Impact of Dietary Restriction on Brain Aging and Neurodegenerative Disorders: Emerging Findings from Experimental and Epidemiological Studies

Summary: Calorie restriction helps mice and rat models of Alzheimer's, Parkinson's and stroke. 2-doxyglucose does too.

Interestingness: 2

Paper by Mark P Mattson in the Journal of Anti-Aging Medicine, Volume 2, Issue 4, Winter 1999.

(((
Rats and mice models of Alzheimer's disease (AD) did better when they were on a calorie restriction diet (CR). The same for Parkinson's disease (PD). Also for Huntington disease (HD). Also for rats given a stroke. I don't like the models, except the one for stroke, so I don't care much about these results.

They think this effect comes from over-expression of heat shock proteins (HSP-70) when glucose goes low. When given 2-deoxygluose (2-DG), a modified glucose that competes with glucose for the energy chain enzymes but is not able to be broken down properly (http://readingrejuvenationresearch.blogspot.com/2010/07/2-deoxy-d-glucose-feeding-in-rats.html), rats and mice also did better in the AD, PD and stroke models, even though they lived under all-you-can eat buffet conditions.

Finally, some lame-sounding correlation studies between caloric intake surveys with PD, AD and stroke are listed.
)))


Abstract follows:

Although dietary restriction (DR) extends life span and reduces levels of cellular oxidative stress in several different organ systems of laboratory rodents and monkeys, its impact on the brain is unknown. As is the case with age-related disorders in other organ systems (e.g., cardiovascular disease, diabetes, and many cancers), neurodegenerative disorders such as Alzheimer disease (AD), Parkinson disease (PD), and stroke involve increased levels of cellular oxidative stress and metabolic compromise. Recent studies of experimental rat and mouse models of AD, PD, and stroke have shown that DR increases resistance of neurons to dysfunction and degeneration. DR can attenuate age-related and disease-specific deficits in cognitive and motor functions in rodents. The available data suggest at least two possible mechanisms whereby DR protects neurons. One involves decreased levels of mitochondrial oxyradical production, and the second involves induction of the expression of "stress proteins" and neurotrophic factors. The latter mechanism is supported by data showing that the neuroprotective effect of DR can be mimicked by administration of 2-deoxyglucose to animals fed ad libitum. Recent findings in epidemiological studies of human populations suggest that individuals with a low daily calorie intake have reduced risk for AD and PD. Collectively, the available data suggest that DR may prove beneficial in reducing both the incidence and severity of neurodegenerative disorders in humans.

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.

(((
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.
)))


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.

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.

(((
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.
)))


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.

Estrogen and Brain Aging

Summary: Description of mostly suggestive data about the effects and importance of estrogen on aging in the brain

Interestingness: 1

Paper by Mahendra K Thakur in the Journal of Anti-Aging Medicine, Volume 2, Issue 2, Summer 1999.


(((
The most interesting part of the paper is a mention of a result in some other paper that women receiving estrogen replacement therapy (ERT) are 40% less likely to have Alzheimer's disease (AD) than women not receiving ERT.

The rest is a description of the changes in neurotransmitter and receptor densities in the brain as it ages, how estrogen might affect those neurons that produce and receive those neurotransmitters, mainly going by rat studies, results of women's mental scores going down when taking medication that suppresses estrogen production, and how those scores are rescued when taking ERT. I'm not good at absorbing the neurotransmitter information, so I glazed over a lot of it. Nerve growth factor seemed to be mentioned a lot.

There was also mention of estrogen as an antioxidant and its relation to AD. My biases prevailed and I discounted all of it before it even hit my long term memory.
)))


Abstract follows:

Recent research findings have made it clear that the female sex-steroid hormone estrogen has several functions other than regulation of sexual and reproductive behavior. In addition to this hormone's well-known influence on bone and the heart, this hormone exerts a wide variety of effects on the brain, including both development and function. The current interest in aging of the brain derives, in part, from the enormous and global increase in the proportion of elderly people. Old age is associated with several health problems including a general decline in mental function, especially in dementia, and specifically Alzheimer's dementia (AD). To focus on this issue, it is essential to understand the changes taking place in the aging brain and the role that estrogen plays in this process. This article reviews the data on the involvement of estrogen in the aging brain and discusses the potential consequences of estrogen replacement therapy.
Free first page