Just some F.Y.I. stuff.
Chaperone Mediated Autophagy:
It appear the thing functions as follows:
Protein substrates* are delivered to the surface of lysosomes**
by a chaperone, the 70 kDa heat shock cognate protein
(hsc70). hsc70. promotes the interaction
of the substrates with a receptor protein at the lysosomal membrane,
the lysosome-associated membrane protein type 2A (LAMP-2A) . Then the protein gets unfolded and is translocated to the lumen*** with the help
of a luminal-resident chaperone (lys-hsc70). (1)
This is the form of autophagy that renewed the old mouse liver and with all probability will extend life if fixed.
The rate limiting factor here is Lamp-2A, that is a protein transcripted through the gene Lamp2. However the decreased levels of LAMP-2A
with age is not a consequence of transcriptional downregulation. The transcription power remains the same in old age (2).
What appear to be going on in aged individuals is:
a) While Lamp-2A is present in the lumen, it is not retreived in sufficient numbers to the lysomal membrane making the whole CMA process to bog down (2). This appears to be because of some defect in the membrane that stop Lamp-2A to associate with the membrane.
b) Apparantly because Lamp-2A can not associate, an abnormal accelerated degradation of LAMP-2A sets in in the lumen. reducing overall Lamp-2A levels in the cell. making the situation even worse.
This could be solved by a supplement as follows:
- The supplement fixing this must work either directly or indirectly on the lysomal membrane to fix the defect. What would be good for the lysomal membrane?
- The supplement could increase the Lamp-2A protein in cells. A Lamp-2A increase appears to have worked for the Lamp2A mouse (2), as it kept Lamp-2A level up through old age.
1
http://www.ncbi.nlm....Pubmed_RVDocSum2
http://jcs.biologist.../full/120/5/782* Substrate: junk protein, ** Lysosome: organelle that contain digestive enzymes ,*** lumen: (space inside the lysosome)