Thanks to a small international multidisciplinary team, we have a good set of hypotheses and an overview of potential therapeutic compounds for treating the HGPS. Some of these should be tested for the effects on progerin accumulation.
The paper "Potential therapeutic approaches for modulating expression and accumulation of defective lamin A in laminopathies and age-related diseases, Zhavoronkov A, Smit-McBride Z, Guinan KJ, Litovchenko M, Moskalev A., J Mol Med (Berl). 2012 Oct 23" in open access and is freely available for download as PDF.
Abstract:
Scientific understanding of the genetic components of aging has increased in recent years, with several genes being identified as playing roles in the aging process and, potentially, longevity. In particular, genes encoding components of the nuclear lamina in eukaryotes have been increasingly well characterized, owing in part to their clinical significance in age-related diseases. This review focuses on one such gene, which encodes lamin A, a key component of the nuclear lamina. Genetic variation in this gene can give rise to lethal, early-onset diseases known as laminopathies. Here, we analyze the literature and conduct computational analyses of lamin A signaling and intracellular interactions in order to examine potential mechanisms for altering or slowing down aberrant Lamin A expression and/or for restoring the ratio of normal to aberrant lamin A. The ultimate goal of such studies is to ameliorate or combat laminopathies and related diseases of aging, and we provide a discussion of current approaches in this review.
Wednesday, October 24, 2012
Tuesday, August 16, 2011
DNA Damage and Repair During Cellular Aging
We managed to find a PDF of a seminal 1989 review article on DNA damage and Repair titled "DNA Damage and Repair During Cellular Aging", Suresh I. S. Rattan, International Review of Cytology 116, pp. 47-88, 1989.
We could not find this article in PDF for a very long time and here it is. Read, add to your collections, enjoy and reference!
We could not find this article in PDF for a very long time and here it is. Read, add to your collections, enjoy and reference!
Thursday, March 3, 2011
One of the best tools for aging research spotted - www.agingportfolio.org
Ever wondered about how much money governments worldwide spend on aging research and specifically on YOUR AREA OF INTEREST?
Would you like to see the answer to these questions with graphs, charts and publications?
Wonder no more, now you can start using The International Aging Research Portfolio (IARP) - a free resource for aging research. We will post a few notes here once we are done playing with it, but the site looks amazing!
We used it when it was still in development and since then it greatly improved. Congrats to the development team!!!
Would you like to see the answer to these questions with graphs, charts and publications?
Wonder no more, now you can start using The International Aging Research Portfolio (IARP) - a free resource for aging research. We will post a few notes here once we are done playing with it, but the site looks amazing!
We used it when it was still in development and since then it greatly improved. Congrats to the development team!!!
Thursday, May 6, 2010
NIH-supported projects related to aging with "deuterium" as a keyword
We did a beta test of a widely-expected project called the AgingPortfolio.Org looking for aging projects using deuterium. Did not find anything, which would remotely resemble the current work at Retrotope, Inc.
It looks like it is up to the private sector to answer some fundamental questions on role of isotopicaly-fortified organic compounds in aging...
It looks like it is up to the private sector to answer some fundamental questions on role of isotopicaly-fortified organic compounds in aging...
Tuesday, December 8, 2009
"light" water and its proposed impact in aging
Very interesting experiment results on gamma-irradiated irradiated mice:
Aviakosm Ekolog Med. 2009 Mar-Apr;43(2):29-32.
[The "light" water effect on lenticular opacity development in mice after repeated low dose gamma-irradiation]
[Article in Russian]
Abrosimova AN, Rakov DV, Siniak IuE.
Action of "light" water with reduced quantities of heavy stable hydrogen and 18O ions on incidence and progress of lenticular opacity was studied in gamma-irradiated mice (60Co, 1.0 Gy). The animals were subjected to electroophthalmoscopy regularly till end of life time. The observation showed that chronic intake of "light" water safeguarded the irradiated mice against lenticular opacity. The experimental data indicate that "light" water strengthens the general body resistance as well as slows down aging of mammals.
Aviakosm Ekolog Med. 2009 Mar-Apr;43(2):29-32.
[The "light" water effect on lenticular opacity development in mice after repeated low dose gamma-irradiation]
[Article in Russian]
Abrosimova AN, Rakov DV, Siniak IuE.
