By the abstracts:
"Targeting Telomerase". Review of techniques and issues regarding hammering telomerase as an anti-cancer treatment, and whether that would select for ALT-cancers (ALT constitute 10-15% of cancers atm). Of note, the existence of a TERT vaccine.
"Telomere and TRF2/MTBP Localization in Respect to Satellite DNA During the Cell Cycle of Mouse Cell Line L929" About what happens to telomeres as the cells goes through its cycle in mice. Mostly goes over my head.
"Werner Syndrome as an Example of Inflamm-aging: Possible Therapeutic Opportunities for a Progeroid Syndrome?" Title is a good summary of the abstract.
"Stimulation of Macroautophagy Can Rescue Older Cells from 8-OHdG mtDNA Accumulation: A Safe and Easy Way to Meet Goals in the SENS Agenda" They stimulate macroautophagy by injecting agents that stop the breakdown of triglycerides in rat liver cells. This gets rid of 8-OHdG accumulation in the mtDNA in six hours.
Also, a report on SENS 2 by Aubrey de Grey that I'd like to read.
Overall, I don't mind as much not having access to the articles in this issue.
Monday, February 10, 2014
Cryopreservation of Complex Systems: The Missing Link in the Regenerative Medicine Supply Chain
Interestingness: 6
By Gregory M. Fahy, Brian Wowk, and Jun Wu. Rejuvenation Research. Summer 2006, 9(2): 279-291. doi:10.1089/rej.2006.9.279.
They pump the idea of using cryogenics to store pre-produced organs for use in transplants. They start with some interesting numbers regarding yearly US deaths that could be prevented if there were available organs:
in total forming 36.2% of all yearly US deaths. They seem to be assigning all heart disease deaths as solvable by a heart transplant, etc. They also have a corresponding graph showing survival curves (ie age vs percentage alive) for status quo vs with those transplants, assuming no deaths during the transplants, with the transplant curve really diverging after 70 years of age with the transplant survival to status quo survival ratio of two at 80 and of 18 at 90. I don't know why they chose to show numbers that are so clearly not conservative.
They see cryopreservation as a necessary tool to manage the supply chain of organs manufactured through regenerative medicine to make mass organ availability viable. This is seen by them as the interim solution until in-situ recreation of the organ becomes a possibility.
They then describe a brief history of the cryopreservation of organs by straight freezing:
They claim straight-freezing of vital organs won't work because the vascular system is too easily damaged by freezing. This leads to methods that try to avoid freezing damage by avoiding ice formation.
In 1965, red blood cells and guinea pig uteri were lowered to -79C by lowering the freezing point of water and keeping it liquid all the way to the target temperature. Then in the 1980s, vitrification experiments started where the material is cooled into a glass without forming ice, starting with the vitrification of mouse embryos in 1985.
Experiments with vitrifications suggest that toxicity of cryoprotectant is due to reduced water availability for biomolecules. "Winner" of the cryoprotectants is M22 which seems to be used only below -22C with some other cryoprotectant (VMP) used to go from room temperature to -22C. Not much idea of what M22 consists of but it has a carrier solution that is meant to lower the toxicity combined with many anti-nucleating substances.
When ten rabbit kidneys were cooled to -22C, M22ised, deM22ised and rewarmed, then transplanted into rabbits, all rabbits survived (the non-cooled kidney is extracted in the experiments to make sure that the rabbits depend on the transplanted kidney), but there is more injury to the M22-ised kidneys than what is seen when just cooling them to -3C with VMP. Eight rabbit kidneys taken to -50C using M22 seem fine once rewarmed/deM22ised. Extra injury in M22-ised kidneys might be due to extra handling or extra time at cold temperature.
Newest experiment (2005) does the same rabbit kidney vitrification and transplantation on one rabbit with the rabbit surviving for 48 days after transplantation before it is killed. The cryoprotected kidney is cooled to below the glass transition temperature for M22 (-123C). Lots of damage to the kidney on this one, with hints that more even perfusion is needed.
