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.

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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.
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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.

2-Deoxy-D-Glucose Feeding in Rats Mimics Physiologic Effects of Calorie Restriction

Summary: There's almost nothing interesting to say about 2-deoxy-D-glucose yet.

Interestingness: 1

Paper by Mark A Lane, Donald K Ingram and George S Roth in the Journal of Anti-Aging Medicine, Volume 1, Issue 4, Winter 1998.

(((The previous paper was about the effects of calorie restriction (CR). This one is by the same group of people, about a potential CR mimic (ie a substance that has similar effects to practicing CR). I assume there will be many more of these type of papers through the rest of the journal history)))

Since CR is unlikely to be taken up by a large proportion of the population, it'd be good to find substances that trigger the same effects. While the mechanism by which CR extends lifespan is unknown, there are many hypotheses, including reduced oxidative stress, elevated glucocorticoids, reduction in body temperature, and altered glucose metabolism. This study looks at this last one by introducing a substance into rats diet, 2-deoxy-D-glucose (2DG), that is a competitive inhibitor of glycolysis. 2DG is phosphorylated by hexokinase (((energy-consuming step))), but the process stops there (((no energy released))).

120 rats were split into four groups of 25 and one group of 20, the smaller group acting as a control, three other groups being fed 0.2, 0.4 and 0.6 percent 2DG, and the final group matched to consume only as much food as the group taking the smallest amount out of the rest (((to control for direct CR effects I think))). The study lasted 24 weeks and started when the rats were 6 weeks old.

Since four rats died in the first 5 weeks in the high dose group, the diet was modified to be one week of 0.6% 2DG intermixed with a week free of 2DG (((hack))). There was one death in each of the two other dose groups but they were not attributed to 2DG.

In all but two of the 2DG rats, autopsies of rats killed at the half way point and at the end of the study showed vacuoles in their heart (((holes of fluid?))). Food intake was slightly (5%) lower in the 2DG rats throughout the study. Weight was also a lot lower throughout in the higher 2DG dose rats, and in the pair matched (((about 10% from the graph))), and a little lower in the 0.4% group (((5% or so))), with very low variance. Temperature was also lower in the two higher dose groups (((by about 0.25 degrees from the graph, even though the text says 0.5 degrees))), but variance was higher. Finally, insulin levels were lower in the 0.4% dose group at both autopsy points (((by about 25% with respect to controls))), but no statistical effect on glucose (((but still a bit lower))).

(((0.6% kills, and 0.2% has no effect, and they all leave holes in the heart. The supposedly beneficial effects in the 0.4% group are not impressive (lower weight, slightly lower temperature, lower insulin) and were matched by the pair-matched group in all but temperature. Lifespan data would be nice, but until then there's nothing to see here)))


Abstract follows:

Calorie restriction (CR) extends the life span, slows the rate of aging, and delays the onset of many age-related diseases in short-lived laboratory species, primarily rodents. Although it is unknown if CR extends the life span in long-lived mammals, findings emerging from CR studies in rhesus monkeys agree with the extensive rodent literature that suggests this intervention can have beneficial effects in primates. Even if CR is shown to extend the life span in long-lived species, it is unlikely that the 30% to 40% reduction in intake used typically in this paradigm would become a widespread practice in humans. An alternative strategy may be to design interventions that "mimic" biologic effects of CR but do not significantly reduce food intake. The present study was designed to test the hypothesis that administration of a glucose analogue, 2-deoxy-D-glucose (2-DG) would mimic certain effects of CR. Specifically, we administered three doses (0.2%, 0.4%, and 0.6% w/w) of 2-DG in the diet to male Fischer-344 rats. Rats fed 0.4% 2-DG weighed slightly less than controls and exhibited significant reductions in body temperature and fasting serum insulin levels. Our findings suggest that it might be possible to design interventions to mimic certain metabolic effects, and perhaps other beneficial effects of CR such as life span extension and retardation of physiologic aging.