level incompatible with life, primarily because of genetic damage. * Involving Random Chance

13. Molecular Theories of Aging, Con’t Error catastrophe Errors in information transfer due to alterations in RNA polymerase and tRNA synthetase may increase with age resulting in increased production of abnormal proteins Gene regulation Aging is caused by changes in the expression of genes regulating both development and aging Dysdifferentiation Gradual accumulation of random molecular damage impairs regulation of gene expression

14. Cellular Theories of Aging Wear-and-tear Intrinsic and extrinsic factors influence life span Free radical accumulation Oxidative metabolism produces free radicals which are highly reactive and thus damages DNA and/or proteins and thus degrades the system structure and function. Apoptosis Process of systematically dismantling key cellular components as the outcome of a programmed intracellular cascade of genetically determined steps.

15. System Theories of Aging Rate-of-living An old theory that assumes that there is a certain number of calories or heart beats allotted to an individuals and the faster these are used the shorter the life. Neuroendocrine Alterations in either the number or the sensitivity of various neuroendocrine receptors gives rise to homeostatic or homeodynamcis changes that results in senescence. Immunologic Immune system reduces its defenses against antigens and thus results in an increasing incidence of infections and autoimmune diseases.

16. The Free Radical Theory of Aging “Aging results from the deleterious effects of free radicals produced in the course of cellular metabolism” It is a molecule having unpaired electrons Therefore, free radicals are unstable Oxygen can be converted to reactive singlet oxygen • For example: Reactive oxygen molecule produced by respiratory burst in immune cells, phagocytes, are toxic to microbial cells Harman D., Aging: A theory based on free radical and radiation chemistry, J. Gerontol. 11: 298, 1956

18. What are the Major Oxidants? • Hydroxyl radical (OH.) • Hypochlorite (HOCl) • Singlet oxygen 1O2 • Peroxynitrite (OONO-) • Hydrogen peroxide (H2O2) • Free or loosely-bound iron, copper or heme • Superoxide radical (O2.-) • Nitric oxide (NO.)

19. Major Antioxidants • Vitamins E and C • Thiols, particularly glutathione • Uric acid • Superoxide dismutases (Cu/Zn or Mn SOD) • Catalase and glutathione peroxidase • Heme oxygenases • Protein surface groups (Msr) For More Information about Oxidants and Antioxidants Read Chapter 5