This issue and the next are all about the SENS 2005 meeting. I'm still going by the abstracts though, since that's the best I've got.
Section 1: Stem Cells and Regeneration
"Conjecture: Can Continuous Regeneration Lead to Immortality? Studies in the MRL Mouse". Separate summary since I found the article and it sounded interesting
"Sustained Stromal Stem Cell Self-Renewal and Osteoblastic Differentiation During Aging". Characterisation of a line of stem cells isolated in bone marrow that can differentiate into all (?) other types. Frequency decreases from 0.01% of bone marrow cells when 3 years old to 0.0018% at 45 but doesn't go down after that. Interesting but probably too basic-sciency to incorporate.
"To Make a New Intestinal Mucosa". Grabbed some rats, chopped a quarter of their small intestine, making them leak bile in their shit, grabbed intestinal stem cells from newborn rats, and combined them with a separate bit of cleaned up section of intestine (from different rats I assume), and inserted the reformed bit at the end of their small intestines. Worked (as in no more bile leakage). They also did some other experiment with plastic scaffolds and being able to look at the implanted cells in vivo. It all sounds interesting.
"Transfection of CCE Mouse Embryonic Stem Cells with EGFP and BDNF Genes by the Electroporation Method". They show they can insert genes into stem cells by electroporation of plasmids and have them expressed.
"Glucose-Induced Replicative Senescence in Mesenchymal Stem Cells". Calorie restriction experiment in-vitro in which the mesenchymal stem cells which get less sugar die less and have higher replicative potential.
Section 2: Cancer, Cell Senescence, and Telomeres
"Gene Therapy That Safely Targets and Kills Tumor Cells Throughout the Body". Separate summary.
"Catechin-Vanilloid Synergies with Potential Clinical Applications in Cancer". Combination of two molecules inhibit expression of tNOX which is a molecule supposedly expressed only in cancers, and supposedly necessary for cancer growth.
"Multilocus Genotypes Spanning Estrogen Metabolism Associated with Breast Cancer and Fibroadenoma". Analysis of correlations between multiple SNPs associated with estrogen and breast cancer and fibroadenoma. They think they found something that increases risk 25 times. Study of 2500 people.
"Analysis of Telomere Length and Telomerase Activity in Tree Species of Various Lifespans, and with Age in the Bristlecone Pine Pinus longaeva". They compare telomere length and telomerase activity of bristlecone pines, which live for thousands of years to shorter lived trees. They think there's something there.
"Mitochondrial Dysfunction and Cell Senescence: Cause or Consequence?". Look at evidence of mitochondria's role in senescence. They say it's complicated. Sounds interesting but can't find it.
"Chromatin Modification and Senescence: Linkage by Tumor Suppressors?". Investigation of chromatin-modification path to senescence and potential genes involved. Maybe interesting.
Section 3: Neurodegeneration
"Amyloid-Beta Immunotherapy for the Prevention and Treatment of Alzheimer Disease: Lessons from Mice, Monkeys, and Humans". Seems to be a review of the experiments that have been performed in attacking amyloid beta through immunotherapy.
"Synaptic Pathology in the Brain Cortex of Old Monkeys as an Early Alteration in Senile Plaque Formation". Measurements of synaptic density in old monkeys compared to adult monkeys. I don't understand the measurements, except for the one where it says that the number of synapses per neuron go down by about 20% in the temporal cortex, but not in the frontal cortex.
"Membership in Genetic Groups Predicts Alzheimer Disease". Allele group analysis correlations with Alzheimer's. They think they found something with 800 times risk. 300 people in study.
"Level and Distribution of Microtubule- Associated Protein-2 (MAP2) as an Index of Dendritic Structural Dynamics". More comparison of measurements between the brains of old rats and adult rats that I don't understand.
"Association Between the HLA-A2 Allele and Alzheimer Disease". They find that 46% of their study group with AD have the HLA-A2 allele vs 38% of controls.
"Structural Synaptic Remodeling in the Perirhinal Cortex of Adult and Old Rats Following Object-Recognition Visual Training". And yet more measurements comparing synaptic densities in old and adult rats. This time, it is after the rats learn something.
