Download Cell Aging

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