Action of "light" water with reduced quantities of heavy stable hydrogen and 18O ions on incidence and progress of lenticular opacity was studied in gamma-irradiated mice (60Co, 1.0 Gy). The animals were subjected to electroophthalmoscopy regularly till end of life time. The observation showed that chronic intake of "light" water safeguarded the irradiated mice against lenticular opacity. The experimental data indicate that "light" water strengthens the general body resistance as well as slows down aging of mammals.
Tuesday, September 22, 2009
Isotope-Reinforced Polyunsaturated Fatty Acids Protect Yeast Cells from Oxidative Stress
Dr. Catherine Clarke, a prominent lab head from UCLA, presented her findings on using the isotope-fortified PUFAs in yeast:
K. Hirano, V. V. Shmanai, B. N. Marbois, R. Molinari, S. Morvaridi, M. Shchepinov, C. F. Clarke
Department of Chemistry and Biochemistry University of California, Los Angeles 607 Charles E Young Dr E Los Angeles CA 90095-1569
Polyunsaturated fatty acids (PUFAs) are exquisitely sensitive to autoxidation damage. The autoxidation products include peroxyl and alky radicals, and small molecule aldehydes that form cross-links to other membrane components, or diffuse to other cellular sites and damage proteins and nucleic acids. Cells protect themselves from these autoxidation products by maintaining an arsenal of enzymes designed to keep reactive oxygen species in check, as well as a defensive system of small molecule antioxidants that terminate radical chain reactions. The enhanced vulnerability of PUFAs to such autoxidation stems from the labile nature of the bis-allylic hydrogen atoms. The facile abstraction of bis-allylic hydrogens from PUFAs is the hallmark chemistry responsible for initiation and propagation of autoxidation reactions. PUFAs synthesized to contain Deuterium atoms uniquely at the bis-allylic sites (termed isotope-reinforced PUFAs) would be expected to be more resistant to autoxidation reactions due to the isotope effect. This hypothesis was tested by making use of the coenzyme Q-deficient Saccharomyces cerevisiae model. The yeast coq mutants have defects in biosynthesis of coenzyme Q (CoQ, or ubiquinone). CoQ plays a well-known role in respiratory energy metabolism and also functions as a lipid soluble chain terminating antioxidant. Although yeast cannot synthesize PUFAs, they are able to incorporate exogenously supplied PUFAs into their membrane lipids. Yeast coq mutants incubated in the presence of linolenic acid (C18:3) exhibit profound loss of viability as ascertained by greater than 99% loss of colony formation at 4 hours. In contrast, the coq mutants treated with either the monounsaturated oleic acid (C18:1), or the isotope-reinforced linolenic acid (bis-allylic D4-C18:3) retain 80-90% viability, a value similar to wild-type or CoQ-replete yeast. These results indicate that isotope reinforced PUFAs are stabilized as compared to standard PUFAs, and the coq mutant yeast cells containing the D4-linolenic acid are protected against the toxic effects of lipid autoxidation products.
Presenting author: Clarke, Catherine
Keywords: Isotope Effect, Lipid Autoxidation, Coenzyme Q, Ubiquinone, Fatty Acid
K. Hirano, V. V. Shmanai, B. N. Marbois, R. Molinari, S. Morvaridi, M. Shchepinov, C. F. Clarke
Department of Chemistry and Biochemistry University of California, Los Angeles 607 Charles E Young Dr E Los Angeles CA 90095-1569
Polyunsaturated fatty acids (PUFAs) are exquisitely sensitive to autoxidation damage. The autoxidation products include peroxyl and alky radicals, and small molecule aldehydes that form cross-links to other membrane components, or diffuse to other cellular sites and damage proteins and nucleic acids. Cells protect themselves from these autoxidation products by maintaining an arsenal of enzymes designed to keep reactive oxygen species in check, as well as a defensive system of small molecule antioxidants that terminate radical chain reactions. The enhanced vulnerability of PUFAs to such autoxidation stems from the labile nature of the bis-allylic hydrogen atoms. The facile abstraction of bis-allylic hydrogens from PUFAs is the hallmark chemistry responsible for initiation and propagation of autoxidation reactions. PUFAs synthesized to contain Deuterium atoms uniquely at the bis-allylic sites (termed isotope-reinforced PUFAs) would be expected to be more resistant to autoxidation reactions due to the isotope effect. This hypothesis was tested by making use of the coenzyme Q-deficient Saccharomyces cerevisiae model. The yeast coq mutants have defects in biosynthesis of coenzyme Q (CoQ, or ubiquinone). CoQ plays a well-known role in respiratory energy metabolism and also functions as a lipid soluble chain terminating antioxidant. Although yeast cannot synthesize PUFAs, they are able to incorporate exogenously supplied PUFAs into their membrane lipids. Yeast coq mutants incubated in the presence of linolenic acid (C18:3) exhibit profound loss of viability as ascertained by greater than 99% loss of colony formation at 4 hours. In contrast, the coq mutants treated with either the monounsaturated oleic acid (C18:1), or the isotope-reinforced linolenic acid (bis-allylic D4-C18:3) retain 80-90% viability, a value similar to wild-type or CoQ-replete yeast. These results indicate that isotope reinforced PUFAs are stabilized as compared to standard PUFAs, and the coq mutant yeast cells containing the D4-linolenic acid are protected against the toxic effects of lipid autoxidation products.