"The nACHR4 594C/T Polymorphism in Alzheimer Disease". Analysis of correlations between variants of the neuronal nicotinic acetylcholine receptor and AD. Study of 140.
Section 4: Immunosenescence
"Immunorejuvenation in the Elderly". About possible ways to restore the immune system from its cytomegalovirus obsession by killing those T-cells, regrowing the thymus and hammering CMV with drugs. Sounds interesting but I can't find it.
"Antibody Quality in Old Age". So supposedly, the specificity of antibodies produced against antigens decreases with age. They think this is due to laxer selection in the germinal centers of mucosal tissue.
"Immunomodulatory Vaccines Against Autoimmune Diseases". Description of therapeutic vaccines against multiple sclerosis and myasthenia gravis, an autoimmune neuromuscular disease.
"A Novel Approach to Thymic Rejuvenation in the Aged". They implant cells that produce interleukin-7 into old thymus and it seems to help. Another one that sounds interesting but that I cannot find.
"Biology of Longevity: Role of the Innate Immune System". Seems to be a review of the links between the immune system and longevity. Could be interesting. Hard to tell from the abstract. Can't find it anyway.
"Memory B Cell Subpopulations in the Aged". Lower blood levels of IgD in the blood of old people, higher level of CD19+CD27+ memory cells. Negative correlation between the two. Too many memory cells, not enough naive.
"Analysis of Candidate Genes in Celiac Disease: A Tool to Identify Life-Threatening Associated Genes?" They find no difference in the frequencies of the transforming growth factor beta 2 alleles between celiac disease patients, healthy patients and healthy people over 95 year old.
"Analysis of HLA-DQA, HLA-DQB Frequencies in a Group of Sardinian Centenarians". No significant differences between observed and expected frequencies of HLA-DQA1 and HLA-DQB1 in centenarians.
Monday, April 1, 2013
Sunday, March 31, 2013
Gene Therapy That Safely Targets and Kills Tumor Cells Throughout the Body
Interestingness: 3
By Alicia Hurtado, Jen-Chieh Tseng, and Daniel Meruelo. Rejuvenation Research. Spring 2006, 9(1): 36-44. doi:10.1089/rej.2006.9.36.
I've heard about these cancer-killing viruses many times but I've never read one of the papers.
In this one, they injected cells from human ovarian cancer into mice, and after five days they started injecting them with a non-replicating version of the Sindbis virus. They modified the virus to also express green fluorescent protein (GFP) so they could also check that the bits that were green inside the mouse were the bits where in the tumours and not in the healthy tissue or in control mice that weren't injected with cancers. They also tried two other variants adding genes for interleukin-15 and -17 to the infected virus.
They claim that tumour sizes reduced in the places where the virus infected, and lifespan of the mice was extended, especially for the IL-15 and IL-17 versions. They don't show survival curves which is a pity. They also say that they weren't able to clear the tumours.
Their theory for specificity is that the cancer expresses higher amounts of laminin receptor (LAMR) and that the virus binds to it. LAMR is upregulated in many cancers. They tested the theory by blocking LAMR production through siRNA and saw the amount of virus infection drop in those cancers.
By Alicia Hurtado, Jen-Chieh Tseng, and Daniel Meruelo. Rejuvenation Research. Spring 2006, 9(1): 36-44. doi:10.1089/rej.2006.9.36.
I've heard about these cancer-killing viruses many times but I've never read one of the papers.
In this one, they injected cells from human ovarian cancer into mice, and after five days they started injecting them with a non-replicating version of the Sindbis virus. They modified the virus to also express green fluorescent protein (GFP) so they could also check that the bits that were green inside the mouse were the bits where in the tumours and not in the healthy tissue or in control mice that weren't injected with cancers. They also tried two other variants adding genes for interleukin-15 and -17 to the infected virus.
They claim that tumour sizes reduced in the places where the virus infected, and lifespan of the mice was extended, especially for the IL-15 and IL-17 versions. They don't show survival curves which is a pity. They also say that they weren't able to clear the tumours.
