RNA Oxidation in Alzheimer and Parkinson Diseases

Summary: RNA is oxidised in some of Alzheimer's, Parkinson's and Down syndrome patients' neurons

Interestingness: 2

Paper by Akihiko Nunomura, George Perry, Jing Zhang, Thomas J Montine, Atsushi Takeda, Shigeru Chiba and Mark A Smith in the Journal of Anti-Aging Medicine, Volume 2, Issue 3, Fall 1999.

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They measured 8-hydroxydeoxyguanosine (8-OHdG) and 8-hydroxyguanosine (8-OHG) as markers for DNA and RNA oxidation respectively in an unknown number of brains of postmortem Alzheimer's (AD), Parkinson's (PD) and Down syndrome (DS) patients. They found more 8-OHG in some parts of the brains of some types of disease, and less in others, but the parts of the brain still don't mean much to me. In any case, here they are:

• More oxidation in the cytoplasm than in the nucleolus and nuclear envelope in the neurons of AD and DS, clean in controls
• No difference in cerebellum between AD, DS and controls
• RNA oxidation was the main thing being detected in AD and DS
• Less oxidation with increased amyloid beta (AB) and neurofibrillary tangles (NFT)
• Increased oxidation in substantia negra in PD, dementia with Lewy bodies (DLB), and multiple system atrophy-Parkinsonian type (MSA-P). More in PD than other two
• Both RNA and DNA oxidation in PD, DLB and MSA-P
• No increase in RNA oxidation in PD in cerebellum or cerebral cortex, but increase in cerebral cortex for DLB

They think the source of oxidation is damaged mitochondria spewing hydrogen peroxide, and it transforming to hydroxyl radicals through the Fenton reaction in the cytoplasm. They don't know what effect oxidation has on RNA's functionality or if it is important. Probably some translation issues with wrong base pairing.
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Abstract follows:

In Alzheimer and Parkinson diseases, oxidative alterations, affecting lipids, proteins, and DNA, have been described. Using an in situ approach to identify 8-hydroxyguanosine, an oxidized nucleoside, we recently identified RNA as a major target of oxidation in Alzheimer and Parkinson diseases as well as Down syndrome, where premature Alzheimer-like neuropathology is invariably found. RNA oxidation is localized to the neuronal populations potentially affected in these diseases. Together with the known mitochondrial dysfunction in Alzheimer and Parkinson diseases, the cytoplasmic predominance of neuronal 8-hydroxyguanosine supports mitochondria as the most likely source of reactive oxygen responsible for RNA oxidation. The consequence of oxidatively damaged RNA is not fully understood; however, the potential of oxidized RNA to cause errors in translation indicates a metabolic abnormality in neurodegenerative diseases.

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.

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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.

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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.

Area-Specific Differences in OH8dG and mtDNA4977 Levels in Alzheimer Disease Patients and Aged Controls

Summary: Mitochondrial DNA in the brain gets damaged at different rates across brain regions depending on type of damage, age, and Alzheimer's diseasedness.

Interestingness: 1

Paper by AMS Lezza, P Mecocci, A Cormio, M Flint Beal, A Cherubini, P Cantatore, U Senin and MN Gadaleta in the Journal of Anti-Aging Medicine, Volume 2, Issue 3, Fall 1999.

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They track two different common mutations to mitochondrial DNA (mtDNA) in post-mortem brains of 14 people, 8 with Alzheimer's, 6 control. One type of mutation is a deletion of 4977 bases in the mtDNA, which, going by the large amount of google results, seems to be quite a common thing to check for. The other is a product of oxidation, 8-hydroxy-2'-deoxyguanosine (OH8dG).

