By the abstracts:
"A New Tool in the Battle Against Alzheimer's Disease and Aging: Ex Vivo Gene Therapy". Analysis of a phase 1 trial of using ex-vivo gene therapy to somehow pump nerve growth factor to the basal forebrain of people with Alzheimer's, results of which are seen as mildly beneficial. I can't tell how they got the cells to go into the brain. More interesting from the gene therapy side than from the Alzheimer's side.
"H2S-Induced Ectothermy: Relevance to Aging". Look at the use of hydrogen sulfide as a suspended-animation conduit to extend lifespan of currently living till engineered negligible senescence arrives.
"Oxidative Stress and Aging: Catalase Is a Longevity Determinant Enzyme". Analysis of result where catalase was upregulated in cardiac mitochondria and skeletal muscle in mice, which led to lifespan increase of 20%. Famous result. I should have a look at it, and maybe find the original research by Schriner too.
"Ontogenetic Decline of Regenerative Ability and the Stimulation of Human Regeneration". Description of the problem of in-situ tissue regeneration, and on getting useful information from salamanders on how they do it. Two steps to tissue regeneration in salamanders, the first, which we are not capable of, is formation of a regeneration blastema, while he claims we are capable of the second step. Fibroblasts drive the first step by dedifferentiating into the blastema. Interesting.
"The Concept of Telomeric Non-Reciprocal Recombination (TENOR) Applied to Human Fibroblasts Grown in Serial Cultures: Concordance with Genealogical Data". Review of what is currently known about telomere-shortening triggering senescence in fibroblasts, and how those telomeres are sometimes elongated by telomeric non-reciprocal recombination. I should have a look.
"Mitochondrial Microheteroplasmy and a Theory of Aging and Age-Related Disease". The majority of mitochondria contain mutations, but each specific mutation is rare (1-2%). Theorising from that. Should read.
Monday, February 4, 2013
Sunday, February 3, 2013
Issue 2, 2005
By the abstracts:
"Replicative Aging in E. coli". About pausible aging in E Coli. Cells from parts of the cell that are older grow slower and die more. The rate seemed to be linear, not exponential, although it would be hard to tell with low numbers.
"The Role of Microglial Cellular Senescence in the Aging and Alzheimer Diseased Brain". What the title says. Microglias get fucked up in old people. This could be due to or cause senescence. This could be bad for the brain.
"Testing Whether Male Age or High Nutrition Causes the Cessation of Reproductive Aging in Female Drosophila melanogaster Populations". Reproduction in fruit flies drops with age but then stops dropping at late age (fecundity plateau). They test whether giving old female fruit flies young male studs helps, and whether amount of food helps. Both interventions changed things, but didn't get rid of the fecundity plateau.
"Clinical Anti-Aging Hormetic Strategies". Seems to be an analysis or reinterpretation of several life extension strategies (calorie restriction, exercise, social interaction) as forms of hormetic therapy. Hormetic = low level and repeated stress that causes benefits by triggering the body's defenses.
"Kidney Aging: From Phenotype to Genetics". What the title says. A review.
Nothing that I'm very pissed off on missing out on.
"Replicative Aging in E. coli". About pausible aging in E Coli. Cells from parts of the cell that are older grow slower and die more. The rate seemed to be linear, not exponential, although it would be hard to tell with low numbers.
"The Role of Microglial Cellular Senescence in the Aging and Alzheimer Diseased Brain". What the title says. Microglias get fucked up in old people. This could be due to or cause senescence. This could be bad for the brain.
"Testing Whether Male Age or High Nutrition Causes the Cessation of Reproductive Aging in Female Drosophila melanogaster Populations". Reproduction in fruit flies drops with age but then stops dropping at late age (fecundity plateau). They test whether giving old female fruit flies young male studs helps, and whether amount of food helps. Both interventions changed things, but didn't get rid of the fecundity plateau.