Their theory for specificity is that the cancer expresses higher amounts of laminin receptor (LAMR) and that the virus binds to it. LAMR is upregulated in many cancers. They tested the theory by blocking LAMR production through siRNA and saw the amount of virus infection drop in those cancers.
Thursday, March 28, 2013
Conjecture: Can Continuous Regeneration Lead to Immortality? Studies in the MRL Mouse
Interestingness: 2
By Ellen Heber-Katz, John Leferovich, Khamilia Bedelbaeva, Dmitri Gourevitch, and Lise Clark. Rejuvenation Research. Spring 2006, 9(1): 3-9. doi:10.1089/rej.2006.9.3.
Heber-Katz is the creator of the MRL mouse, which is a mouse with higher regeneration capabilities (regenerates chopped fingers, closes holes on ears and closes holes in their heart). They are trying to make some claim for it having longer longevity potential by making parallels with the hydra.
The hydra is a little (1 centimetre?) aquatic thing that probably doesn't age. It continuously produces cells from somewhere near the middle of the body. Those cells migrate to the extremities and die or bud off or just fall/float off. Their whole body gets replaced every 4 days. Their rate of cell reproduction and probability of death doesn't seem to change, at least for the few years that's been studied.
The parallel alluded to then is that of high cell generation/high cell death. In this paper, they show high cell generation in their injured hearts, and probably high cell death in a brain injury study.
By Ellen Heber-Katz, John Leferovich, Khamilia Bedelbaeva, Dmitri Gourevitch, and Lise Clark. Rejuvenation Research. Spring 2006, 9(1): 3-9. doi:10.1089/rej.2006.9.3.
Heber-Katz is the creator of the MRL mouse, which is a mouse with higher regeneration capabilities (regenerates chopped fingers, closes holes on ears and closes holes in their heart). They are trying to make some claim for it having longer longevity potential by making parallels with the hydra.
The hydra is a little (1 centimetre?) aquatic thing that probably doesn't age. It continuously produces cells from somewhere near the middle of the body. Those cells migrate to the extremities and die or bud off or just fall/float off. Their whole body gets replaced every 4 days. Their rate of cell reproduction and probability of death doesn't seem to change, at least for the few years that's been studied.
The parallel alluded to then is that of high cell generation/high cell death. In this paper, they show high cell generation in their injured hearts, and probably high cell death in a brain injury study.
Thursday, March 14, 2013
Issue 4, 2005
By the abstracts:
"Two Hands Make Light Work of Gene Modification". About a then new DNA-modification technique where they combined zinc-fingers and nucleases to chop the DNA wherever they wanted. The idea is to put a suitable replacement patch into the cell, and letting the cell's repair system patch the substitute in. A very similar idea has been making the rounds lately and has been advertised as an easier and cheaper version of the one used in this paper.
"Mitochondrial DNA Mutations, Apoptosis, and the Misfolded Protein Response" seems to be a theoretical paper postulating a mechanism explaining the results of experiments in mice with mutant mitochondrial DNA polymerase. They claim that the main way that mitochondrial mutations drive aging is that mutated proteins occasionally trigger apoptosis by interacting with mitochondrial membrane proteins. This then triggers compensatory effects of the tissue to this loss of cells. In the abstract they mention that heart tissue upregulates anti-apoptotic signals and also drives the rest of the surviving heart cells hard to compensate for pumping loss. In this model, ROS triggers the mtDNA mutations but is not a major part of the downstream mechanism (sort of the reverse of http://readingrejuvenationresearch.blogspot.com.au/2013/03/mitochondrial-microheteroplasmy-and.html, although very obviously related). I found a summary that looks to be an extract from the paper at http://crabsallover.blogspot.com.au/2006/11/mitochondrial-dna-mutations-apoptosis.html. I'll read the rest if I find it.
"Cellular Responses to Protein Accumulation Involve Autophagy and Lysosomal Enzyme Activation". Study of what happens when high level of protein gunk builds up on neurons in vitro. Lysosomes and macroautophagy are activated, but not enough to compensate.
"A Yang-Invigorating Chinese Herbal Formula Enhances Mitochondrial Functional Ability and Antioxidant Capacity in Various Tissues of Male and Female Rats". Chinese herbal formula upregulates SODs in rats.