By Gregory M. Fahy, Brian Wowk, and Jun Wu. Rejuvenation Research. Summer 2006, 9(2): 279-291. doi:10.1089/rej.2006.9.279.
They pump the idea of using cryogenics to store pre-produced organs for use in transplants. They start with some interesting numbers regarding yearly US deaths that could be prevented if there were available organs:
- Heart 710,760
- Lung 122,009
- Kidney 37,251
- Liver 16,214
in total forming 36.2% of all yearly US deaths. They seem to be assigning all heart disease deaths as solvable by a heart transplant, etc. They also have a corresponding graph showing survival curves (ie age vs percentage alive) for status quo vs with those transplants, assuming no deaths during the transplants, with the transplant curve really diverging after 70 years of age with the transplant survival to status quo survival ratio of two at 80 and of 18 at 90. I don't know why they chose to show numbers that are so clearly not conservative.
They see cryopreservation as a necessary tool to manage the supply chain of organs manufactured through regenerative medicine to make mass organ availability viable. This is seen by them as the interim solution until in-situ recreation of the organ becomes a possibility.
They then describe a brief history of the cryopreservation of organs by straight freezing:
- 1950s - Freezing of guinea pig uteri to dry ice temperature (< -79C) and back. Contractile responses in vitro.
- 1973 - Freezing of dog intestines to liquid nitrogen temperature (< -196C). Long term survival of small parts of it.
- 2002 - Freezing of rat ovaries. Survival of some and offspring in one after transplantation back into rats. They say this is not a good test since the ovaries can regenerate even if completely screwed up.
- 2003 - Freezing of sheep ovaries. Vascular patency (unobstructed) retained in 3 of 11 grafts and follicle-stimulating hromone levels kept to normal limits. Second report claiming higher patency rates using directional freezing.
They claim straight-freezing of vital organs won't work because the vascular system is too easily damaged by freezing. This leads to methods that try to avoid freezing damage by avoiding ice formation.
In 1965, red blood cells and guinea pig uteri were lowered to -79C by lowering the freezing point of water and keeping it liquid all the way to the target temperature. Then in the 1980s, vitrification experiments started where the material is cooled into a glass without forming ice, starting with the vitrification of mouse embryos in 1985.
Experiments with vitrifications suggest that toxicity of cryoprotectant is due to reduced water availability for biomolecules. "Winner" of the cryoprotectants is M22 which seems to be used only below -22C with some other cryoprotectant (VMP) used to go from room temperature to -22C. Not much idea of what M22 consists of but it has a carrier solution that is meant to lower the toxicity combined with many anti-nucleating substances.
When ten rabbit kidneys were cooled to -22C, M22ised, deM22ised and rewarmed, then transplanted into rabbits, all rabbits survived (the non-cooled kidney is extracted in the experiments to make sure that the rabbits depend on the transplanted kidney), but there is more injury to the M22-ised kidneys than what is seen when just cooling them to -3C with VMP. Eight rabbit kidneys taken to -50C using M22 seem fine once rewarmed/deM22ised. Extra injury in M22-ised kidneys might be due to extra handling or extra time at cold temperature.
Newest experiment (2005) does the same rabbit kidney vitrification and transplantation on one rabbit with the rabbit surviving for 48 days after transplantation before it is killed. The cryoprotected kidney is cooled to below the glass transition temperature for M22 (-123C). Lots of damage to the kidney on this one, with hints that more even perfusion is needed.
Monday, February 3, 2014
Issue 2, 2006
This issue is the second part of the papers presented in SENS 2005. By the abstracts:
Section 5: Mitochondria and Oxidative Damage
"Extracellular Redox State: Refining the Definition of Oxidative Stress in Aging" suggests that blood glutathione/glutathione disulfide ratio does not equilibrate with blood cysteine/cystine ratio, that the latter is not just a diagnostic but that it affects cell proliferation and oxidant-induced apoptosis, and that both ratios are good controlling indicators of oxidative stress. Or something like that, I haven't done this for a while and seem to have lost the knack. Lots of citations for this one.
