X-Message-Number: 27646
Date: Tue, 21 Feb 2006 20:34:00 -0800 (PST)
From: Doug Skrecky <>
Subject: lithium antagonizes one aspect of aging

[Upregulating autophagy may prevent some age-associated problems, such as
cardiac enlargement. Increased autophagy can be achieved the hard way, by
means of either caloric restriction, or alternatively by periodic fasting,
without any net reduction in total caloric intake. Lithium offers a much
easier alternative means for achieving increased autophagy. Autophagy is
greatly reduced in old age.]

J Cell Biol. 2005 Sep 26;170(7):1101-11.
Lithium induces autophagy by inhibiting inositol monophosphatase.
Macroautophagy is a key pathway for the clearance of
aggregate-prone cytosolic proteins. Currently, the only suitable
pharmacologic strategy for up-regulating autophagy in mammalian
cells is to use rapamycin, which inhibits the mammalian target of
rapamycin (mTOR), a negative regulator of autophagy. Here we
describe a novel mTOR-independent pathway that regulates autophagy.
We show that lithium induces autophagy, and thereby, enhances the
clearance of autophagy substrates, like mutant huntingtin and
alpha-synucleins. This effect is not mediated by glycogen synthase
kinase 3beta inhibition. The autophagy-enhancing properties of
lithium were mediated by inhibition of inositol monophosphatase
and led to free inositol depletion. This, in turn, decreased
myo-inositol-1,4,5-triphosphate (IP3) levels. Our data suggest
that the autophagy effect is mediated at the level of
(or downstream of) lowered IP3, because it was abrogated by
pharmacologic treatments that increased IP3. This novel
pharmacologic strategy for autophagy induction is independent of
mTOR, and may help treatment of neurodegenerative diseases, like
Huntington's disease, where the toxic protein is an autophagy

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