"NANOG Changes in Mouse Kidneys with Age". Tracking of expression of NANOG, gene needed to keep pluripotency and one of the genes introduced to create iPSCs later, in mice's kidneys as they age. Expression goes down.
Also, there was a report on the 11th Congress of the International Association of Biomedical Gerontology which I'd like to read.
"Two Hands Make Light Work of Gene Modification". About a then new DNA-modification technique where they combined zinc-fingers and nucleases to chop the DNA wherever they wanted. The idea is to put a suitable replacement patch into the cell, and letting the cell's repair system patch the substitute in. A very similar idea has been making the rounds lately and has been advertised as an easier and cheaper version of the one used in this paper.
"Mitochondrial DNA Mutations, Apoptosis, and the Misfolded Protein Response" seems to be a theoretical paper postulating a mechanism explaining the results of experiments in mice with mutant mitochondrial DNA polymerase. They claim that the main way that mitochondrial mutations drive aging is that mutated proteins occasionally trigger apoptosis by interacting with mitochondrial membrane proteins. This then triggers compensatory effects of the tissue to this loss of cells. In the abstract they mention that heart tissue upregulates anti-apoptotic signals and also drives the rest of the surviving heart cells hard to compensate for pumping loss. In this model, ROS triggers the mtDNA mutations but is not a major part of the downstream mechanism (sort of the reverse of http://readingrejuvenationresearch.blogspot.com.au/2013/03/mitochondrial-microheteroplasmy-and.html, although very obviously related). I found a summary that looks to be an extract from the paper at http://crabsallover.blogspot.com.au/2006/11/mitochondrial-dna-mutations-apoptosis.html. I'll read the rest if I find it.
"Cellular Responses to Protein Accumulation Involve Autophagy and Lysosomal Enzyme Activation". Study of what happens when high level of protein gunk builds up on neurons in vitro. Lysosomes and macroautophagy are activated, but not enough to compensate.
"A Yang-Invigorating Chinese Herbal Formula Enhances Mitochondrial Functional Ability and Antioxidant Capacity in Various Tissues of Male and Female Rats". Chinese herbal formula upregulates SODs in rats.
"NANOG Changes in Mouse Kidneys with Age". Tracking of expression of NANOG, gene needed to keep pluripotency and one of the genes introduced to create iPSCs later, in mice's kidneys as they age. Expression goes down.
Also, there was a report on the 11th Congress of the International Association of Biomedical Gerontology which I'd like to read.
Saturday, March 2, 2013
Mitochondrial Microheteroplasmy and a Theory of Aging and Age-Related Disease
Interestingness: 6
By Rafal M. Smigrodzki and Shaharyar M. Khan. Rejuvenation Research. Fall 2005, 8(3): 172-198. doi:10.1089/rej.2005.8.172.
Long theoretical paper that tries to make a case for an accumulation of lots of rare mutations in mitchondrial DNA being a major cause of aging. By rare I mean that each individual mutation is rareish (1-2% of mitochondrial genomes), but between all of them it means that most of the mtDNA in a person is mutated in some way or other. The claim is that it is this accumulation of mtDNA mutations across the body plus the inherited component from the person's mother and, importantly, from the mutations accumulated in the mother's egg cell during her life prior to giving birth to the person in question, that causes the deterioration of the body.
The paper focuses a lot on Parkinson's and Alzheimer's disease, understandable since the first author is a neurologist. This made it harder for me to read as a "theory of aging" since I know almost nothing about either and Parkinson's is a relatively rare disease.
A lot of the arguments for why the primary cause should be in mtDNA or in DNA are similar to de Grey's arguments in de Grey's arguments in his version of the mitochondrial theory of aging so I will skip those. There are major differences in the details so I'll concentrate on those.
