Membrane viscosity and aging
A few years ago I wrote a paper about membrane viscosity for a
cell biology class. Certain of the papers I read asserted that
cells get stiffer with age, and that this shift, (and hence aging
itself), is reversible. The purpose of this post is to ask the
group about attitudes today about aging vis-a-vis membrane
viscosity. I haven't kept up with the literature, and don't know
if this is still a direction viewed as fruitful or relevant.
The essence of the idea was that aging at the cellular level is
caused by a shift in the ratio of phosphatidyl choline (PC)
(lecithin) to sphyngomyelin (SM), the major lipid components of
plasma membranes. PC has a fluid character because it is liquid
in the physiological temperature range. It is a membrane
liquefier; cholesterol does not associate with it, and it tends
to wash cholesterol out of membranes. SM, by contrast, is gelid
and associates with cholesterol at physiological temperature, and
is thus a membrane stiffener. Because of an unknown mechanism,
the PC/SM ratio shifts toward SM in older cells. Therefore,
older cells are stiffer and slower to respond to stimuli than
younger cells.
The stiffness or deformability of cells affects their interaction
with other cells, and their ability to undergo exocytosis,
phagocytosis and division. Also, the functional efficiency of
membrane-bound proteins may be determined by how high or low they
float in the membranes: antigens or active sites may be
overexposed or suppressed, multimeric subunits may aggregate too
slowly, loosely bound proteins may be shed into the medium, etc.
M Shinitsky and Y Barenholz, Israeli biochemists, took the view
that the flexibility of membranes could be restored by loading
them with PC. They supposed that this could be accomplished
simply through a lecithin-rich diet. Of course, if the membranes
have been in a rigid condition long enough for membrane proteins
to become abnormally cross-linked, or for covalent bonding to
occur in the membrane-protein complex, adjusting the lipid
balance would not do any good. But if the membrane proteins were
still functionally intact, said the Israelis, their function
could be restored or enhanced by fluidizing the membrane.
They demonstrated their idea by feeding a lecithin-rich diet to
rodents. They said the results, as measured by longevity and
fertility of the animals, were dramatically better from those of
the control group.
They devised another controlled lipid exchange method by means of
liposomes and demonstrated it in myocytes. Twitch frequency and
other indicators of proficiency of these cells were also said to
improve dramatically.
A US patent covering "lipid replacement therapy" was granted to
Barenholz and Shinitzky in '89; the licensee is Liposome
Technology of Menlo Park, CA. I talked to this company some time
ago; they were having financial difficulties then and were not
doing anything with the patent. I have no recent news on the
status of the patent.
I'm interested to know if lipid replacement therapy is a
reputable idea. I think the argument summarized here, and the
potential value of lipid replacement treatments, depends on the
assertion that the ratio of SM to PC increases with age. Is this
true? What research is being done today? Who's doing it?
Comments?
Potter Wickware
Oakland, CA
wick at netcom.com
