Durk Pearson & Sandy Shaw’s®
Life Extension NewsTM
Volume 15 No. 4 • August 2012

Every impossible rule has its loopholes; every general prohibition creates its bootleggers.
— Robert A. Heinlein (“Time Enough for Love” (1973)

Dietary Restriction—A Natural Cholinesterase Inhibitor?
Decreased Acetylcholinesterase Activity in
Brains of Female Mice Undergoing
Dietary Restriction

Decline of brain cholinergic function is found in normal aging and is associated with impairment of learning and memory. In Alzheimer’s disease (AD), the cholinergic nervous system is a key area of degeneration and many of the drugs used in the treatment of AD are cholinesterase inhibitors. Acetylcholine (ACh), the neurotransmitter of the cholinergic nervous system, is regulated by the enzyme acetylcholinesterase (AChE), which acts to terminate the activity of ACh in the neuronal synapse. Thus, a cholinesterase inhibitor is a substance that prevents AChE from terminating the activity of acetylcholine (ACh) in the synapse, thus prolonging ACh action. In a recent paper1 authors reported that, “AChE [acetylcholinesterase] has been used as a marker for cholinergic function in neural tissue because of its implications in synaptogenesis [formation of synapses] and its involvement in neurodegeneration in adult tissues. Serum AChE evaluation and the checking of different isoforms present in different tissues is being used as an effective marker in detecting several diseases.”

Because of the improved cognitive function, including enhancements of learning and memory and increased neurogenesis, in many strains of rodents subject to dietary restriction (caloric reduction without malnutrition) the authors1 studied the effects of 3 months of DR (dietary restriction in the form of feeding every other day) on brain levels (in the cerebral hemispheres and the cerebellum) of AChE in female Swiss albino (Balb/C strain) mice. They also examined AChE levels in the same type mice (at 1 month and 18 months) as modulated by 24 hours of fasting and refeeding.

The region of the brain that the researchers studied that contained the highest normal endogenous level of AChE was in the cerebral hemispheres of 1 months old mice, which had declined significantly by 45% in 18 month old mice. They found no significant changes in AChE levels in the cerebellum between the young and old mice. 24 hours of fasting resulted in a decrease of 30% in the level of AChE activity in the cerebral hemispheres of 1 month old mice, but no significant change in the cerebral hemispheres of the 18 month old mice. (There was also no significant change in the cerebellum.) After 24 hours of refeeding, the AChE levels of the 1-month-old mice returned to their initial value, with no significant change in comparison to the age-matched control mice.

The authors suggest that the reduced levels of AChE activity resulting from fasting in the 1 month old mice (a rapid decrease taking place over 24 hours) and suggest that this may reflect the effect of dietary changes on AChE during early development.

A possible explanation for the lack of changes in AChE level of the cerebral hemispheres of the 18 month old mice in the 24 hour fasting and refeeding is that it might reflect age-induced alterations of ACh/DA signaling in the regulation of initiation and discontinuation of eating (as suggested by the cholinergic hypothesis of the regulation of eating behavior discussed above).

The 1-month-old mice on the DR (feeding every other day) had a significant decrease of AChE level (50%, p<0.001) on the non-feeding day and a decrease of 40% (p<0.001) on the feeding day. No significant changes were observed in the cerebellum level of AChE in either 1 month old or 18 month old mice in comparison to their age-matched control mice. As the authors report, these findings are in agreement with earlier findings (a 1973 paper was cited) where the activity of AChE was highest in 9-week-old female rats and decreased by 50% after 29 weeks and which further decreases in old age. The authors suggest that the lower levels of AChE in old rodents may be due to loss of neurons and/or decrease in the rate of protein synthesis of AChE.

In the 18 month old mice, the researchers report a significant decrease of 15% (p<.05) and 12% (p<.05) on the non-feeding and feeding day, respectively.

“In the cerebral hemispheres of older mice where there is less reduction of AChE activity during DR, we suggest that DR might act as a natural cholinesterase inhibitor by maintaining the level of the already declining ACh, thus enhancing cholinergic neurotransmission in the cerebral hemispheres of the aged brain. Alternatively, DR may produce free radical scavengers which prevent the binding of free radicals on the sites of AChE molecules, analogous to reports on inhibitors of AChE that improve brain function.”1


  1. Suchiang and Sharma. Dietary restriction regulates brain acetylcholinesterase in female mice as a function of age. Biogerontology published online 26 Aug. 2011 DOI 10.1007/s10522-011-9356-1.

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