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Theories of Aging

Possible Mechanisms

3 Criteria of Aging Theories


1. Must occur in all individuals of the population 2. Produce Changes in function/ structure

3. Changes increase with age (progressive)

Change in Structure / Function


Cellular- previous lecture Acellular- extracellular matrix ground substance fibers collagen (up to 30% of protein) elastin

3 Catagories of Theories
1. Wear and Tear (Damage) Theory 2. Physiological/ Chemical Changes 3. Genetically Programmed (Senescence Genes)

Wear and Tear Theories


Weismann (1891)

Ordinary insults and injuries of daily living accumulate and decrease function to some sub-vital level e.g. loss of teeth --> starvation molecular level: enzymes accumulation of harmful metabolites (cell garbage theory) e.g. aldehydes, free radicals, lipofuscins interfere with cell function

Wear and Tear Theories (cont.)


finite energy theories animals with high metabolic rates have shorter life spans rats on calorie restrictive diets live longer mammals and birds should live shorter lives People that exercise should live shorter lives

Wear and Tear Theories Refuted


1. Animals in protected environs. have no change in maximum life span. 2. Time-dependent changes cannot initiate aging 3. Cellular/ Genetic evidence
Reformulated as Failure to Repair Theories

Physical/ Chemical Changes


1. Cross Linkage Theory (Post-translational modification) macromolecules cross linked (denatured) leading to a decline in function e.g. proteins- collagen, elastin
How ? Disulfide Bonds (cys-cys) Advanced Glycation End-Products (AGEs) accelerated in diabetics

DNA cross-linkage occurs also

Physical/ Chemical Changes


2. Altered Protein Theory protein folding no change in primary structure decline in catalytic activity with age e.g. enolase in nematodes denature/renature experiments shape change can be reversed
increased carbonyl content (ketones, aldehydes) of proteins (oxidative)

Physical/ Chemical Changes


3. Free Radical Theory (Oxidative Damage) Free Radicals: contain unpaired electrons making them highly reactive therefore only exist for a short time. e.g. Superoxide, hydroxyl , peroxide Lipid peroxidation- damage to cell membranes especially mitochondrial Protein cross linkage DNA damage Antioxidants - Vitamins A, C, E, Cellular Defenses- Catalase, Superoxide Dismutase

Reactive Oxygen Species

Aging By Program
Assumptions: Biological Clock Molecular Clock- the Telomere ? Life Span Inheritable Twin Studies

Biological Clock: Hypothalamus Decline in Signal Decreased Sensitivity to Feedback


Programmed senescence does not require central control - cell culture evidence

Aging By Program
Gene Mutation Theory- accumulation of somatic cell mutations leads to a decline in function Liver cells of older mice have more mutations than young Short life span strains have more mutations at same age DNA repair mechanisms Decrease in repair function??

Aging By Program
Gene Theory One or more harmful genes active only later in life Evidence? Microarray analysis Death Genes or Gerontogenes

Microarray Analysis
C. elegans

Evolutionary Theories
Disposable Body TheoryPost-reproductive individual has no benefit No genes favoring long life-span should evolve Genes do not cause aging, but fail to prevent it from happening

Antagonistic Pleiotropy TheoryGenes that promote success at a young age have a negative effect at old age
Late-acting error theory- errors occuring before reproduction eliminated by natural selection no selective pressure to eliminate them after