Fight Aging!

As you might recall, it wasn't so long ago that researchers discovered the source of progeria in lamin A defects, which also occur - far less dramatically - in the course of normal aging. Lamin proteins, you might recall, help to form the important structural shell of the cell nucleus. Things start to go wrong when cells are improperly formed:

Malformed lamin A proteins lie at the root of the accelerated aging condition progeria. ... In cells taken from the elderly, the nuclei tend to be wrinkled up, the DNA accumulates damage, and the levels of some proteins that package up DNA go askew ... This mirrors the same changes that they previously observed in cells from [Hutchinson-Gilford progeria syndrome (HGPS)] children. ... The team suggests that healthy cells always make a trace amount of an aberrant form of lamin A protein, but that young cells can sense and eliminate it. Elderly cells, it seems, cannot. Critically, blocking production of this deviant protein corrected all the problems with the nucleus. ... You can take these old cells and make them young again."

Recently, it has come to light that lamin (also known as progerin) protein defects, and the resulting mishaped and stucturally deficient cell nucleui, also damage stem cell capacity. It might be this stem cell deterioration that largely causes the accelerated aging of progeria - and, by extension, contributes to age-related degeneration in the rest of us too:

researchers postulate that the biochemical root of HPGS, or progeria, causes accelerated aging by affecting stem cell populations: "The cause of HGPS, a mutated protein called progerin, was identified in 2003. However, the mechanism by which progerin causes the widespread clinical effects of HGPS has been unclear. ... [researchers have now] found that progerin activates genes involved in the Notch signaling pathway, a major regulator of stem cell differentiation - the process by which stem cells give rise to the mature cells that make up different tissues. ... Their experiments revealed that progerin profoundly affects the fate of these stem cells, greatly skewing the rate at which they mature into different tissues. ... Progerin is present at low levels in the cells of healthy people. One could envision a scenario in which progerin's effects on the Notch pathway and, by extension, on adult stem cells could, over time, lead to many of the tissue changes we commonly associate with the aging process

I bumped into a couple of papers today that expand on the mechanisms linking defective lamin proteins, poorly formed cell nuclei and stem cell dysfunction.

Gone with the Wnt/Notch: stem cells in laminopathies, progeria, and aging:

Specific mutations in the human gene encoding lamin A or in the lamin A-processing enzyme, Zmpste24, cause premature aging. New data on mice and humans suggest that these mutations affect adult stem cells by interfering with the Notch and Wnt signaling pathways.

Nuclear envelope defects cause stem cell dysfunction in premature-aging mice:

Nuclear lamina alterations occur in physiological aging and in premature aging syndromes. Because aging is also associated with abnormal stem cell homeostasis, we hypothesize that nuclear envelope alterations could have an important impact on stem cell compartments.

To evaluate this hypothesis, we examined the number and functional competence of stem cells in Zmpste24-null progeroid mice, which exhibit nuclear lamina defects. We show that Zmpste24 deficiency causes an alteration in the number and proliferative capacity of epidermal stem cells. These changes are associated with an aberrant nuclear architecture of bulge cells and an increase in apoptosis of their supporting cells in the hair bulb region.

...

We also report that molecular signaling pathways implicated in the regulation of stem cell behavior, such as Wnt and microphthalmia transcription factor, are altered in Zmpste24(-/-) mice. These findings establish a link between age-related nuclear envelope defects and stem cell dysfunction.

It seems unclear as to where this will all lead for those of us fortunately enough not to suffer from progeria. Some calibration of the degree to which normal levels of lamina damage contibute to aging would be a good first step - it is by no means clear that this mode of age-related change is as important as the others we are presented with.