"Factors That Might Affect the Allotopic Replacement of a Damaged Mitochondrial DNA-Encoded Protein". Review of successful allotopic expression of mitochondrial genes ported to the nuclear DNA and possible issues with getting those proteins into the inner membrane of the mitochondria. Sounds interesting.
"Can a Single Subunit Yeast NADH Dehydrogenase (Ndi1) Remedy Diseases Caused by Respiratory Complex I Defects?" They introduced NDi1, which transfers electrons from NADH to ubiquinone in yeast, into mammalian cells, some missing Complex 1. NDi1 inserted itself into the inner membrane of mitochondria and rescued the cells that were lacking Complex 1. They got it working on mice muscles and brains. Interesting.
"Protective Efficacy of α-Lipoic Acid on Acetylcholinesterase Activity in Aged Rat Brain Regions". Pumped alpha-lipoic acid into old rats, saw acetylcholinesterase levels restored in some parts of their brain.
"Cytochemical Estimation of Cytochrome Oxidase Activity as a Morphofunctional Mitochondrial Check-Up". They propose that measuring the ratio of cytochemical precipitate to mitochondrial area would give a good indication of mitochondrial function since the ratio decreased by 25% with aging.
"From Disease-Oriented to Aging/Longevity-Oriented Studies". Not sure what this is. Abstract sounds like the general aging IS a disease drive, with a focus on epigenetics, but hard to tell. Quite a few citations.
"Tissue-Specific Effect of Age and Caloric Restriction Diet on Mitochondrial DNA Content". CR reversed the drop in mtDNA in old rat livers and leg muscles, and increased the mtDNA of the brain, even though there is no drop there in ad-libitum rats.
"Testing Mitochondrial Metabolic Competence by Cytochrome Oxidase Preferential Cytochemistry Versus Immunoreactivity of Subunits I and IV". COX activity dropped with age in rats but not levels of two of its subunits.
"Caloric Restriction Protects Mitochondrial Function with Aging in Skeletal and Cardiac Muscles" 25 to 46% drop in oxidative capacity markers for ad-libitum-fed 'animals' (who knows what animals). None for CR. A lot of citations.
"Mitochondrial Genome Anatomy and Species-Specific Lifespan" Maximum lifespan is correlated with amount of cytosine in the DNA of mammal species, especially for primates. Vaguely interesting.
"Relationship Between Aging and Susceptibility of Erythrocytes to Oxidative Damage: In View of Nutraceutical Interventions". Placebo-controlled study feeding fermented papaya preparation to old people. Rescued abnormal higher concentration of nitric oxide synthase and malondialdehyde (a marker for oxidative stress) in red blood cells of old people compared to young people.
"Aging-Related Cell Surface ECTO-NOX Protein, arNOX, a Preventive Target to Reduce Atherogenic Risk in the Elderly". Cell-surface electron-transport protein associated with aging that can produce superoxide and thus oxidise circulating lipoproteins.
Section 6: Molecular Crosslinking and Aggregation
"Emerging Strategies for the Treatment of Hereditary Metabolic Storage Disorders" looks at solutions other than enzyme replacement for Gaucher and Fabry disease, which are diseases caused by mutations to enzymes that break down the stuff left over when senescent cells die.
"Advanced Atherosclerotic Foam Cell Formation Has Features of an Acquired Lysosomal Storage Disorder". Reviews the evidence for the foam cells in atherosclerosis to be due to an acquired lysosomal storage disorder. That is, the lysosomes are failing to break down what is sent to them so the material acumulates in the cell. Quite a few citations for this one.
"Indirect Antioxidant Protection Against Photooxidative Processes Initiated in Retinal Pigment Epithelial Cells by a Lipofuscin Pigment". Claims lipofuscin A2E triggers oxidation damage in retinal epithelial cells and is protected from this by glutathione and sulforaphane.
