Interestingness:5
By Robert Arking and Craig Giroux in the Journal of Anti-Aging Medicine, June 2001, pp125-136. doi:10.1089/10945450152466170.
It didn't end up being as interesting as expected, since they skipped/assumed the question of the effect of late-life mortality deceleration or even decrease being real in humans. They mostly work on fruit flies, and that's where most of their data comes from.
I still find overarching theories interesting though, so it was a decent read, even though there isn't much more there to summarise than what was on the abstract.
Their hypothesis can be summarised as follows: there are some stressors that will kick what they call the antioxidant defense system (ADS) and heat shock proteins (hsps) into action and will wipe some "aging" off the body, thus leading to lower mortality. This activation is semi-locked by an epigenetic mechanism, thus leading to a clustering of people with lower mortality separate from the main cluster. They hypothesis that testing young people to see whose ADS get upregulated easiest will tell you which people will leave longer.
One big issue with the paper for me is their evidence that upregulated ADS and hsps lead to longer lifespan. Their data is from fruit flies, but they mention mice, in which just upregulating CuZnSOD (superoxide dismutase) doesn't lead to longer lifespan. In mice, they go by the suggestion that since calorie-restricted mice have upregulated CuZnSOD and catalase, that these two are important reasons of the lifespan extension. I suspect the situation in humans to be even fuzzier.
Another bit of the paper I found interesting is at the beginning where they list possible theories for the decelerated/decreased mortality effect: one, that this is just part of the aging process; second, that this is a predicted effect of the reliability theory I'm fond of by the Gavrilovs (I find these two explanations to be compatible), and third, that the population is genetically heterogenous, so each subsection would have its own Gompertz gradient.
Showing posts with label 5. Show all posts
Showing posts with label 5. Show all posts
Tuesday, February 7, 2012
Sunday, January 15, 2012
When Does Human Longevity Start?: Demarcation of the Boundaries for Human Longevity
Interestingness:5
By Natalia S. Gavrilova and Leonid A. Gavrilov. Journal of Anti-Aging Medicine. June 2001, 4(2): 115-124. doi:10.1089/10945450152466161.
More Gavrilovs. This one is another paper where they continue to extract results from the historical records of the european aristocracy from the 1600s onwards. In this one, they focus on the period 1800-1880s so as to have complete data for women (recent records are more complete) but also to make sure everyone in it is dead.
They analyse longevity of 5800 daughters that made it to adulthood (30 years) compared to longevity of their mothers and fathers (separately). They avoid sons due to frequent military deaths. They find almost no correlation if the mother died before 85 years of age, but strong correlation otherwise, with a line of best fit with a slope of 0.412±0.204. Similarly for the father, with no correlation if he died before 75 years of age, but a strong correlation with a slope of 0.236±0.078 otherwise. They don't show results with a combined mother plus father variable. The graphs are quite nice.
There's something somewhat dodgy about the method since they were looking for a piecewise linear regression, and they determined where to start the significant line by inspecting the graph visually. I don't know how much that detracts from the result.
Like they mention, this does "resolve" the contradictions found where some research says that the genetic component of longevity is small, while others show that people with very old age are bunched in families.
By Natalia S. Gavrilova and Leonid A. Gavrilov. Journal of Anti-Aging Medicine. June 2001, 4(2): 115-124. doi:10.1089/10945450152466161.
More Gavrilovs. This one is another paper where they continue to extract results from the historical records of the european aristocracy from the 1600s onwards. In this one, they focus on the period 1800-1880s so as to have complete data for women (recent records are more complete) but also to make sure everyone in it is dead.
They analyse longevity of 5800 daughters that made it to adulthood (30 years) compared to longevity of their mothers and fathers (separately). They avoid sons due to frequent military deaths. They find almost no correlation if the mother died before 85 years of age, but strong correlation otherwise, with a line of best fit with a slope of 0.412±0.204. Similarly for the father, with no correlation if he died before 75 years of age, but a strong correlation with a slope of 0.236±0.078 otherwise. They don't show results with a combined mother plus father variable. The graphs are quite nice.