Low levels of lots of different mutations in the mtDNA (microheteroplasmy) are different from the uniform per-cell mutations of de Grey's. Its existence is much harder to detect but other studies supposedly show such microheteroplasmy exists in all tissue and increases with age, from about 45 mutations per million base pairs at birth to about 200 per million in old age (with a high starting level in the substantia nigra). Each mutation is usually only present in 1-2% of mtDNA across tissue but up to 10-20% in single cells. By calculations, based on a low estimate of mutation rate, 90% of mitochondrial genomes have a mutation somewhere important. Based on a high estimate of mutation rate, there are on average 3 mutations per mitochondrial genome. These numbers are very different from the usual numbers quoted and this is due to the trickiness of detecting microheteroplasmy (ie they are not detected at all by the usual methods of sequencing mtDNA) they say. Their referencing of reports of low levels of different types of mutations leading to high levels of mutations overall in sequencing of single neurons and glia are also at odds with the one mutational mtDNA taking over the cell's mitochondria that de Grey tends to reference.
The suggested mechanism of action is only in small part by causing insufficient amounts of ATP to be produced in the cell, but mainly by increasing reactive oxygen species (ROS) production to levels that damage the cell and/or drive it into senescence or apoptosis, with a possible feedback mechanism involved. They also postulate that even post-mitotic cells are regularly killed and replaced by cells derived from stem cells, and that accumulation of microheteroplasmy in the stem cells would lead to quicker reaching of the threshold amount of mutations in the derived cells needed for it to stop functioning properly (due to the above-mentioned mechanism). Overall though, the paper doesn't focus on the mechanism of action and does not rule out a different mechanism of action that would not go through ROS. In private communications with the first author, who gracefully supplied me with a copy of the paper and comments (Thanks Rafal), he mentioned he would downplay the effect of ROS on causing microheteroplasmy nowadays.
The paper has a long list of supporting evidence, but most of it seems quite tenuous. The strongest seems to be the case for Parkinson's disease correlating with mutations in a particular region of the mtDNA, which showed good predictive results in a small study. They mention correlations between Alzheimer's and complex IV dysfunction; cybrid models of both Parkinson's and Alzheimer's producing disease-specific responses (cybrids are hybrids of healthy cells without mitochondria fused with mitochondria from disease patients); faulty mitochondria in relatives and offspring of diabetes patients; oxidative stress and inheritance patterns in hypertension; glycolysis and cancer; metastasis in cancer as being a side-effect of old evolutionary reaction of the cell switching away from mitochondrial respiration as a source of power (due to mutated mtDNA).
The paper describes a particular type of mutation that they call focal microheteroplasmy, where a particular mutation becomes prevalent throughout a person due to it having originated during the mother's life prior to giving birth. While this mutation would be prevalent in the person's tissue, it would be completely different from other people in the family, even identical twins, who would have inherited a different half of the mitochondria. This mechanism is used as a partial explanation of the pattern of inheritance seen in certain diseases (eg Parkinson's and Alzheimer's).
The paper has an interesting list of corollaries/predictions of its hyptothesis:
Overall, I'm not particularly fond of the mechanism of action being mainly down to ROS action. The predictions are quite good though, and if microheteroplasmy is as prevalent as stated then it should become quite clear shortly with the amount and variety of sequencing going on nowadays.
By Rafal M. Smigrodzki and Shaharyar M. Khan. Rejuvenation Research. Fall 2005, 8(3): 172-198. doi:10.1089/rej.2005.8.172.
Long theoretical paper that tries to make a case for an accumulation of lots of rare mutations in mitchondrial DNA being a major cause of aging. By rare I mean that each individual mutation is rareish (1-2% of mitochondrial genomes), but between all of them it means that most of the mtDNA in a person is mutated in some way or other. The claim is that it is this accumulation of mtDNA mutations across the body plus the inherited component from the person's mother and, importantly, from the mutations accumulated in the mother's egg cell during her life prior to giving birth to the person in question, that causes the deterioration of the body.
The paper focuses a lot on Parkinson's and Alzheimer's disease, understandable since the first author is a neurologist. This made it harder for me to read as a "theory of aging" since I know almost nothing about either and Parkinson's is a relatively rare disease.
A lot of the arguments for why the primary cause should be in mtDNA or in DNA are similar to de Grey's arguments in de Grey's arguments in his version of the mitochondrial theory of aging so I will skip those. There are major differences in the details so I'll concentrate on those.
