Author: JW Larrick, AR Mendelsohn.
Rejuvenation Res. 2015 Dec;18(6):581-4.
Understanding the interplay between reversible epigenetic changes and potentially more difficult to reverse accumulation of damaged macromolecules is a central challenge in developing treatments for aging-associated dysfunction. One hypothesis is that epigenetic drift leads to subtle losses of homeostatic maintenance mechanisms, that in turn, lead to the accumulation of damaged macromolecules, which then further degrade homeostasis. A key mechanism of maintaining optimal cell function is asymmetrical division, whereby cellular damage is segregated away from cells that need to undergo further proliferation, such as stem cells. Such asymmetrical distribution of damaged macromolecules has been observed during cell division in many organisms, from yeast to human embryonic stem cells, and depends on diffusion barriers (DBs) in the membrane of the endoplasmic reticulum (ER). In a recent study, these results have been extended to neural stem cells (NSCs), in which the ability of the ER DB to promote asymmetrical distribution of damaged proteins deteriorates with age. NSC function declines with age as proliferative capacity is reduced. The loss of asymmetric protein distribution correlates with the loss of NSC proliferative capacity. Ectopic expression of progerin, an altered form of lamin A, is associated with the premature aging disorder, Hutchinson-Gilford progeria syndrome (HGPS). Progerin’s expression also increases with normal aging due to mis-splicing, weakening the ER DB. Recent work suggests that many cell signaling pathway changes associated with HGPS are replicated during normal aging in cultured cells. Moreover, the detrimental changes associated with progerin expression in HGPS are partially reversible experimentally after treatment with statins, a farnesyltransferase inhibitor, a isoprenylcysteine carboxyl methyltransferase inhibitor, or sulforaphane. It will be of great interest if these compounds can also reverse the aging-associated permeability of the ER DB and restore stem cell function.