Progerin, HGPS and a possible new theory of aging

HGPS, standing for Hutchinson-Gilford progeria syndrome is an extremely rare but well-studied genetic disease. Young children born with HGPS seem to age at an extraordinary rate, exhibit many of the symptoms of old age, become wrinkled and bald, are particularly vulnerable to cardiovascular diseases and usually die of a cardiovascular disease of old age by the age of 14.  Up until about five years ago neither the cause of the disease nor a cure were in sight.  Then a chain of exciting research developments emerged indentifying not only cause and possible cure but also what might amount to a new theory of normal aging.  The developments are complex and the puzzle is still far from complete.  I attempt to summarize them here in simple language and speculate on the implications involved.  I will study these matters further and embody this content into my Anti-Aging Firewalls treatise at some point, possibly as an extension of the 14th theory, Decline in adult stem cell differentiation, possibly as a new 15th theory.  So, here is the situation: 

1.    HGPS is caused by a mutation in the LMNA gene which is responsible for making lamin proteins which provide “scaffolding (supporting) components of the nuclear envelope, the structure that surrounds the nucleus in cells.”  The mutation produces a lamin that is “farnesylated but cannot be further processed to mature lamin A.(ref)”  That mutant farnesylated lamin is called progerin.  (Farnesylation is a post-translational chemical modification of a protein involving addition of a farnesyl group.) In progerin, a DNA sequence of 50 amino acids which would normally appear in the lamin is spliced out.

2.   Progerin targets itself to the nuclear envelope of a cell, “where it interferes with the integrity of the nuclear envelope and causes misshapen cell nuclei.” (ref),  There is strong reason to believe it is responsible for the symptoms of HGPS(ref).

3.   An obvious research idea was to see what could happen if the farnesylation of progerin was inhibited.  An exciting development was the discovery that, treating cells misshaped by the expression of progerin, inhibiting farnesylation with a farnesyltransferase inhibitor (FTI) could restore their normal cell shapes(ref,ref,ref,ref).  FTIs block the attachment of the farnesyl chemical group onto progerin. FTIs are a class of recently-developed anti-cancer drugs. 

4.   Sure enough and better yet, using the FTI  drug Tipifarnib (Zarnestra) in a progeria mouse model it was possible to prevent both the onset and late progression of cardiovascular disease(ref). This led to a hope that a cure for human HGPS might be based on use of an FTI.

5.   A clinical trial was launched on May 7, 2007 to test FTI therapy in HGPS patients(ref).  It was difficult finding patients because of the rarity of the disease.  Twenty eight children from 16 countries are participating and the trial is about halfway through.

6.   Progerin appears also to play possibly important similar roles in normal aging(ref).  Biochemical studies sugest that progerin may well cause similar effects in HGPS cells and normal cells and possibly a common molecular mechanism might underlie HGPS-type aging and normal physiological ageing. “Cell nuclei from old individuals acquire defects similar to those of HGPS patient cells, including changes in histone modifications and increased DNA damage.  Age-related nuclear defects are caused by sporadic use, in healthy individuals, of the same cryptic splice site in lamin A (progerin) whose constitutive activation causes HGPS. Inhibition of this splice site reverses the nuclear defects associated with aging(ref).”

7.   Supporting this idea, recent research indicates that progerin builds up in normal cells with age.  A powerful new technique has been developed for measuring the expression of the progeria gene. . A Swedish research group has found that both normal and progeria cells make larger and larger amounts of progerin RNA as they age(ref).

8.   Supporting this idea even further, research indicates that progerin creates all kinds of downstream biomolecular signaling mischief, including the introduction of errors in the normal differentiation of stem cells.  Progerin interferes with cell division in both HGPS and normal cells(ref).  In one key study(ref), the presence of progerin produced a profound impact on renewal and differentiation of adult mesenchymal stem cells, affecting the rates at which they mature into different tissues. “Our results support a model in which accelerated ageing in HGPS patients, and possibly also physiological ageing, is the result of adult stem cell dysfunction and progressive deterioration of tissue functions.”  

