Theories of Aging MCB135k, 2/10/03

Molecular Theories

Codon restriction - Fidelity/accuracy of mRNA translation is

impaired due to inability to decode codons in mRNA.

Error catastrophe - Fidelity of gene expression declines with age,

resulting in increased fraction of abnormal proteins.

Somatic mutation - Accumulation of molecular damage,

primarily to DNA/genetic material.

Dysdifferentiation - Gradual accumulation of random molecular

damage impairs regulation of gene expression.

Gene regulation - Aging caused by changes in gene expression

regulating both aging and development.

Cellular Theories

Wear and tear - accumulation of normal injury (weak theory).

Free radical - Oxidative metabolism produces highly reactive

free radicals that subsequently damage protein and DNA.

(B. Ames, 10 and R. Melhorn, 12)

Apoptosis - Programmed cell death resulting from genetically

determined events or genome crisis.

(J. Campisi, 11)

Senescence - Phenotypes of aging are caused by an increase in

frequency of senescent cells. Senescence may be the

result of telomere loss (replicative senescence) or

cell stress (cellular senescence).

System Theories

Rate-of-living - Assumes a fixed amount of metabolic potential

for every living organism (live fast, die young).

Neuroendocrine - Alterations in neuroendocrine control of

homeostasis results in age-related physiological changes.

(P. S. Timiras, F. Yaghmaie, 35)

Immunologic - Well documented decline of immune function

with age results in increased incidence of disease.

(H. Sternberg, 25+26)

Evolutionary Theories

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.

Mutation Accumulation - Mutations that affect health at older

ages are not selected against (no strong evidence).

Cause or Effect

- It is difficult to determine cause from effect in aging theories, many theories are based on an observation of some parameter that changes with age. However, it is difficult to determine if a change in function is a cause or an effect of the aging process.

- we do not know what causes aging, a combination of theories may be correct, or some theories may be correct only in specific organisms.

Evolution Theory of Aging

- First proposed by Haldane and Medawar in the 1940’s

- based on observations of Huntington’s Disease

- Dominant mutations cannot be selected against if they manifest in the post-reproductive period of life.

- Theory = Aging results from a decline in the force of natural selection

Aging versus Life Span

Aging - can not be selected for, results from an absence

of natural selection.

Life Span - results from a balance between two major

selective forces.

Social Selection - parental investment, sexual behavior

Evironmental Selection - predators, natural hazards

 

 

Opossums

Mainland Opossums

- ~80% die from predators in the first year

- typically reproduce only once

- Age very rapidly

Sapelo Island Opossums

- out in daylight (no predators)

- reproduce twice (fewer offspring/litter)

- longer average life span

*Sapelo island opossums live longer because they age more slowly than mainland opossums. Demonstrated by reduced levels of collagen cross-linking in Sapelo island opossums when compared to mainland opossums. (Collagen X-linking measures the amount of molecular damage accumulated over time)

Drosophila

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).

 

4) Experimental evidence supports theory of antagonistic pleiotropy,

does not support the mutation accumulation theory.

Natural Selection, Aging and Life Span

- Aging results from a decline in the force of natural selection, therefore genes that promote aging should not exist (can not be selected for).

*this prediction is contrary to the Gene Regulation theory of aging

Diet and Life Span

- Calorie restriction will extend the life span of every multi-cellular, sexually reproducing organism tested to date.

- reduce caloric intake to 60% ad libidum (normal, unregulated consumption)

- Life span extended 30-50%

- Adaptation (Neuroendocrine)? or Metabolic (Rate-of-living)?

- Evolutionary argument - When food is scarce, an

organism can extend life span and thereby delay

reproduction until the famine has passed.

(supports adaptation)

Reproduction and Life Span

- Irradiation of Drosophila germ line cells extends life span.

- Laser ablation of C. elegans germ line cells extends life span.

- Monarch butterflies live longer when the reproductive system

is removed by surgery.

- Passive versus Regulated ? (again!)

Two hypothesis...

1)Energy otherwise spent on reproduction is rather used to live longer.

(Rate-of-Living theory of aging)

2)Reproductive state determines the rate of physiological aging

through a series of regulated genetic changes.

(genetics in C. elegans favors this hypothesis)

Insulin-like signaling in C. elegans

-Evidence for genetic regulation of life span.

1- Mutations that reduce insulin-like signaling can extend

C. elegans lifespan - significantly.

2- A conserved transcription factor is required for life

span extension, indicating a regulated genetic

response to reduced insulin-like signaling.

3- System responds to signals from sensory neurons near

the mouth, and from germ line reproductive cells.

(Diet? and Reproduction)

4- Conserved in Drosophila and mouse.

- Insulin levels rise when we consume food, and drop in the absence of food, because reducing insulin-like signaling in C. elegans extends life span we want to know if calorie restriction extends life span by reducing insulin-like signaling, does it?

C. elegans — most likely NO

Drosophila — most likely YES

Mice - ??? we don’t know

Free Radical Theory

- Oxidative metabolism produces highly reactive free radicals

that subsequently damage protein and DNA.

Evidence from model organisms...

- Super oxide dismutase (SOD) transgenes can extend the

life span of Drosophila.

- Life span extension by Insulin-like signaling mutants in

C. elegans requires catalase activity.

- Chemicals that mimic catalase activity can extend C. elegans

life span.

- Long-lived mutants are typically stress resistant, including

free radicals.