"Clinical Anti-Aging Hormetic Strategies". Seems to be an analysis or reinterpretation of several life extension strategies (calorie restriction, exercise, social interaction) as forms of hormetic therapy. Hormetic = low level and repeated stress that causes benefits by triggering the body's defenses.
"Kidney Aging: From Phenotype to Genetics". What the title says. A review.
Nothing that I'm very pissed off on missing out on.
Reactive oxygen species production in the mitochondrial matrix: implications for the mechanism of mitochondrial mutation accumulation
Interestingness: 3
By Aubrey D.N.J. De Grey. Rejuvenation Research. Spring 2005, 8(1): 13-17. doi:10.1089/rej.2005.8.13.
Comparison between three different theories of mitochondrial DNA mutation, and the how to interpret new findings that alpha-ketoglutarate dehydrogenase (AKDH), an enzyme in the mitochondrial matrix, makes hydrogen peroxide and possibly superoxide when exposed to high concentrations of NADH.
One of the theories is the vicious cycle hypothesis, in which mutations in the mtDNA trigger creation of superoxides which then trigger more mtDNA mutations, etc. Another is de Grey's own survival of the slowest (SOS) hypothesis described earlier in the blog. The third is the crippled mitochondrion (CM) (underspecified) hypothesis in which mutant mitochondria are stimulated to replicate by some mechanism internal to the mitochondria.
de Grey claims that the vicious cycle theory is refuted by the commonality of mutations that would get rid of the possibility to make superoxide (mtDNA deletions that get rid of the genes encoding for Complex I and III, and also get rid of at least one tRNA, for which there are no redundancies in the mtDNA), and also by the observation that the mutations in all the mitochondria's DNA tend to be the same within any one individual cell.
Differences in predictions by the other two theories:
That last prediction by the SOS hypothesis, lack of ROS production, seems to run counter with findings that oxidation-damaged DNA and RNA are found in respiration-deficient muscle fiber segments. This is the reason for bringing up the new findings of generation of ROS by AKDH when under high concentration of NADH, a state de Grey claims would be more common in mitochondria with broken respiratory chains, giving the oxidised DNA an alternate cause.
By Aubrey D.N.J. De Grey. Rejuvenation Research. Spring 2005, 8(1): 13-17. doi:10.1089/rej.2005.8.13.
Comparison between three different theories of mitochondrial DNA mutation, and the how to interpret new findings that alpha-ketoglutarate dehydrogenase (AKDH), an enzyme in the mitochondrial matrix, makes hydrogen peroxide and possibly superoxide when exposed to high concentrations of NADH.
One of the theories is the vicious cycle hypothesis, in which mutations in the mtDNA trigger creation of superoxides which then trigger more mtDNA mutations, etc. Another is de Grey's own survival of the slowest (SOS) hypothesis described earlier in the blog. The third is the crippled mitochondrion (CM) (underspecified) hypothesis in which mutant mitochondria are stimulated to replicate by some mechanism internal to the mitochondria.
de Grey claims that the vicious cycle theory is refuted by the commonality of mutations that would get rid of the possibility to make superoxide (mtDNA deletions that get rid of the genes encoding for Complex I and III, and also get rid of at least one tRNA, for which there are no redundancies in the mtDNA), and also by the observation that the mutations in all the mitochondria's DNA tend to be the same within any one individual cell.
Differences in predictions by the other two theories:
| SOS | CM |
|---|---|
| Autophagy of mitochondria selects mitochondria with damaged membranes | No prediction |
| Loss of ATP-synthase does not preferentially replicate | All functional losses replicate |
| No prediction | Cell overpopulated with mitochondria comes before or at the same time as loss of respiratory function |
| ROS production by mutant mitochondria eliminated | No prediction |
That last prediction by the SOS hypothesis, lack of ROS production, seems to run counter with findings that oxidation-damaged DNA and RNA are found in respiration-deficient muscle fiber segments. This is the reason for bringing up the new findings of generation of ROS by AKDH when under high concentration of NADH, a state de Grey claims would be more common in mitochondria with broken respiratory chains, giving the oxidised DNA an alternate cause.