Low levels of lots of different mutations in the mtDNA (microheteroplasmy) are different from the uniform per-cell mutations of de Grey's. Its existence is much harder to detect but other studies supposedly show such microheteroplasmy exists in all tissue and increases with age, from about 45 mutations per million base pairs at birth to about 200 per million in old age (with a high starting level in the substantia nigra). Each mutation is usually only present in 1-2% of mtDNA across tissue but up to 10-20% in single cells. By calculations, based on a low estimate of mutation rate, 90% of mitochondrial genomes have a mutation somewhere important. Based on a high estimate of mutation rate, there are on average 3 mutations per mitochondrial genome. These numbers are very different from the usual numbers quoted and this is due to the trickiness of detecting microheteroplasmy (ie they are not detected at all by the usual methods of sequencing mtDNA) they say. Their referencing of reports of low levels of different types of mutations leading to high levels of mutations overall in sequencing of single neurons and glia are also at odds with the one mutational mtDNA taking over the cell's mitochondria that de Grey tends to reference.
The suggested mechanism of action is only in small part by causing insufficient amounts of ATP to be produced in the cell, but mainly by increasing reactive oxygen species (ROS) production to levels that damage the cell and/or drive it into senescence or apoptosis, with a possible feedback mechanism involved. They also postulate that even post-mitotic cells are regularly killed and replaced by cells derived from stem cells, and that accumulation of microheteroplasmy in the stem cells would lead to quicker reaching of the threshold amount of mutations in the derived cells needed for it to stop functioning properly (due to the above-mentioned mechanism). Overall though, the paper doesn't focus on the mechanism of action and does not rule out a different mechanism of action that would not go through ROS. In private communications with the first author, who gracefully supplied me with a copy of the paper and comments (Thanks Rafal), he mentioned he would downplay the effect of ROS on causing microheteroplasmy nowadays.
The paper has a long list of supporting evidence, but most of it seems quite tenuous. The strongest seems to be the case for Parkinson's disease correlating with mutations in a particular region of the mtDNA, which showed good predictive results in a small study. They mention correlations between Alzheimer's and complex IV dysfunction; cybrid models of both Parkinson's and Alzheimer's producing disease-specific responses (cybrids are hybrids of healthy cells without mitochondria fused with mitochondria from disease patients); faulty mitochondria in relatives and offspring of diabetes patients; oxidative stress and inheritance patterns in hypertension; glycolysis and cancer; metastasis in cancer as being a side-effect of old evolutionary reaction of the cell switching away from mitochondrial respiration as a source of power (due to mutated mtDNA).
The paper describes a particular type of mutation that they call focal microheteroplasmy, where a particular mutation becomes prevalent throughout a person due to it having originated during the mother's life prior to giving birth. While this mutation would be prevalent in the person's tissue, it would be completely different from other people in the family, even identical twins, who would have inherited a different half of the mitochondria. This mechanism is used as a partial explanation of the pattern of inheritance seen in certain diseases (eg Parkinson's and Alzheimer's).
The paper has an interesting list of corollaries/predictions of its hyptothesis:
- Focal microheteroplasmy in Parkinson's, Alzheimer's, diabetes and hypertension.
- Locations of the mutations in focal microheteroplasmy to be more detrimental than other locations of microheteroplasmy or of homoplasmic mutations.
- Accumulation rate of microheteroplasmy to be modulated by level of ROS.
- Menopause caused by microheteroplasmy, and trisomy 21 to protect the cell from microheteroplasmic-induced apoptosis
- Therapeutic interventions hammering secondary responses (eg amyloid in Alzheimer's) to be harmful
- Replacement of mitochondrial genomes to reverse many symptoms of aging
Overall, I'm not particularly fond of the mechanism of action being mainly down to ROS action. The predictions are quite good though, and if microheteroplasmy is as prevalent as stated then it should become quite clear shortly with the amount and variety of sequencing going on nowadays.
Tuesday, February 5, 2013
Extension of Murine Life Span by Overexpression of Catalase Targeted to Mitochondria
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).
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).
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.
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