There's something somewhat dodgy about the method since they were looking for a piecewise linear regression, and they determined where to start the significant line by inspecting the graph visually. I don't know how much that detracts from the result.
Like they mention, this does "resolve" the contradictions found where some research says that the genetic component of longevity is small, while others show that people with very old age are bunched in families.
Monday, December 6, 2010
Mitochondrial DNA Oxidation
Summary: Most of the oxidising damage in mitochondrial DNA (mtDNA) is in bits/fractions of mtDNA, not in the circular form. And iron relaxes mtDNA loop and increases its replication.
Interestingness: 5
Paper by Christoph Richter in the Journal of Anti-Aging Medicine, Volume 2, Issue 3, Fall 1999.
(((
This paper starts by describing how mtDNA gets oxidised: superoxide radicals (O2-) are formed "when cytochrome oxidase is blocked, when cytochrome c is detached from the inner mitochondrial membrane, " ... and " when mitochondrial oxidative phosphorylation is inhibited". The superoxide radical then gives the electron to a water molecule, which forms hydrogen peroxide (H2O2), which then forms hydroxyl radical (OH.) in the presence of iron or copper (Fenton reaction). The hydroxyl radical is the bastard that then goes and reacts with everything.
It then mentions radical nitrogen species, usual description of mtDNA (16.3 kb pair coding for 13 peptides, 22 tRNAs and 2 rRNAs), how people started thinking of mtDNA damage as important for diseases, measurement of mtDNA damage (usually measuring 8-hydroxyguanine and strand breaks), sidetrack into azidothymidine (AZT, the anti-AIDS drug) causing problems in mitochondria, and Friedreich's ataxia (FA) probably being a problem with oxidation damage in mitochondria.
Now, interesting bit, measurements of amount of oxidative damage in mtDNA differ depending on methodology. Detection of 8-hydroxydeoxyguanosine (8-OHdG) gives big numbers (4 modifications per mtDNA molecule) while numbers from repair enzymes (dunno how it works) give much lower numbers. High number doubted also from seemingly high number of working mitochondria. They do analysis of mtDNA from rat's livers, detecting 8-OHdG. They get 0.051 picomole per microgram of DNA for circular mtDNA, which they say is about one 8-OHdG mutation every two mtDNA molecules, 0.014 picomole per microgram of DNA for nDNA, which is contamination in the sample, but 0.741 picomole per microgram in low molecular mtDNA, ie fractions of floating mtDNA. They don't know what the fractions of mtDNA are doing or why they are so highly oxidised. It could be that they are being actively degraded, or they could be new chunks being made. Having found these fragments, he then hypothesises that these fragments integrate with nDNA, and that this is the main mechanism of aging of mtDNA oxidation damage.
The part that follows is also interesting. Experimenting with iron overload into the mtDNA of rat's livers in vitro they find that it (iron, in the form of Fe3+ gluconate), relaxes mtDNA from the standard supercoiled form to the open circular form. Anti-oxidants prevent some of the change but not all. The iron forms colloids that bind to mtDNA, and there may be a purely physical mechanism of relaxation. They then repeat the experiment in vivo also observing more relaxed circular DNA compared to controls, as well as increased mitochondrial surface and volume density, increased intracellular ferritin and hemosiderin, and higher replication of mtDNA.
It then switches to mtDNA damage prevention, mentions caloric restriction as reducing 8-OHdG counts, AZT leading to higher urinary 8-OHdG but vitamins C and E reducing those levels in AZT-taking people (I thought vitamins C and E didn't enter the mitochondria). Finishes by looking at future studies, evidence that mtDNA inserts in nDNA are more common in tumours, Drosophila overexpressing superoxide dismutase and catalase having increased lifespan, and some wacky suggestion of using bacteria to transfect genes into mitochondria.
)))
Abstract follows:
Interestingness: 5
Paper by Christoph Richter in the Journal of Anti-Aging Medicine, Volume 2, Issue 3, Fall 1999.
