Exotic genetic diseases often provide important clues for the aging process, and I have previously discussed implications of Hutchinson-Gilford progeria and Werner Syndrome in this Blog. This time, a research item on Hoyeraal-Hreidarsson Syndrome(HHS) came to my attention. “Hoyeraal-Hreidarsson syndrome is a multisystem disorder affecting males and is characterized by aplastic anemia, immunodeficiency, microcephaly, cerebellar hypoplasia, and growth retardation. HHS is a severe variant of dyskeratosis congenita(ref).”(ref). HHS is “mainly characterized by telomerase deficiency, accelerated telomere shortening, impaired cell proliferation, bone marrow failure, and immunodeficiency(ref).” Telomere shortening and damage is the 12th theory of aging covered in my Anti-Aging Firewalls Treatise.
The key conclusion of the new research is “Altogether, these results suggest that the primary defect in these patients lies in the telomere structure, rather than length. We postulate that this defect hinders the access of telomerase to telomeres, thus causing accelerated telomere shortening in blood cells that rely on telomerase to replenish their telomeres. In addition, it activates the DDR (DNA damage response) and impairs cell proliferation, even in cells with normal telomere length such as fibroblasts. This work demonstrates a telomere length-independent pathway that contributes to a telomere dysfunction disease(ref).” The problem in the case of HHS is apparently due to diminished 3′ overhangs which are part of telomeric DNA, that is, defective telomere caps. Telomerase works by adding telomeric repeats off of the 3” overhangs and, if the overhangs are not normal, cannot do its job of extending telomeres. The researchers tracked the problem down to mutations in the telomerase subunits and in the Shelterin component Tin2. Shelterin is a protein complex that is essential for shaping and protecting human telomeres. It has six components: TRF1, TRF2, TIN2, Rap1, TPP1, and POT1. Shelterin is important for enabling cells to distinguish telomeres from sites of DNA damage.
The study demonstrates the complexity involved in telomerase activation and that many pathways can contribute to either telomere extension or shortening. The devil is in the details. The results are related to those posted in previous blog entries: More research progress on telomerase, and Stem cells, telomeres and telomerase and DNA repair.
Hi Vince,
I have seen some studies in which resveratrol was fed to the mice and they lived 30% longer.
There was no tumerogenesis observed in the mice?
Also what is their telomere status? Mice have long telomeres, so I am told. What is the status of the telomeres of the resveratol fed mice?
What happens if we feed telomere extending molecules and resveratrol to these mice? Will they live even longer.
I am seeing many lifeextenders are adopting the strategy of taking both resveratrol and astragalosides to extend their life on this premise.
There has to be a study to test that hypothesis.
Hi Vince
A latest news on genetic basis of aging
http://www.news24.com/News24/Technology/News/0,,2-13-1443_2517517,00.html
Res
With regard to your second comment, thanks for the link. I will check it out.
With regard to your first comment, I have seen no data on the telomere lengths of resveratrol-fed mice. Because of their long telomere status, the assumption as I understand it was that their cause of death was other than cell senescence caused by too-short telomeres.
I do not know what would would happen to mice fed both telomerase activators and resveratrol. Or, for that matter I don’t know what would happen to mice fed either of those substances in combination with alpha-lipoic acid and acytl-l-carnitine, a combination with mouse life-extending capabilities. In fact, many substances have been shown experimentally to extend the lives of mice somewhat but nobody has bothered to check them out in combinations. Sadly, most experimental longevity research has been pursued by separate groups of researchers who appear to be interested in a single theory of aging and who seem to have conducted their research ignoring other theories of aging.
I too would like to see experiments on small animals of combinations of anti-aging substances. It is ironical that such multi-substance experiments are being conducted on ourselves by some of us in the anti-aging community, and are not controlled or coordinated.
Vince
Thanks Vince for the comments Yes that is what is troubling me. Anti-agers are experimenting on themselves all such combinations without a study to validate their assumptions. I beleived that the mice were dead at the end of their telomere lenths. They died of hayflick limit. The life extension of 30% is because of the non tumour life that utilized their full telomere lengths. This is my assumption. An experiment can be constucted (at least starting with c-elegans worms) one set fed usual food, another set fed with resveratrol, another set fed with astragalosides, yet another set fed both resveratrol and astragalosides, another set with alcar/ala combination and yet another set with alcar/ala, resveratrol, astragalosides. We could easily find out what is causing the life extension and what is not. if it extends the life, we would know how much. Most of these experments start with c-elegans. Because it is cheaper, and the life time for the c-elegans is in just 2 weeks. start to finish would take hardly 1 month to find out the results for the worms. Based on these studies then we can think of mice studies. Anyway, i am disappointed that no such study is sponsered by the life extension groups or companies
Res: The lack of practical nematode and mouse anti-aging experimentation bothers me too. It seems that the existing research is either drug-development oriented or is oriented to narrow objectives related to specific substances or biomolecular pathways. Nobody is saying “These substances seem to have anti-aging properties. I am going to conduct research to see which ones in what combinations work best, first on worms and fruit flies, then on mice and eventually on people.” And they would start out by doing tests such as those you suggest. I think the problem lies in part in the structure of science which rewards extremely specific findings, in the public health domain where life-extension is regarded as too visionary to be concerned with, and in the commercial domain where the money is in proprietary drugs.
If us anti-agers want to see experiments like you suggest we are going to have to organize politically to motivate the funding of them or pay for them ourselves, If we want to go the political route we will have to bring scientific credibility and integrity to the table or the science establishment will ignore and denegrate us. That is why I am pursuing my work with as much scientific integrity as I can muster.
Vince