The New Stem Cell Science of Progeria

Great inroads have been made in recent years into an understanding of the accelerated aging condition called Hutchinson-Gilford progeria syndrome, or progeria. Despite its extreme rarity - there are less than a hundred sufferers known worldwide - the condition is of great interest to aging researchers, and this is because of what progeria might teach us about a range of important cellular mechanisms and their impact on "normal" aging.

The breakthrough discovery linking progeria with malformed lamin A protein back in 2003 came about as a result of advances in biotechnology. Thanks to rapid technological progress, the means to make this discovery became cheap enough that one determined researcher could push through to succeed in a comparatively short time frame. Ten years previously, that would have been impossible for such a small research effort.

Today the tools of cellular biotechnology are at least as far advanced over the state of the art in 2003 as that year was over the early 1990s. As a result new avenues are opening up in the investigation of progeria's mechanisms - and their relevance to the rest of us. A recent research release from EurekAlert!, for example, shows how application of the comparatively recent technologies of induced pluripotency (used to produce induced pluripotent stem cells, or iPS cells) are leading to further discoveries in both aberrant and "normal" aging:

Hutchinson-Gilford Progeria Syndrome is caused by a single point mutation in the gene encoding lamin A, which forms a protein scaffold on the inner edge of the nucleus that helps maintain chromatin structure and organize nuclear processes such as RNA and DNA synthesis. The mutation creates an alternative splice site that leads to the production of a truncated version of the protein known as progerin. Unlike the full-length protein, progerin does not properly integrate into the nuclear lamina, which disrupts the nuclear scaffold and causes a host of problems.

"There is also evidence that defective lamin A accumulates during the normal aging process via the sporadic use of the alternative splice [site]. Therefore we are very keen [to] identify new aging markers and explore other aspects of human premature and physiological aging."


Compared to normal skin fibroblasts, cells from Progeria patients have misshapen nuclei and a range of other nuclear defects, including a disorganized nuclear lamina, loss of super-condensed DNA, telomere shortening and genomic instability. Yet, despite their "old" appearance and characteristics, these cells could be readily converted into iPS cells.

"The reprogramming process erased all nuclear and epigenetic defects and the rejuvenated pluripotent cells looked and acted like perfectly normal healthy cells."

Which is a very interesting result. You might compare it with another demonstration made recently in which damaged cells lost their damaged status when altered to become induced pluripotent stem cells. Unlike that case, however, here the induced pluripotent cells still bear the seeds of the damage: when they differentiate into other types of cell, those cells once again produce the bad lamin A and suffer the characteristic effects of progeria.

The researchers conclude that a therapy might be built through genetic manipulation and cell transplant, as they were able to fix the differentiated cells via that approach:

Genetically modifying progeria-derived iPS cells to shut down the expression of progerin staved off the premature appearance of aging phenotypes after differentiation. "Transplantation of the progenitor cells derived from the 'corrected' progeria iPS cells might hold the promise to treat these progeria children in the future."

As I have noted in the past, a comprehensive fix for progeria may well be of some benefit to those of us suffering "normal" aging as well.


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