Cell Aging

1. Cell Aging

2. Aging is generally characterized by the declining ability to respond to stress, increasing homeostatic imbalance and increased risk of aging-associated diseases. • Death is the ultimate consequence of aging. • Differences in maximum life span between species correspond to different "rates of aging". For example, inherited differences in the rate of aging make a mouse elderly at 3 years and a human elderly at 90 years. • Genetic differences affect physiological processes like efficiency of DNA repair, antioxidant enzymes, rates of free radical production etc

3. Senescence The process by which a cell looses its ability to divide, grow, and function. This loss of function ultimately ends in death. • A degenerative process, only. • Has no positive features.

4. Traditionally aging was explained two theories • Programmed theories imply that aging is regulated by biological clocks operating throughout the life span. This regulation would depend on changes in gene expression that affect the systems responsible for maintenance, repair and defense responses. • Stochastic theories blame environmental impacts on living organisms that induce cumulative damage at various levels as the cause of aging, examples which range from damage to deoxyribonucleic acid (DNA), damage to tissues and cells by oxygen radicals (free radicals), and cross-linking.

5. More recently theories of aging are categorized as • Molecular Gene Theory • Codon restriction • Somatic mutation • Gene regulation • Cellular theory • Free radical theory • Wear and tear theory • Apoptosis • Senescence • telomere loss (replicative senescence) • cellular stress (cellular senescence). • System theory • Rate of living theory • Neuro endocrine theory • Immunologic theory • Evolutionary theory • Disposable soma • Antagonistic pleiotropy • Mutation accumulation

6. Molecular Gene 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. • • Dys-differentiation - 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. Gene expression protein folding and activity

7. Cellular Theories • Free radical - Oxidative metabolism produces highly reactive free radicals that subsequently damage protein and DNA. Mitochondrial DNA Damage • Wear and tear - Accumulation of normal injury – Glyco-oxidation Theory of Aging (products from glucose with proteins + oxidation; AGE (advanced glycation endproducts – Inflammation Theory of Aging • Apoptosis - Programmed cell death resulting from intrinsic damage and genetically determined events or genome crisis. • 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).

8. Telomere shortening causes cell senescence • Somatic cells usually lack telomerase activity, which means that telomeres shorten with each cell division. • Cultured cells may go into crisis as the result of reaching zero telomere length. • Reactivation of telomerase enables cells to survive crisis and to become immortal.

9. 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 also referred as Neuroendocrine Theories of Aging • Immunologic – decline of immune function with age results in increased incidence of disease also referred as Immunological Theory of Aging

10. 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

11. The Free Radical Theory of Aging Oxygen free radicals generated cause cumulative oxidative damage, resulting in structural degeneration, (apoptosis), functional decline, and age-related diseases. Some believe that oxidative stress is the predominant cause of age-associated degenerative change.

15. Oxidative Stress and Aging • What happens when oxidant production is greater then antioxidant defenses? – Oxidative Stress • DNA damage • Protein damage • Lipid Damage

16. Free Radical Theory • - Oxidative metabolism produces highly reactive free radicals that subsequently damage protein and DNA. • Evidence from model organisms... • - Superoxide dismutase (SOD) transgenes can extend the life span of Drosophila. • - Chemicals that mimic catalase (peroxidase) activity can extend C. elegans life span. • - Long-lived mutants are typically stress resistant, including resistant to drugs (i.e. paraquat stress, which induces increases in free radicals) • - Life span extension by insulin-like signaling mutants in C. elegans requires catalase activity.

23. p53 may affect aging Key Concepts • Shortening of telomeres below a critical length is associated with reduced longevity. • Increase of p53 above wild-type levels can decrease tumor formation, but also decreases longevity.