J.D. Furber

The many observable signs and symptoms of human senescence have been hypothesized by various researchers to result from several primary causes. Close inspection of the biochemical and physiological pathways associated with each of the hypothesized causes reveals several parallel cascades of events with multiple interactions and feedback loops among them.

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 this flow chart include subcellular, extracellular, and hormonal interactions:
-- 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, and leaks into cytoplasm.
-- 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.
-- Nuclear DNA damage and telomere shortening induce altered phenotype and arrest 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.
-- Arrested cells export toxic reactive species and inflammatory cytokines.
-- Abnormal aggregations of proteins damage brain cells.
-- Consequences include athersclerosis, cancer, stroke, macular degeneration, and other age-associated diseases.

Theoretically powerful points for the development of new interventions 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 takeover of postmitotic cells by mutant mitochondrial DNA.
-- Enhancing turnover of damaged macromolecules and organelles.


This flow chart is continuously maintained on the Web as a reference to researchers, and is updated as new information comes to light.

[ ]

Keywords (Optional):