Confirming the Involvement of Wnt in Progeria

For the past few years, researchers have been following the trail of biochemistry in the accelerated aging condition Hutchinson-Gilford Progeria Syndrome (HGPS or progeria). This research started with the discovery that progeria patients had a mutant form of the lamin A protein, involved in the mechanics of cell structural stability amongst other things, and continues today. This is of interest because the same harmful processes that drive progeria appear to operate over the course of "normal" aging, albeit to a far lesser degree:

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.

If your memory is very good, you'll recall that aberrant lamin A also appears to damage the ability of stem cells to maintain tissue. Interestingly, the Wnt signaling pathway appears to be somehow involved here - and you'll find an introduction to Wnt and aging back in the Fight Aging! archives:

Wnt has a great deal to do with regulation of regeneration, and its operation changes with age. Researchers have shown that altering the Wnt pathway may restore youthful levels of regenerative capability - but may well also increase the risk of cancer. This is one small part of the well known evolutionary trade-off between aging and cancer: regenerative capacity shuts down with age to reduce the risk of damaged cells involved in the healing process running amok.

In any case, a few years ago, researchers had this to say:

Specific mutations in the human gene encoding lamin A [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.

Here is news from a more recent investigation:

Progeria is caused by a mutation in the gene for lamin A that leads to production of "progerin", a truncated form of the lamin A protein that causes the cell nucleus to become misshapen. ... a progerin-like truncation of lamin A [causes] post-natal connective tissue cells to stop producing an extracellular matrix. The lack of this surrounding matrix then causes the cells to stop dividing and to die.

...

The researchers [show] that the defects in the extracellular matrix in mouse and human progeria cells are due to abnormalities in a protein network called the Wnt signaling pathway. "Our results provide support for the hypothesis that progeria is a disease of the connective tissue extracellular matrix which manifests as abnormalities in the skeleton, teeth, skin and vasculature," concludes Dr. Stewart. "If these failures are due to defective Wnt signaling and/or cytoskeletal-extracellular matrix function, they suggest possible new routes of intervention that may help in treating this disease."

As there is also evidence for defective lamin production in the vascular system during the normal aging process, the researchers are keen to explore potential implications of their new findings in these and other aspects of both progeria and normal aging.

No-one ever said that biology was simple. Fortunately, the contribution to degenerative aging of bad forms of lamin A is likely small when compared to, say, the forms of biochemical damage outlined in the Strategies for Engineered Negligible Senescence.

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