Thursday, January 31, 2013
Selective Mitochondrial Autophagy, or Mitophagy, as a Targeted Defense Against Oxidative Stress, Mitochondrial Dysfunction, and Aging
Interestingness: 6
By Dr. John J. Lemasters. Rejuvenation Research. Spring 2005, 8(1): 3-5. doi:10.1089/rej.2005.8.3.
Short speculative piece about the importance of a mitochondrial outer membrane protein, Uth1p, in aging. Yeast cells with mutant versions of the gene have lower levels of mitochondrial autophagy when induced by rapamycin and starvation. If this means that the particular mitochondria that don't express Uth1p are not recycled, then it would give an "evolutionary" advantage for mitochondria to have mutant versions of this gene, as long as they are picked as often as others for mitochondrial replication. If this is the case, then other mutations in the same mitochondrion as ones with Uth1p mutations would proliferate throughout the cell.
As a downer, it seems there isn't (wasn't?) much information about the human analogue/s of the gene.
By Dr. John J. Lemasters. Rejuvenation Research. Spring 2005, 8(1): 3-5. doi:10.1089/rej.2005.8.3.
Short speculative piece about the importance of a mitochondrial outer membrane protein, Uth1p, in aging. Yeast cells with mutant versions of the gene have lower levels of mitochondrial autophagy when induced by rapamycin and starvation. If this means that the particular mitochondria that don't express Uth1p are not recycled, then it would give an "evolutionary" advantage for mitochondria to have mutant versions of this gene, as long as they are picked as often as others for mitochondrial replication. If this is the case, then other mutations in the same mitochondrion as ones with Uth1p mutations would proliferate throughout the cell.
As a downer, it seems there isn't (wasn't?) much information about the human analogue/s of the gene.
Issue 1, 2005
By the abstracts:
"Selective Mitochondrial Autophagy, or Mitophagy, as a Targeted Defense Against Oxidative Stress, Mitochondrial Dysfunction, and Aging". Piece reviewing the autophagy of mitochondria, and that it seems to be targeted, and maybe important. Has over 100 citations. Might have to find it.
"Mitochondrial DNA Gene Therapy: A Gene Therapy for Aging?". Talks about the possible importance of mtDNA problems and probably of the mtDNA to nDNA therapy paper in this issue.
"Novel Routes for Metabolism of 7-Ketocholesterol". About a possible new breakdown path for 7-ketocholesterol. 7-ketocholesterol is one of the substance in atherosclerotic plaques.
"Reactive Oxygen Species Production in the Mitochondrial Matrix: Implications for the Mechanism of Mitochondrial Mutation Accumulation". Theorising about implications of newly discovered ways in which mtDNA mutations can trigger increases in reactive oxygen species. Interesting.
"Stable Transformation of CHO Cells and Human NARP Cybrids Confers Oligomycin Resistance (olir) Following Transfer of a Mitochondrial DNA–Encoded olir ATPase6 Gene to the Nuclear Genome: A Model System for mtDNA Gene Therapy". They grabbed a gene that gave chinese hamster cells resistance to oligomycin (some antibiotic) that sat in their mtDNA, changed it so that it would work if inserted into nuclear DNA, and tested it by inserting it into normal chinese hamster cells and dipping them in oligomycin. de Grey thinks this is the most important paper yet published in Rejuvenation Research, so I'll have to read it.
"Thermodynamics and Information in Aging: Why Aging Is Not a Mystery and How We Will Be Able to Make Rational Interventions". Theoretical paper deriving aging from thermodynamics. Sometimes I like these papers, sometimes they are terrible. I'll have to have a glance.
"Genetically Modified Hairy Roots of Withania somnifera Dunal: A Potent Source of Rejuvenating Principles". I don't have much idea of what this one is about. I found the abstract very confusing. Something about enhancing the antioxidant effects of Withania somnifera, maybe.
