The many observable signs 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 age-related changes and with the hypothesized causes reveals several parallel cascades of events that involve multiple interactions and feedback loops. We present a network diagram to aid in conceptualizing the many processes and interactions among them, including promising intervention points for therapy development. This diagram is maintained on the Web as a reference for researchers and students. Content is updated as new information comes to light.
In addition, our collaborators are adapting the network model's contents into an interactive website with links to references and background materials. A symposium to promote this development was held at Arizona State University, December 2008; abstracts are at
A second symposium is planned for 8-9 Dec 2009 at the National Institute on Aging in Baltimore, Maryland. This network model includes both intracellular and extracellular processes. It ranges in scale from the molecular to the whole-body level. Important pathways include:
·Extracellular proteins become damaged by glycation, oxidation, crosslinking, and lytic enzymes, resulting in mechanical stiffness, weakness, and inflammation. Altered environmental niches for cells contribute to transdifferentiation, arrested cell division, cell death, cancer, stem cell depletion, tissue wasting, neurodegeneration, and organ malfunction. Stiffer blood vessels promote stroke and heart disease.
·Lysosomes accumulate reactive, crosslinked lipofuscin, which impairs autophagic turnover of macromolecules and organelles, and leaks into cytoplasm, triggering apoptosis of cells, which are not readily replaced.
·Mitochondrial DNA mutates. Mutations are copied, resulting in altered cell physiology.
·Lamin-A spice-variant, progerin, accumulates in nucleus, impairing cell division.
·Nuclear envelope pore proteins become oxidized, allowing inappropriate traffic of other proteins into and out of the nucleus.
·Nuclear mutations, telomere shortening, chromosome breaks, chromatin alterations and epigenetic DNA adducts change gene expression.
·Oxidized aggregates in cytoplasm become crosslinked, resist turnover, inhibit proteasome activity, increase redox poise, and physically interfere with intracellular transport, especially in axons. Inhibited proteasomes reduce turnover of damaged molecules and of expired molecular signals. Increased redox poise alters signaling and enzyme activities, and erodes telomeres.
·Damaged molecules and sick cells promote inflammatory cascades that further damage tissues. Neuroendocrine and immune systems degrade.
·ER stress: Misfolded proteins accumulate in ER.