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!