"Gerontomodulatory and Youth-Preserving Effects of Zeatin on Human Skin Fibroblasts Undergoing Aging In Vitro". Another one which I didn't understand very well. Something about zeatin, a plant growth factor, keeping fibroblasts young-looking, but without increasing proliferative capacity.
"Selective Mitochondrial Autophagy, or Mitophagy, as a Targeted Defense Against Oxidative Stress, Mitochondrial Dysfunction, and Aging". Piece reviewing the autophagy of mitochondria, and that it seems to be targeted, and maybe important. Has over 100 citations. Might have to find it.
"Mitochondrial DNA Gene Therapy: A Gene Therapy for Aging?". Talks about the possible importance of mtDNA problems and probably of the mtDNA to nDNA therapy paper in this issue.
"Novel Routes for Metabolism of 7-Ketocholesterol". About a possible new breakdown path for 7-ketocholesterol. 7-ketocholesterol is one of the substance in atherosclerotic plaques.
"Reactive Oxygen Species Production in the Mitochondrial Matrix: Implications for the Mechanism of Mitochondrial Mutation Accumulation". Theorising about implications of newly discovered ways in which mtDNA mutations can trigger increases in reactive oxygen species. Interesting.
"Stable Transformation of CHO Cells and Human NARP Cybrids Confers Oligomycin Resistance (olir) Following Transfer of a Mitochondrial DNA–Encoded olir ATPase6 Gene to the Nuclear Genome: A Model System for mtDNA Gene Therapy". They grabbed a gene that gave chinese hamster cells resistance to oligomycin (some antibiotic) that sat in their mtDNA, changed it so that it would work if inserted into nuclear DNA, and tested it by inserting it into normal chinese hamster cells and dipping them in oligomycin. de Grey thinks this is the most important paper yet published in Rejuvenation Research, so I'll have to read it.
"Thermodynamics and Information in Aging: Why Aging Is Not a Mystery and How We Will Be Able to Make Rational Interventions". Theoretical paper deriving aging from thermodynamics. Sometimes I like these papers, sometimes they are terrible. I'll have to have a glance.
"Genetically Modified Hairy Roots of Withania somnifera Dunal: A Potent Source of Rejuvenating Principles". I don't have much idea of what this one is about. I found the abstract very confusing. Something about enhancing the antioxidant effects of Withania somnifera, maybe.
"Gerontomodulatory and Youth-Preserving Effects of Zeatin on Human Skin Fibroblasts Undergoing Aging In Vitro". Another one which I didn't understand very well. Something about zeatin, a plant growth factor, keeping fibroblasts young-looking, but without increasing proliferative capacity.
Monday, September 3, 2012
Issue 4, 2004
By the abstracts:
"Are Expanded Polyglutamine Proteins a Proteasome Substrate?". Enquiry into whether the accumulation of polyglutamine aggregation that causes neurodegeneration is due to non-working proteasome function.
"Lifelong Aspirin Supplementation as a Means to Extending Life Span". Protocol proposal and rational for the experiment of what they suggest on the title. Not the results of such an experiment. Seems to focus mostly on the anti-inflammatory properties. Maybe interesting, although I would rather read the paper on the results of the experiment.
"Is Carnosine a Naturally Occurring Suppressor of Oxidative Damage in Olfactory Neurones?". What is says on the title.
A meeting report on "The 8th International Symposium on the Maillard Reaction (Charleston, South Carolina, August 28 to September 1, 2004)". Maillard reaction = glycation = non-enzimatic glycosylation. Didn't get to the meat, but I always like meeting reports.
A review of the book "Aging, Death, and Human Longevity: A Philosophical Inquiry" by Christine Overall (the book, not the review). Philosophy.
A review of the book "Aging, Death, and Human Longevity: A Philosophical Inquiry" by Gina Smith. Popular science.
Overall, I'm not as upset as usual at not having the papers for this one.
