Theories of Aging January 26, 2007 PS Timiras

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

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?

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? 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)

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

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

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

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).

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?

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).

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

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

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.

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.

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

What are the Major Oxidants? Hydroxyl radical (OH. )Hydroxyl radical (OH. ) Hypochlorite (HOCl)Hypochlorite (HOCl) Singlet oxygen 1 O 2Singlet oxygen 1 O 2 Peroxynitrite (OONO - )Peroxynitrite (OONO - ) Hydrogen peroxide (H 2 O 2 )Hydrogen peroxide (H 2 O 2 ) Free or loosely-bound iron, copper or hemeFree or loosely-bound iron, copper or heme Superoxide radical (O 2. - )Superoxide radical (O 2. - ) Nitric oxide (NO. )Nitric oxide (NO. )

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