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    How Cells Change Their

    Phenotype

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    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.

    Cellular changes

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    Changes in senescent cells

    Youssef and Badr, 1999

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    Mitochondrial DNA lives in a harsherenvironment than nuclear DNA and has muchhigher rates of damage.

    mDNA mutation levels rise. mDNA accumulates deletions.

    Problem worsened by replication advantage ofmutated mitochondria (muscle especially).

    Causes loss of mitochondria function.

    Cellular energy production declines.

    Mitochondrial DNA damage

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    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 mitochondrial-

    generated 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

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC19544/pdf/pq000514.pdfhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC19544/pdf/pq000514.pdf
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    Schematic representation of the role of mitochondria inthe generation of ROS and oxidative stress

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    Progressive decrease in the creation ofnew protein.

    Reduction in the rate of protein

    degradation.

    Inaccessible protein deposits.

    Result: damaged proteins in cells increase aswe age

    Protein turnover

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    Muscle mitochondrial protein synthesis

    decline

    A decline in fractional muscle mitochondrial protein synthesis occurred withage. 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

    proteinfr

    actionalsynthesis

    rate

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    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.

    Advanced Glycosylation End-products:

    AGEs

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    10/12http://www.chm.bris.ac.uk/webprojects2002/rakotomalala/maillard.htm

    http://www.chm.bris.ac.uk/webprojects2002/rakotomalala/maillard.htmhttp://www.chm.bris.ac.uk/webprojects2002/rakotomalala/maillard.htm
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    Models of activation of microgliaMicroglia 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 Immunology7, 161-167 (February 2007) http://www.nature.com/nri/journal/v7/n2/fig_tab/nri2015_F1.html

    http://www.nature.com/nri/journal/v7/n2/fig_tab/nri2015_F1.htmlhttp://www.nature.com/nri/journal/v7/n2/fig_tab/nri2015_F1.htmlhttp://www.nature.com/nri/journal/v7/n2/fig_tab/nri2015_F1.html
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