Investigation of a Role for Progerin in Normal Aging

Progerin is a malformed variant of lamin A, a protein vital in the nuclear lamina. These are structures that provide mechanical support for the cell, but are also involved in a variety of fundamental and important processes in the cell cycle. The genetic disorder Hutchinson-Gilford progeria syndrome, HGPS or progeria for short, is caused by a rare spontaneous mutation that leads to progerin being created in place of lamin A. Cells are malformed and dysfunctional as a result, and patients rarely live past their early teens. Progeria has the appearance of accelerated aging, characterized by poor tissue maintenance and the development of normally age-related diseases such as atherosclerosis, but at root it is a specific dysfunction in cellular metabolism that is thought to play little to no role in aging.

As an aside there are all sorts of ways to break important aspects of cellular biology to produce results that look at least somewhat like accelerating aging at the high level. The class of DNA repair deficiencies fall into this category, but pretty much anything that causes a significant reduction in stem cell activity will do it. At root aging is damage, but it is a particular balance of various forms of damage. It can be argued either way as to whether we should in fact refer to any of these conditions as accelerating aging, given that they involve forms of cellular damage that do not occur to a significant degree in normal aging.

Over the years since the identification of the cause of progeria there has been some investigation into the degree to which progerin exists and causes harm in old people subject to normal aging. Is it in fact the case that the consensus on this as an insignificant effect is correct? That malformed lamin A is present in small amounts in old tissues seems fairly settled, but this is probably to be expected given the rise in random DNA mutations with age. Are these small amounts sufficient to make it a significant cause of degeneration in comparison to all of the other issues that occur in cellular biochemistry with age? These researchers suggest that at least some stem cell populations are accumulating enough progerin over a human life span to make an impact on their function and thus on their ability to maintain tissues. That in turn would indicate that some mechanism other than random mutation is involved. By the sound of it this group should move on to a proof of concept in an animal model at this point, so as to link the observations made in cell cultures to a meaningful effect on health or stem cell activity - or rule it out, as the case may be:

Progerin expression disrupts critical adult stem cell functions involved in tissue repair

The vascular system is under constant mechanical and inflammatory stress. Fluid pressure and sheer stress combined with inflammatory cytokines lead to damage of the arterial compartment primarily, resulting in injury and death of endothelial, vascular smooth muscle cells and pericytes in the arterial and arteriole walls. In order to repair injured arteries and maintain vascular integrity, damaged or dying cells need to be replaced in a rapid and efficient manner. This is achieved by progenitor or stem cells sensing the damage, migrating to the injured area, differentiating into the needed cell phenotype, and modulating the inflammatory milieu at the injury site. Furthermore, sufficient numbers of these cells are needed in order to maintain a vascular reparative capacity throughout adult life. Thus, these stem/progenitor cells need to self-renew and proliferate in order to maintain a suitable pool of cells available for repair.

The arterial compartment is extremely sensitive to progerin expression, demonstrated by the robust atherosclerosis and vascular diseases exhibited by HGPS patients. Progerin is also expressed in atherosclerotic vascular tissues collected from aged, non-HGPS individuals. Both cases indicate a mechanistic role for progerin expression in interfering with general vascular tissue homeostasis. Efficient vascular repair that is unimpaired by disease or aging requires an adult stem cell population that can maintain their immature status (self-renewal), proliferate, detect damaged tissue and migrate toward it, and contribute to tissue repair by decreasing inflammation and differentiating into necessary cell lineages. We have shown that Marrow Isolated Adult Multilineage Inducible (MIAMI) cells, an immature subpopulation of mesenchymal stem cells, can perform all these described functions and participate in the repair of the arterial compartment both in vivo and in vitro. Interrupting any of these key stem cell functions could decrease vascular repair, increase persistent vascular damage, and result in atherosclerosis and eventual vascular accidents.

The results presented here demonstrate that progerin protein interferes with basic, critical stem cell functions that play an essential role during vascular repair. Endogenous progerin expression observed in MIAMI cells collected from a non-HGPS older donor suggest that MIAMI cells can accumulate progerin in vivo, and therefore are likely subject to the effects of progerin expression. One remarkable observation is that progerin mRNA in MIAMI cells from an aged (65-year old) donor appears to be expressed at similar levels when compared to transduced GFP-progerin MIAMI cells. Because it is likely that cells from aged individuals express progerin at lower levels than cells from HGPS patients, we consider our transduced GFP-Progerin MIAMI cells provide a suitable model to assess the effects of progerin expression in the context of physiological aging in a defined stem/progenitor cell population, with implications to age-related disorders during organismal aging.

Comments

Is it possible or desirable to attack progerin directly, like with 7KC and A2E?

Posted by: Slicer at December 22nd, 2014 6:01 PM

This new press release may be relevant -

"Antioxidant in broccoli 'shows promise' as treatment for progeria"
http://www.medicalnewstoday.com/articles/287375.php

Excerpt -
"...an antioxidant (sulforaphane) present in broccoli appears to give the protein-clearing system a boost, potentially reducing the effects of the disease."

Possibly, though, sulforaphane's effect is due to its HDAC inhibition.

Posted by: Lou Pagnucco at December 24th, 2014 12:08 PM

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