  There are strong hints here of important possibilities

:·        That a 15th theory of aging exists, stating that aging is due to age-related accumulation of progerin in normal cells which creates age-related damage of all kinds similar to that observed in HGPS and inhibits the normal differentiation of adult stem cells into normal cells.  At present I am not sure the extent to which such progerin accumulation is the cause of or the result of other age-related collateral damage and how serious its impact is.·        That it may be possible to design a therapeutic intervention for normal aging based on use of FTIs.  I am not sure how safe it is to use these for anti-aging purposes  given that farnesylation is important for protein binding and happens as part of normal biochemical body functioning.  I have seen no research on the impacts taking FTIs may have on normal old people or even normal old mice for that matter.

I will be thinking about these matters further and on the lookout for additional research results.  You can expect to hear from me on this subject again soon.

Please chime in!

About Vince Giuliano

Being a follower, connoisseur, and interpreter of longevity research is my latest career. I have been at this part-time for well over a decade, and in 2007 this became my mainline activity. In earlier reincarnations of my career. I was founding dean of a graduate school and a university professor at the State University of New York, a senior consultant working in a variety of fields at Arthur D. Little, Inc., Chief Scientist and C00 of Mirror Systems, a software company, and an international Internet consultant. I got off the ground with one of the earliest PhD's from Harvard in a field later to become known as computer science. Because there was no academic field of computer science at the time, to get through I had to qualify myself in hard sciences, so my studies focused heavily on quantum physics. In various ways I contributed to the Computer Revolution starting in the 1950s and the Internet Revolution starting in the late 1980s. I am now engaged in doing the same for The Longevity Revolution. I have published something like 200 books and papers as well as over 430 substantive.entries in this blog, and have enjoyed various periods of notoriety. If you do a Google search on Vincent E. Giuliano, most if not all of the entries on the first few pages that come up will be ones relating to me. I have a general writings site at www.vincegiuliano.com and an extensive site of my art at www.giulianoart.com. Please note that I have recently changed my mailbox to vegiuliano@agingsciences.com.
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9 Responses to Progerin, HGPS and a possible new theory of aging

  1. prophets says:

    interesting, what are your thoughts about it being used as a treatment for cardiovascular disease in general?

  2. Res says:

    Thanks Vince
    Nice summarization.

  3. Res says:

    on a side note, Imatinib (Gleevec) restores the blackness to gray hair

    http://news.bbc.co.uk/2/hi/health/2180244.stm

    This is also a cancer medication.

    More research is needed.

  4. Res says:

    FTIs are not exotic medications.
    Statins are also FTIs.

    Check google
    http://www.google.com/search?hl=en&q=farnesylation+statin

  5. Res says:

    http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2525700

    Progerin elicits disease phenotypes of progeria in mice whether or not it is farnesylated

    These data support the concept that inhibition of protein farnesylation in progeria could be therapeutically useful but also suggest that this approach may be limited, as progerin elicits disease phenotypes whether or not it is farnesylated

  6. admin says:

    Res
    As to progerin inducing disease phenotypes of progeria even when it is not farmesylated, I am not surprised because progerin lacks a chain of 50 amino acids that is spliced out of normal LMNA. Apparently farnesylation and gene deletion are separate issues with progerin.

    As to imatrib bringing back black hair, most interesting! Some of the white hair on my previously-bald scalp has been slowly coming back since I started taking astragaloside IV. I have been wondering about what it would take to turn it black as a next step. I am not going to take imatrib but will see if I can find out how it works to turn hair black.

    As to statins being FTIs, also interesting. As you may know I have mixed feelings about them.. I will check the Google ref you sent.
    Vince

  7. admin says:

    Prophets
    Good questi:on about FTIs being potentially useful to treat cardiovascular disease. As of now, I don’t know. I plan to look more into FTIs and plan to write more up on the whole subject.
    Vince

  8. admin says:

    Res
    Regarding the article you suggested I look at, it is one of several that deal with the issue of telomerase geometric structure and helicases – an arcane and complex area of research related to telomere shortning I need to look further into. My impression at this point is that the researchers working in that area and the researchers concerned with FTIs and snd progerin are different bunches who probably don’t read each other’s stuff or talk to each other. It may or may not be possible at this point to develop conjectures that relate the two areas but I am far from being there.
    As you probably know Werner’s Syndrome is yet another genetic disease of premature aging different from HGPS, involving yet another set of genes. There do appear to be research linkages relating Werner’s Syndrom to telomere architecture and shortning, and I am going to have a look at those later today. Vince

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