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.
Sunday, March 31, 2013
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.
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