It seems like very little data to be taking the conclusions seriously, but the abstract is a good summary of the results. If nothing else, it seems that Alzheimer's disease patients have more oxidised mtDNA than non-Alzheimer's disease patients.
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Abstract follows:

The levels of mitochondrial DNA (mtDNA) 4977-bp deletion (mtDNA4977) and 8-hydroxy-2'-deoxyguanosine (OH8dG) have been measured in different brain areas of aged controls and Alzheimer disease patients. An area-specific distribution of the OH8dG level among three cortices and the cerebellum in aged controls as well as in Alzheimer disease patients has been found. It seems that in control subjects the age-related oxidative damage to mtDNA, represented by OH8dG content, shows a faster increase in the temporal and parietal cortices than in the frontal and in the cerebellum. In Alzheimer disease patients, where the OH8dG values are always higher than those of the control counterparts, such an area-specific distribution is maintained, but with a less significant difference among the cortices. The mtDNA4977 levels, on the other hand, are very different between frontal and parietal cortices on one side and temporal cortex and cerebellum on the other, both in control subjects and in Alzheimer disease patients. In general, it seems that the lowest mtDNA4977 levels coexist with the highest OH8dG contents in controls and, even more, in Alzheimer disease patients. This suggests that oxidative stress takes place both in aging and in Alzheimer disease, where it is amplified; however, mtDNA4977 level correlates with OH8dG content only in the frontal cortex of controls.

Free Radical Theory of Aging: Increasing the Average Life Expectancy at Birth and the Maximum Life Span

Summary: The founder of the free radical theory of aging again summarising the results that back the theory, and theorising on what could help slow down this process.

Interestingness: 2

Paper by Denham Harman, MD, PhD, in the Journal of Anti-Aging Medicine, Volume 2, Issue 3, Fall 1999.

(((This is a rewrite of the paper two issues ago, summarised here: http://readingrejuvenationresearch.blogspot.com/2010/09/aging-minimizing-free-radical-damage.html, with better editing and slightly abridged (no cool graphs). It was more interesting the first time around, but this version is more polished.

This one puts more emphasis on substances that could slow down the aging process. There are a couple mentioned in this one that weren't mentioned in the first one, but nothing particularly intesting.
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Abstract follows:

Continued improvements in general living conditions—e.g., better nutrition, medical care, and housing—during the past two millennia have increased average life expectancies at birth from about 30 years in ancient Rome to almost 80 years in the developed countries with no change in the maximum life span. Current average life expectancies at birth will be increased little by further improvements. The rate of accumulation of damage inflicted on us by our inherent aging process limits average life expectancy at birth under optimal living conditions to around 85 years and the maximum life span to about 122 years. The inherent aging process is caused by chemical reactions that arise in the course of normal metabolism. Attempts to significantly increase average life expectancies at birth and the maximum life span in the future, unlike in the past, will require an understanding of aging. The free radical theory of aging postulates that this process is caused by free radical reactions, largely initiated by superoxide radicals arising from the mitochondria at an increasing rate with age. Some measures based on the free radical theory of aging may further increase the life span without interfering with the activities of normal life include: (a) caloric restriction, (b) compounds that decrease O2 access to "electron-rich areas" of the mitochondria, and (c) substances that help to minimize mitochondrial damage. The foregoing are discussed briefly along with the amelioration of damaging reactions in early life that predispose to life-shortening diseases. The feasibility of the measures suggested above needs to be evaluated. This task should be both interesting and rewarding.

Rest of volume 2, Issue 2

The rest of issue 2 of 1999 consists of:

Some book reviews:

• "Gray dawn: How the coming age wave will transform America and the world", by PG Peterson. Populist-sounding book warning that the US is getting old. Not reading it going by that review.
• "Living to 100: Lessons in living to your maximum potential at any age", by TT Perls, M Hutter Silver, JF Lauerman and M Hutter-Silver. Book about how life at 100 can still be good. Feel-good book? Not reading it going by that review.
• "Life without disease: The pursuit of medical utopia", by WB Schwartz. Using genes to predict and prevent disease. Sounds populist. Not reading it going by that review.
• "The causes of aging", by AP Wickens. Sounds like introduction to biology of aging. Maybe ok.
• "Super T: The complete guide to creating an effective, save, and natural testosterone enhancement program for men and women", by K Ullis, J Shackman, and G Ptacek. Guide on how to use testosterone as a supplement. Even though it sounds like marketing crap, it could be interesting.