"Prevention and Repair of Protein Damage by the Maillard Reaction In Vivo". Equivalence between Maillard recation and advanced glycation end products (AGEs). 20 AGEs in human skin. No evidence of AGE breakers of breaking crosslinks in vivo. Maybe interesting, at least to learn about AGEs.
"Extracellular Glycation Crosslinks: Prospects for Removal". Two proposed methods of getting rid of glucosepane and K2P crosslinks. One is upping extracellular matrix turnover. A second one is high-throughput screening for molecules that can break those two down.
Section 7: Miscellaneous
"Cryopreservation of Complex Systems: The Missing Link in the Regenerative Medicine Supply Chain". On the potential use of vitrification to store organs, created through regenerative medicine, for transplanting when necessary. Claims routine recovery of vitrified rabbit kidneys cooled to -45 degrees celsius functioning properly after rewarming and being transplanted back into rabbits. Found the article. Might write one for it.
"Cryptobiosis, Aging, and Cancer: Yin-Yang Balancing of Signaling Networks". Aging as unbalanced complex signaling pathways.
"The Neurosecretory System Is Hypertrophied in Senescence-Accelerated Mice". Analysis of the neurosecretory system of senescence-accelerated mice.
"Natural Background Radioactive Carbon and the Natural Death Rate of People". Correlation between levels of carbon-14 in the atmosphere and death rates over the last 150 years. Notable mainly because the author's organisation is given as 'independent researcher'. Didn't think that was possible in this century.
"Radiocarbon Mechanism of Aging". More on carbon-14 and death rates by independent researchers, offering a mechanism of aging by carbon-14.
"Variations of Humans' Natural Death Rate and the Radiocarbon Aging Mechanism". More carbon-14 and mortality.
"Statistical Issues of Regression Analysis on Development of an Age-Predictive Equation". Equations to predict age from physical fitness measurements training on 31 Japanese males.
"Soft Strategies for Postponing Aging and Prolonging Human Life". Postponing aging by looking at things that cause discomfort and stopping things from becoming major.
"Psychosocial Aspects and Zinc Status: Is There a Relationship with Successful Aging?". Low albumin, as indicator for zinc, correlated with higher levels of depression in old Italians.
"Liver Exposure to Xenobiotics: The Aging Factor and Potentials for Functional Foods". Study on liver cells from young and old rats cultured with and without alpha-linolenic acid and given YHK (a herbal supplement I'd never heard of) or sylibin. They then gave them copper and iron. YHK did better at some things.
"The Aging Gut Motility Decay: May Symbiotics Be Acting as "Implantable" Biologic Pace-Makers?" Symbiotic (I don't know what that is) SCM-III (also no idea) does something to old rats' colons and jejunum.
"How Evolutionary Thinking Affects People's Ideas About Aging Interventions". From a person that belong to the group that think that aging is an evolutionarily programmed response. Mentions apoptosis and senescence via telomere shortening as behaviours that seem to shorten lifespan. Also, NSAIDs slowing arthritis, cancer and atherosclerosis as evidence for inflammation as programmed autoimmune response.
"Zinc Homeostasis in Aging: Two Elusive Faces of the Same 'Metal'". Aging creates zinc dyshomeostasis, not zinc deficiency.
"Aging and Oral Health Related to Quality of Life in Geriatric Patients". Survey of 53 70-year old Bulgarians regarding reasons they go to the dentist. 32% for acute pain and the rest for caries.
"Is Thrombolytic Therapy Effective in Elderly Patients?". Clinical (single-arm?) study doing thrombolytic therapy on 103 heart attacked people over 75. They say it had a positive effect.
"Negligible Senescence: How Will We Know It When We See It?". Suggests the use of global index of aging rate as units of functional change per time.
