Interestingness: 7
tl;dr 20% lifespan increase from mitochondrially hyperexpressed catalase
By Samuel E Schriner, Nancy J Linford, George M Martin,Piper Treuting, Charles E Ogburn, Mary Emond, Pinar E Coskun, Warren Ladiges, Norman Wolf, Holly Van Remmen, Douglas C Wallace and Peter S Rabinovitch in Science 308, 1909 (2005). doi: 10.1126/science.1106653
This was not published in Rejuvenation Research. It was published in Science. It was commented about by Richard Cutler in issue 3 of 2005 of Rejuvenation Research, but I couldn't find access to the comments. I did find this one though, and since it is a pretty famous result, I read it.
They overexpressed human catalase in mice in six separate lineages, two in their peroxisome, two in their nucleus and two in their mitochondria. That is, there are four different mice lineages per experiment, two for controls, and two with the intervention, one corresponding to each of the controls. They show results per lineage with respect to their corresponding control, and I'll write them down like that too since I can't think of a better way. In all cases, the amount of catalase expressed is very high compared to wild type.
Going by the graphs, control median lifespan was about 26-27 months, and maximum lifespan (age at 10% survival, not average lifespan of top 10% like they measure in the paper (because I don't have the raw data)) at around 33 months. Expression in the nucleus extended median lifespan by 1 and 3 months (p > 0.05) with no increase in maximum lifespan. Expression in the peroxisome increased median by 3 (p > 0.05) and 3.5 months (p < 0.02) with no increase in maximum. Expression in the mitochondria increased median by 4.5 months (p < 0.0001) and 5.5 months (p < 0.0002) with maximum lifespan increases of 4.5 months (p < 0.001 combined lineages)
Most of the paper focuses on the mitochondrial branch since it's the most impressive. In the mitochondrial branch, there's equivalent lifespan increases for males and females. They also observe lots of good shit happening to the heart (less heart disease in general).
In what seems like a side-experiment they cross the peroxisome-expressing mice with a superoxide-dismutase expressing mice, and they get a 18.5% (p < 0.0001) median life extension with respect to wild type and 7% (p=0.036) compared to the peroxisome mice, but no maximum life extension. They note that the mitochondrially expressing mice would be a better one to try.
By the way, superoxide anion O2- goes to hydrogen peroxide H2O2 helped by superoxide dismutase. Hydrogen peroxide goes hammertime unless defused by catalase (or glutathione peroxidase).
Tuesday, February 5, 2013
Monday, February 4, 2013
Issue 3, 2005
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.
"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.
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.
Subscribe to:
Posts (Atom)
Posts