The gerontology literature review:

• "The centenarians are coming", by CG Wagner, in The Futurist. Usual Futurist content. Sounds similar to the "Living to 100" book above.
• "Longevity: The ultimate gender gap", by HB Simon, in Scientific American. Reviewer didn't like it and mostly gave differing explanations and recommendations for the reasons of why men and women have different life expectancies. I don't like the alternative explanations offered.
• "Aging: A message from the gonads", by DL Riddle, in Nature. Burning bits of somatic gonadal tissue in some worms extended their lifespan by 60% compared to standard. Paper-suggested theoretical background: fecundity and longevity are inversely proportional, controlled by hormones. IGF-1 signals lots of food. Interesting. (Further below *).
  
• "Analysis of telomere lengths in cloned sheep", by PG Shiels, AJ Kind, KHS Campbell, D Waddington, I Wilmut, A Colman, and AE Schnieke, in Nature. Dolly, and two other cloned sheep, have 20% shorter telomeres than expected for their age. Theorised that telomere length not reset. Other people (that the reviewer contacted?) not convinced the result is not a fluke, or just experimental error (supposedly hard to distinguish telomeres 19kB long from ones 24 kB long)

The usual other sections: web watch, literature watch and calendar.

* On reading the article/letter, the description above is a bit wrong. The note is a theoretical justification for the gonad ablation result from another group. The 60% longevity expansion effect only happens when they get rid of the germline precursor cells (that generate sperm and eggs) and leave the gonad precursor cells alone, but not when they blast both sets. He interprets this as sperm shortening life and gonads extending it (I didn't get the teleological reasoning). There's more gene analysis ending with DAF-12 and DAF-16 upregulation extending lifespan, maybe through catalase upregulation, and DAF-2 shortening it by inhibiting DAF-16.

How Human Longevity and Species Survival Could Be Compatible with High Mutation Rates

Summary: Hypothesising that humans select against deadly mutations primarily at the zygote stage.

Interestingness: 4

Paper by Leonid A Gavrilov and Natalia S Gavrilova, in the Journal of Anti-Aging Medicine, Volume 2, Issue 2, Summer 1999.


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Another short note, this one on how come the human race still exists considering the large amount of mutations that occur during each generation. They quote a number from a different study claiming 1.6 new harmful mutations per person, per generation. Their suggested mechanism on how to select against deadly combinations is by being very sensitive at the zygote stage, so having the deaths happen early. Their evidence for this is that the time lag between marriage and first child is around 16-19 months, giving time for about 7-10 failures. Doesn't sound like impressive evidence to me, but the idea is appealing anyway. They don't offer a mechanism as far as I can see on how the zygote is made so sensitive to deadly mutations.

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Is Telomere Shortening Related to Progeria?

Summary: Telomere shortening probably doesn't cause Hutchinson-Gilford progeria

Interestingness: 6

Paper by W Ted Brown in the Journal of Anti-Aging Medicine, Volume 2, Issue 2, Summer 1999.


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This is a short note speculating on whether progeria is caused by telomere shortening. The author says unlikely. Hutchinson-Gilford progeria is a fucking rare disease (1 in 8 million) of the type that pop up through a dominant spontaneous DNA mutation. Progerias are diseases that look like accelerated aging. This one starts being noticeable in toddlers between one and two years old, then they start looking old very quickly, going bald and losing subcutaneous fat, and have an expected lifespan of 13 years. 80% of them die of heart attacks and congestive heart failure, but they don't seem to get cancer, cataracts, osteoporosis or Alzheimer's like regular old people.

Fibroblast cultures extracted from progeria patients have an almost normal lifespan, but one paper reported shorter telomeres in them. Studies from Werner's syndrome, a different progeria that hits during early adulthood, give mixed results for shorter telomeres, but maybe some indication of faster telomere shortening.

Mice with telomerase knocked out don't show too many problems and in one study, could reproduce for at least six generations. By the sixth generation, their telomeres were much shorter and there were a lot of chromosome fusions. Other studies on these telomerase knockouts showed slightly lower lifespan, lower wound healing capacity, and more cancer. From this, he says it seems unlikely that telomere shortening would cause progeria. From what I remember, though, mice have way longer telomeres than humans to begin with, which would hide the effect a bit, but he didn't discuss that

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