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How Cells Change Their Phenotype

Cellular changes
Damaged protein levels increase. Protein turnover declines. DNA damage
Somatic DNA accumulates mutation. Mitochondrial DNA damage.

Telomere shortening. Lipofuscin deposits in cells. Mitochondria function declines. Gene expression changes.
Response to cellular stresses.

Changes in senescent cells

Youssef and Badr, 1999

Mitochondrial DNA damage


Mitochondrial DNA lives in a harsher environment than nuclear DNA and has much higher rates of damage. mDNA mutation levels rise. mDNA accumulates deletions. Problem worsened by replication advantage of mutated mitochondria (muscle especially). Causes loss of mitochondria function.
Cellular energy production declines.

Mitochondrial DNA damage is more extensive and persists longerthan nuclear DNA damage in human cells following oxidative stress

A significant amount of reactive oxygen species (ROS) is generated during mitochondrial oxidative phosphorylation. Several studies have suggested that mtDNA may accumulate more oxidative DNA damage relative to nuclear DNA. A model is presented in which chronic ROS exposure, found in several degenerative diseases associated with aging, leads to decreased mitochondrial function, increased mitochondrialgenerated ROS, and persistent mitochondrial DNA damage. Thus persistent mitochondrial DNA damage may serve as a useful biomarker for ROSassociated diseases.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC19544/pdf/pq000514.pdf

Schematic representation of the role of mitochondria in the generation of ROS and oxidative stress

Protein turnover
Progressive decrease in the creation of new protein. Reduction in the rate of protein degradation. Inaccessible protein deposits. Result: damaged proteins in cells increase as we age

Muscle mitochondrial protein synthesis decline


protein fractional synthesis rate

A decline in fractional muscle mitochondrial protein synthesis occurred with age. Approximately a 40 percent decline occurred by middle age (P < 0.01), but there was no further decline with advancing age. ** Indicates significant difference from young age. Source: Rooyackers et al., 1996

Advanced Glycosylation End-products: AGEs


An oxidative reaction of glucose with protein: damages protein and creates protein-protein crosslinks. A Maillard reaction of free amino groups on proteins and glucose.

http://www.chm.bris.ac.uk/webprojects2002/rakotomalala/maillard.htm

Models of activation of microglia


Microglia in the normal, healthy brain have a highly branched morphology and a downregulated phenotype. In response to injury and disease they rapidly change their morphology and upregulate a number of cell-surface and intracellular antigens such microglia are generally referred to as activated

Nature Reviews Immunology 7, 161-167 (February 2007) http://www.nature.com/nri/journal/v7/n2/fig_tab/nri2015_F1.html

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