Theories of Aging

January 26, 2007

PS Timiras

MolecularCodon restriction

Somatic mutation

Error catastrophe

Gene regulation.

Dysdifferentiation

Classification and brief description of main theories of aging

CellularWear-and-tear

Free radical accumulation

Apoptosis

SystemRate-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 onlylive longer, they age slower than mainland animals.

-Sapelo Island opossums have less oxidative damage than mainland opossums.

(collagen X-linking)

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Evolution in the Laboratory

% Surviving

Age in Days

Average life span = ~40d

Drosophila Survival Curve

Michael Rose, U.C. Irvine

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- Reproductive period extended- Stress resistant, -super flies- Early adult fecundity reduced *antagonistic pleiotropy

Offspring of “old” flies are selected

Normal

old flies selected

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Age in Days

Selection at age of reproduction alters lifespan

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Evolution in the Laboratory

old flies selected

young flies selected

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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 ensurecontinued reproductive success, following reproduction

the soma is disposable. (life span theory)

Antagonistic Pleiotropy - Genes that are beneficial at youngerages 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 olderages are not selected against (no strong evidence).

Molecular Theories of Aging

Codon restrictionFidelity 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 mutationType 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 catastropheErrors in information transfer due to alterations

in RNA polymerase and tRNA synthetase may increase with age resulting in increased production of abnormal proteins

Gene regulationAging is caused by changes in the expression of

genes regulating both development and aging

DysdifferentiationGradual accumulation of random molecular damage

impairs regulation of gene expression

Cellular Theories of Aging

Wear-and-tearIntrinsic and extrinsic factors influence life

span

Free radical accumulationOxidative metabolism produces free radicals which

are highly reactive and thus damages DNA and/or proteins and thus degrades the system structure and function.

ApoptosisProcess 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

The Free Radical Theory of Aging

““Aging results from the Aging results from the deleterious effects of free deleterious effects of free radicals produced in the course radicals produced in the course of cellular metabolism”of cellular metabolism”

It is a molecule having unpaired electronsTherefore, 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 Harman D., Aging: A theory based on free radical and radiation chemistry, J. Gerontol. 11: 298, 1956radiation chemistry, J. Gerontol. 11: 298, 1956

What are the Major Oxidants?What are the Major Oxidants?

• Hydroxyl radical (OHHydroxyl radical (OH..))• Hypochlorite (HOCl)Hypochlorite (HOCl)• Singlet oxygen Singlet oxygen 11OO22

• Peroxynitrite (OONOPeroxynitrite (OONO--))• Hydrogen peroxide (HHydrogen peroxide (H22OO22))• Free or loosely-bound iron, copper or hemeFree or loosely-bound iron, copper or heme

• Superoxide radical (OSuperoxide radical (O22..--))

• Nitric oxide (NONitric oxide (NO..))

Major AntioxidantsMajor 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 AntioxidantsRead Chapter 5