Section 5: Mitochondria and Oxidative Damage
"Extracellular Redox State: Refining the Definition of Oxidative Stress in Aging" suggests that blood glutathione/glutathione disulfide ratio does not equilibrate with blood cysteine/cystine ratio, that the latter is not just a diagnostic but that it affects cell proliferation and oxidant-induced apoptosis, and that both ratios are good controlling indicators of oxidative stress. Or something like that, I haven't done this for a while and seem to have lost the knack. Lots of citations for this one.
"Factors That Might Affect the Allotopic Replacement of a Damaged Mitochondrial DNA-Encoded Protein". Review of successful allotopic expression of mitochondrial genes ported to the nuclear DNA and possible issues with getting those proteins into the inner membrane of the mitochondria. Sounds interesting.
"Can a Single Subunit Yeast NADH Dehydrogenase (Ndi1) Remedy Diseases Caused by Respiratory Complex I Defects?" They introduced NDi1, which transfers electrons from NADH to ubiquinone in yeast, into mammalian cells, some missing Complex 1. NDi1 inserted itself into the inner membrane of mitochondria and rescued the cells that were lacking Complex 1. They got it working on mice muscles and brains. Interesting.
"Protective Efficacy of α-Lipoic Acid on Acetylcholinesterase Activity in Aged Rat Brain Regions". Pumped alpha-lipoic acid into old rats, saw acetylcholinesterase levels restored in some parts of their brain.
"Cytochemical Estimation of Cytochrome Oxidase Activity as a Morphofunctional Mitochondrial Check-Up". They propose that measuring the ratio of cytochemical precipitate to mitochondrial area would give a good indication of mitochondrial function since the ratio decreased by 25% with aging.
"From Disease-Oriented to Aging/Longevity-Oriented Studies". Not sure what this is. Abstract sounds like the general aging IS a disease drive, with a focus on epigenetics, but hard to tell. Quite a few citations.
"Tissue-Specific Effect of Age and Caloric Restriction Diet on Mitochondrial DNA Content". CR reversed the drop in mtDNA in old rat livers and leg muscles, and increased the mtDNA of the brain, even though there is no drop there in ad-libitum rats.
"Testing Mitochondrial Metabolic Competence by Cytochrome Oxidase Preferential Cytochemistry Versus Immunoreactivity of Subunits I and IV". COX activity dropped with age in rats but not levels of two of its subunits.
"Caloric Restriction Protects Mitochondrial Function with Aging in Skeletal and Cardiac Muscles" 25 to 46% drop in oxidative capacity markers for ad-libitum-fed 'animals' (who knows what animals). None for CR. A lot of citations.
"Mitochondrial Genome Anatomy and Species-Specific Lifespan" Maximum lifespan is correlated with amount of cytosine in the DNA of mammal species, especially for primates. Vaguely interesting.
"Relationship Between Aging and Susceptibility of Erythrocytes to Oxidative Damage: In View of Nutraceutical Interventions". Placebo-controlled study feeding fermented papaya preparation to old people. Rescued abnormal higher concentration of nitric oxide synthase and malondialdehyde (a marker for oxidative stress) in red blood cells of old people compared to young people.
"Aging-Related Cell Surface ECTO-NOX Protein, arNOX, a Preventive Target to Reduce Atherogenic Risk in the Elderly". Cell-surface electron-transport protein associated with aging that can produce superoxide and thus oxidise circulating lipoproteins.
Section 6: Molecular Crosslinking and Aggregation
"Emerging Strategies for the Treatment of Hereditary Metabolic Storage Disorders" looks at solutions other than enzyme replacement for Gaucher and Fabry disease, which are diseases caused by mutations to enzymes that break down the stuff left over when senescent cells die.
"Advanced Atherosclerotic Foam Cell Formation Has Features of an Acquired Lysosomal Storage Disorder". Reviews the evidence for the foam cells in atherosclerosis to be due to an acquired lysosomal storage disorder. That is, the lysosomes are failing to break down what is sent to them so the material acumulates in the cell. Quite a few citations for this one.