(((
This paper starts by describing how mtDNA gets oxidised: superoxide radicals (O2-) are formed "when cytochrome oxidase is blocked, when cytochrome c is detached from the inner mitochondrial membrane, " ... and " when mitochondrial oxidative phosphorylation is inhibited". The superoxide radical then gives the electron to a water molecule, which forms hydrogen peroxide (H2O2), which then forms hydroxyl radical (OH.) in the presence of iron or copper (Fenton reaction). The hydroxyl radical is the bastard that then goes and reacts with everything.
It then mentions radical nitrogen species, usual description of mtDNA (16.3 kb pair coding for 13 peptides, 22 tRNAs and 2 rRNAs), how people started thinking of mtDNA damage as important for diseases, measurement of mtDNA damage (usually measuring 8-hydroxyguanine and strand breaks), sidetrack into azidothymidine (AZT, the anti-AIDS drug) causing problems in mitochondria, and Friedreich's ataxia (FA) probably being a problem with oxidation damage in mitochondria.
Now, interesting bit, measurements of amount of oxidative damage in mtDNA differ depending on methodology. Detection of 8-hydroxydeoxyguanosine (8-OHdG) gives big numbers (4 modifications per mtDNA molecule) while numbers from repair enzymes (dunno how it works) give much lower numbers. High number doubted also from seemingly high number of working mitochondria. They do analysis of mtDNA from rat's livers, detecting 8-OHdG. They get 0.051 picomole per microgram of DNA for circular mtDNA, which they say is about one 8-OHdG mutation every two mtDNA molecules, 0.014 picomole per microgram of DNA for nDNA, which is contamination in the sample, but 0.741 picomole per microgram in low molecular mtDNA, ie fractions of floating mtDNA. They don't know what the fractions of mtDNA are doing or why they are so highly oxidised. It could be that they are being actively degraded, or they could be new chunks being made. Having found these fragments, he then hypothesises that these fragments integrate with nDNA, and that this is the main mechanism of aging of mtDNA oxidation damage.
The part that follows is also interesting. Experimenting with iron overload into the mtDNA of rat's livers in vitro they find that it (iron, in the form of Fe3+ gluconate), relaxes mtDNA from the standard supercoiled form to the open circular form. Anti-oxidants prevent some of the change but not all. The iron forms colloids that bind to mtDNA, and there may be a purely physical mechanism of relaxation. They then repeat the experiment in vivo also observing more relaxed circular DNA compared to controls, as well as increased mitochondrial surface and volume density, increased intracellular ferritin and hemosiderin, and higher replication of mtDNA.
It then switches to mtDNA damage prevention, mentions caloric restriction as reducing 8-OHdG counts, AZT leading to higher urinary 8-OHdG but vitamins C and E reducing those levels in AZT-taking people (I thought vitamins C and E didn't enter the mitochondria). Finishes by looking at future studies, evidence that mtDNA inserts in nDNA are more common in tumours, Drosophila overexpressing superoxide dismutase and catalase having increased lifespan, and some wacky suggestion of using bacteria to transfect genes into mitochondria.
)))
Abstract follows:
Mitochondrial diseases have been known for more than three decades. A refinement of the free radical theory of aging states that oxidative damage to mitochondria, particularly to mitochondrial DNA (mtDNA), is responsible for aging. About 10 years ago, oxidative damage to mtDNA was first reported, and human diseases were related to mutations of mtDNA. Subsequent reports suggested that oxidative mtDNA damage is more pronounced in old individuals and during certain diseases. Studies of animal models indicated that oxidative mtDNA damage can be ameliorated by dietary antioxidants and caloric restriction, an established method to increase life span. More recent data indicate that fragmented mtDNA is the predominant carrier of oxidized mtDNA bases and that fragments constitute a substantial amount of the total mtDNA. This article discusses the emerging relationship among mtDNA oxidation, diseases, and aging, and suggests experiments by which such a relationship can be further substantiated.
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