"Are Expanded Polyglutamine Proteins a Proteasome Substrate?". Enquiry into whether the accumulation of polyglutamine aggregation that causes neurodegeneration is due to non-working proteasome function.
"Lifelong Aspirin Supplementation as a Means to Extending Life Span". Protocol proposal and rational for the experiment of what they suggest on the title. Not the results of such an experiment. Seems to focus mostly on the anti-inflammatory properties. Maybe interesting, although I would rather read the paper on the results of the experiment.
"Is Carnosine a Naturally Occurring Suppressor of Oxidative Damage in Olfactory Neurones?". What is says on the title.
A meeting report on "The 8th International Symposium on the Maillard Reaction (Charleston, South Carolina, August 28 to September 1, 2004)". Maillard reaction = glycation = non-enzimatic glycosylation. Didn't get to the meat, but I always like meeting reports.
A review of the book "Aging, Death, and Human Longevity: A Philosophical Inquiry" by Christine Overall (the book, not the review). Philosophy.
A review of the book "Aging, Death, and Human Longevity: A Philosophical Inquiry" by Gina Smith. Popular science.
Overall, I'm not as upset as usual at not having the papers for this one.
Sunday, September 2, 2012
Premature ageing in mice expressing defective mitochondrial DNA polymerase
Interestingness: 8
By Trifunovic A, Wredenberg A, Falkenberg M, Spelbrink JN, Rovio AT, Bruder CE, Bohlooly-Y M, Gidlöf S, Oldfors A, Wibom R, Törnell J, Jacobs HT and Larsson NG, in Nature, on the 27th of May, 2004. 429(6990):417-23. http://www.ncbi.nlm.nih.gov/pubmed/15164064
This isn't a paper from Rejuvenation Research, but since it was referenced in the last post, I read it and found it very interesting, notwithstanding de Grey's comments on it not being as interesting as it seems.
They created mice with a mutant version of the mtDNA polymerase instead of the regular version, that resulted in 3-5 times the usual number of mutations in their mtDNA and many more mtDNA deletions (30% less full-length mtDNA than wild type). Mutations were uniform throughout the whole mtDNA. The method of creating these mutant mice is interesting enough, but I won't describe that here.
These mice live for about a year. They have much smaller testes by the 3 month mark. They then get some fucked-up looking back deformations (kyphosis), start losing their hair, losing weight, become anaemic (with larger than usual and paler red blood cells), and get enlarged spleens by around the six-month mark. They develop osteoporosis and enlarged left ventricles at around the 9 month mark.
If de Grey's explanation is right then it's not significant, but if he is wrong, then mtDNA mutations become more important.
By Trifunovic A, Wredenberg A, Falkenberg M, Spelbrink JN, Rovio AT, Bruder CE, Bohlooly-Y M, Gidlöf S, Oldfors A, Wibom R, Törnell J, Jacobs HT and Larsson NG, in Nature, on the 27th of May, 2004. 429(6990):417-23. http://www.ncbi.nlm.nih.gov/pubmed/15164064
This isn't a paper from Rejuvenation Research, but since it was referenced in the last post, I read it and found it very interesting, notwithstanding de Grey's comments on it not being as interesting as it seems.
They created mice with a mutant version of the mtDNA polymerase instead of the regular version, that resulted in 3-5 times the usual number of mutations in their mtDNA and many more mtDNA deletions (30% less full-length mtDNA than wild type). Mutations were uniform throughout the whole mtDNA. The method of creating these mutant mice is interesting enough, but I won't describe that here.
These mice live for about a year. They have much smaller testes by the 3 month mark. They then get some fucked-up looking back deformations (kyphosis), start losing their hair, losing weight, become anaemic (with larger than usual and paler red blood cells), and get enlarged spleens by around the six-month mark. They develop osteoporosis and enlarged left ventricles at around the 9 month mark.
If de Grey's explanation is right then it's not significant, but if he is wrong, then mtDNA mutations become more important.
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