"Indirect Antioxidant Protection Against Photooxidative Processes Initiated in Retinal Pigment Epithelial Cells by a Lipofuscin Pigment". Claims lipofuscin A2E triggers oxidation damage in retinal epithelial cells and is protected from this by glutathione and sulforaphane.
"Prevention and Repair of Protein Damage by the Maillard Reaction In Vivo". Equivalence between Maillard recation and advanced glycation end products (AGEs). 20 AGEs in human skin. No evidence of AGE breakers of breaking crosslinks in vivo. Maybe interesting, at least to learn about AGEs.
"Extracellular Glycation Crosslinks: Prospects for Removal". Two proposed methods of getting rid of glucosepane and K2P crosslinks. One is upping extracellular matrix turnover. A second one is high-throughput screening for molecules that can break those two down.
Section 7: Miscellaneous
"Cryopreservation of Complex Systems: The Missing Link in the Regenerative Medicine Supply Chain". On the potential use of vitrification to store organs, created through regenerative medicine, for transplanting when necessary. Claims routine recovery of vitrified rabbit kidneys cooled to -45 degrees celsius functioning properly after rewarming and being transplanted back into rabbits. Found the article. Might write one for it.
"Cryptobiosis, Aging, and Cancer: Yin-Yang Balancing of Signaling Networks". Aging as unbalanced complex signaling pathways.
"The Neurosecretory System Is Hypertrophied in Senescence-Accelerated Mice". Analysis of the neurosecretory system of senescence-accelerated mice.
"Natural Background Radioactive Carbon and the Natural Death Rate of People". Correlation between levels of carbon-14 in the atmosphere and death rates over the last 150 years. Notable mainly because the author's organisation is given as 'independent researcher'. Didn't think that was possible in this century.
"Radiocarbon Mechanism of Aging". More on carbon-14 and death rates by independent researchers, offering a mechanism of aging by carbon-14.
"Variations of Humans' Natural Death Rate and the Radiocarbon Aging Mechanism". More carbon-14 and mortality.
"Statistical Issues of Regression Analysis on Development of an Age-Predictive Equation". Equations to predict age from physical fitness measurements training on 31 Japanese males.
"Soft Strategies for Postponing Aging and Prolonging Human Life". Postponing aging by looking at things that cause discomfort and stopping things from becoming major.
"Psychosocial Aspects and Zinc Status: Is There a Relationship with Successful Aging?". Low albumin, as indicator for zinc, correlated with higher levels of depression in old Italians.
"Liver Exposure to Xenobiotics: The Aging Factor and Potentials for Functional Foods". Study on liver cells from young and old rats cultured with and without alpha-linolenic acid and given YHK (a herbal supplement I'd never heard of) or sylibin. They then gave them copper and iron. YHK did better at some things.
"The Aging Gut Motility Decay: May Symbiotics Be Acting as "Implantable" Biologic Pace-Makers?" Symbiotic (I don't know what that is) SCM-III (also no idea) does something to old rats' colons and jejunum.
"How Evolutionary Thinking Affects People's Ideas About Aging Interventions". From a person that belong to the group that think that aging is an evolutionarily programmed response. Mentions apoptosis and senescence via telomere shortening as behaviours that seem to shorten lifespan. Also, NSAIDs slowing arthritis, cancer and atherosclerosis as evidence for inflammation as programmed autoimmune response.
"Zinc Homeostasis in Aging: Two Elusive Faces of the Same 'Metal'". Aging creates zinc dyshomeostasis, not zinc deficiency.
"Aging and Oral Health Related to Quality of Life in Geriatric Patients". Survey of 53 70-year old Bulgarians regarding reasons they go to the dentist. 32% for acute pain and the rest for caries.
"Is Thrombolytic Therapy Effective in Elderly Patients?". Clinical (single-arm?) study doing thrombolytic therapy on 103 heart attacked people over 75. They say it had a positive effect.
"Negligible Senescence: How Will We Know It When We See It?". Suggests the use of global index of aging rate as units of functional change per time.
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