Presenting author: Clarke, Catherine
Keywords: Isotope Effect, Lipid Autoxidation, Coenzyme Q, Ubiquinone, Fatty Acid
Wednesday, June 24, 2009
Response to Zhang: another trick of heavy isotopes
Deuterium cannot be kept for long enough at
exchangeable DNA sites to achieve this desired effect in
vivo because it will readily (within a few minutes) be
replaced by hydrogen atoms from normal water, the major
component of live cells, owing to fluctuational openings
of DNA base pairs (DNA ‘breathing’). Otherwise,
normal water would have to be almost completely replaced
by heavy water, which is not possible owing to the
known lethal toxicity of heavy water for mammals at
concentrations >35%. This was the reason that high
KIE was only observed in the condensed phase or in waterfree
solutions whereas even traces of natural water basically
abolished this effect.
For this reason, to achieve the goal of reducing the
amount of unfavorable tautomers it was suggested that
deuterium be placed at non-exchangeable sites of DNA
purines and pyrimidines. In this case, other heavy
isotopes can also be used for KIE (Figure).
However,
caution should be exercised in choosing sites for isotopic
replacement because certain studies estimated an unusually
highamount of unfavorable tautomers in tRNAwhen
the natural 14N isotope was completely replaced with its
heavier 15Nsubstitute.Note that thishighamount of
unfavorable tautomers exceeds the amount of mutationcausing
tautomer of a highly mutagenic analog of cytosine. It is noteworthy that isotopic changes in non-exchangeable
DNA sites might reduce the level of age-related
mutations, including epigenomic modifications, by other
mechanisms too.
Vadim V. Demidov
Trends in Biotechnology
Volume 26, Issue 3, March 2008
exchangeable DNA sites to achieve this desired effect in
vivo because it will readily (within a few minutes) be
replaced by hydrogen atoms from normal water, the major
component of live cells, owing to fluctuational openings
of DNA base pairs (DNA ‘breathing’). Otherwise,
normal water would have to be almost completely replaced
by heavy water, which is not possible owing to the
known lethal toxicity of heavy water for mammals at
concentrations >35%. This was the reason that high
KIE was only observed in the condensed phase or in waterfree
solutions whereas even traces of natural water basically
abolished this effect.
For this reason, to achieve the goal of reducing the
amount of unfavorable tautomers it was suggested that
deuterium be placed at non-exchangeable sites of DNA
purines and pyrimidines. In this case, other heavy
isotopes can also be used for KIE (Figure).
However,
caution should be exercised in choosing sites for isotopic
replacement because certain studies estimated an unusually
highamount of unfavorable tautomers in tRNAwhen
the natural 14N isotope was completely replaced with its
heavier 15Nsubstitute.Note that thishighamount of
unfavorable tautomers exceeds the amount of mutationcausing
tautomer of a highly mutagenic analog of cytosine. It is noteworthy that isotopic changes in non-exchangeable
DNA sites might reduce the level of age-related
mutations, including epigenomic modifications, by other
mechanisms too.
Vadim V. Demidov
Trends in Biotechnology
Volume 26, Issue 3, March 2008
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