As an aid to keeping track of the many processes and interactions, a flow chart is presented. Promising intervention points for the development of new therapeutics are also highlighted on the flow chart.
The mechanisms which are incorporated into the flow chart include:
-- Nonenzymatic glycation of long-lived proteins and nuclear DNA.
-- Mutations accumulate in the mitochondrial genomes of postmitotic
cells.
-- Increasing acetylation of histones opens heterochromatin, permitting
inappropriate expression of nuclear genes.
-- Lipofuscin accumulates in lysosomes of postmitotic cells.
-- Increased redox poise alters signaling and enzyme activities.
-- Redox damage and crosslinking of long-lived macromolecules in
postmitotic cells and extracellular matrix.
-- Stiffer blood vessels promote stroke and heart disease.
-- Telomere shortening induces altered phenotype and halts cell
division in some cells.
-- Apoptosis, necrosis, and cell loss lead to tissue wasting,
neurodegeneration, and organ malfunction.
-- Alterations in neuroendocrine and immune systems.
-- Rate of repair & turnover of macromolecules & organelles slows.
-- Senescent cells export toxic reactive species and inflammatory
cytokines.
-- Abnormal aggregations of proteins damage brain cells.
-- Induction of cancer.
Theoretically powerful points for the development of new interventions
would include:
-- Slowing or reversing the accumulation of lipofuscin in lysosomes of
postmitotic cells.
-- Slowing or reversing the accumulation of AGE crosslinks in
extracellular collagen, elastin, and blood proteins.
-- Preventing homoplasmic takeover of postmitotic cells by mutant
mitochondrial DNA.
-- Enhancing proteasome turnover of damaged macromolecules.
This flow chart will be maintained on the Web as a reference to researchers, and will be updated as new information comes to light.
[ www.LegendaryPharma.com/senescence.html#Mechanisms ]
Key words:
senescence, aging, biochemistry, interactions, causes
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