Monday, August 27, 2012

Mitochondrial Mutations in Mammalian Aging: An Over-Hasty About-Turn?

Interestingness: 7

By Aubrey DNJ De Grey, in Rejuvenation Research, Northern Autumn 2004, 7(3): 171-174. doi:10.1089/rej.2004.7.171.

A short piece of commentary trying to raise the profile of, I think, this paper:  "Construction of transgenic mice with tissue-specific acceleration of mitochondrial DNA mutagenesis", by Zhang D et al (http://www.ncbi.nlm.nih.gov/pubmed/11031098), but mainly about lowering the importance of "Premature ageing in mice expressing defective mitochondrial DNA polymerase" by Trifunovic A et al (http://www.ncbi.nlm.nih.gov/pubmed/15164064 ) . I haven't read the former, and I've only read the latter just now (separate post).

Zhang's paper is  about mice with a mutant mtDNA polymerase which produced more errors, but is only activated in the heart, and only after birth.  Trifunovic's paper is a similar concept but they made it active in all tissue. Also, while in Trifunovic's experiment they modified the built-in version of the mtDNA polymerase, I am not sure if that is what was done in Zhang's version, or if they just added a second copy.

The results of the modifications are that in Zhang's, the mice get cardiomyopathy, while Trifunovic's mice get fucked up all over and die at around the year mark.

de Grey's objection to the importance of Trifunovic's paper is that the effects seem to hit mainly tissue undergoing rapid replication (the spleen, the skin, testes and blood), and that the heart issues were a compensation mechanism for the anaemia.  His claim is that this failure of rapidly replicating tissue cannot cause a shortening of lifespan since the failing cells can just be replaced by the replication of the still-good cells, unless the cells are failing faster than they can be replaced, which is what he thinks is happening during the experiment.

It would be good if he'd have addressed specifically the coincidence that in both cases the mice suffered from enlarged hearts, but according to him due to separate causes (ie is it a coincidence?).  I don't know the timing of the cardiomyopathy in the Zhang experiment though, so it might have come around much later and there might not be anything to address.



Issue 3, 2004

By the abstracts:

"Regulation of Murine Telomere Length via Rtel". What the title says. Rtel being a DNA helicase-like protein gene. Hadn't heard about it.

"Mitochondrial Mutations in Mammalian Aging: An Over-Hasty About-Turn?". This seems, from the abstract, to be de Grey chastising the community both for ignoring mtDNA mutations and then for changing their mind too easily due to a study of a mouse with accelerated mtDNA mutations in which it had aging-like issues.  Sounds interesting.

"The Interdependence of Skin Aging, Skin Cancer, and DNA Repair Capacity: A Novel Perspective with Therapeutic Implications". Review of effects of UV light on skin DNA, and repair against those effects.

"Rejuvenation of Visual Functions in Older Adult Drivers and Drivers with Cataract During a Short-Term Administration of N-Acetylcarnosine Lubricant Eye Drops". RCT of N-acetylcarnosine on 130 people, half of them with cataracts. They seem to think it works at reducing glare sensitivity.

"Paradoxes of Non-Trivial Gene Networks: How Cancer-Causing Mutations Can Appear to Be Cancer-Protective". Model paper supposedly showing how certain alleles that seem onco-protective could actually be onco-causal. Maybe interesting.

Commentary on "A Policy Analysis of Funding for Ambitious Interventional Gerontology: The Possibility of Rejuvenation Research at the National Institute on Aging" about how to get rejuvenation research structured/funded under the National Institute of Aging.

"Science and Politics: World Events Intensify Stem Cell Debate". Some supposed-to-be report about the First International Stem Cell Action Conference, but which seems to be commentary on the US political situation on stem cell research.

A report of the "Regenerate 2004: Tissue Engineering the Human Body, June 10–12, 2004, Seattle" meeting. These are always fun to read.  A bit of a downer in that the topics discussed sound very similar to what I keep reading about currently.




Sunday, August 26, 2012

Telomeres and Telomerase: A Modern Fountain of Youth?

Interestingness: 3

By João Pedro de Magalhães and Olivier Toussaint, in Rejuvenation Research, July 2004, 7(2): 126-133. doi:10.1089/1549168041553044.

Not as much new material in this short paper as I expected, probably because I've read quite a bit on the topic since this was published. Interesting bits picked out:
  • No correlation between maximum number of cell replications (cumulative population doublings) and age (post birth). (I have the vague recollection of some paper saying the opposite)
  • No connection between mean telomere length and mammalian aging. (I think they mean across species, the species with the longer telomeres don't live any longer).
  • Telomere length in vivo has very high variability

In summary, they think that telomerase might be beneficial for specific diseases but they doubt it'll turn out to be an anti-aging agent.

Issue 2, 2004

By the abstracts:


"Inter-Species Therapeutic Cloning: The Looming Problem of Mitochondrial DNA and Two Possible Solutions". Title seems like a good summary.

"Catecholamines and Protein Deposition in Parkinson's and Alzheimer's Disease: Old Medicine, New Targets". Didn't get to the meat. Catecholamines, wiki says, are compounds that have a catechol, which is a benzene with two hydroxil groups attached. eg epinephrine, dopamine.

"A Reproducible Laser-Wounded Skin Equivalent Model to Study the Effects of Aging In Vitro". Trying to create a model of partial wounds on skin (by partial meaning not through the whole thing). They like the look of the wounds produced by a low powered excimer laser (excimer lasers emit UV, wiki tells me).

"Selective Pressure for a Decreased Rate of Asymmetrical Divisions Within Stem Cell Niches May Contribute to Age-Related Alterations in Stem Cell Function". The abstract claims that there is a selection pressure for stem cells to reproduce symmetricaly, and thus produce two stem cells, and probably cancer, but this paper is about a second independent pressure against asymmetrical division of stem cells. Sounds interesting.

"Telomeres and Telomerase: A Modern Fountain of Youth?". Discusses whether telomerase will be used for anti-aging therapies.  They think not.  Want to read the rest, or, more likely, an updated version of it.

"Aging Theories of Primary Osteoarthritis: From Epidemiology to Molecular Biology". Seems to be a review paper on osteoarthritis. Very well cited.

A review of the book "Cells, Aging, and Human Disease" by Michael Fossel