The Durk Pearson & Sandy Shaw®
Life Extension NewsTM
Volume 10 No. 2 • June 2007

If a nation values anything more than freedom, it will lose its freedom.

— W. Somerset Maugham

I called it ignose, not knowing which carbohydrate it was. This name was turned down by my editor. “God-nose” was not more successful, so in the end “hexuronic acid” was agreed upon. Today the substance is called “ascorbic acid” and I will use this name.

— Albert Szent-Györgyi (1893–1986)
Studies on Biological Oxidation and Some of Its Catalysts
(C4 Dicarboxylic Acids, Vitamin C and P, etc.),
1937, p. 73

Recovery of “Lost” Memories Possible with Enriched Environment or Butyrate Treatment

A paper on a potentially great advance in the treatment of degenerative or even dementing disease in humans has just been published.1 Although the study involved mice, the mechanisms of learning and memory are similar between mice and humans.

The researchers used the CK-p25 Tg mouse model, in which expression of the p25 protein causes severe degeneration with losses of synaptic connections and neurons. The resulting animals have impaired ability to remember fear-inducing stimuli or spatial learning (as in the Morris water maze).

They first studied the effects of an “enriched environment” (such as lots of toys and changing cage accessories) for 4 weeks on the learning and memory capabilities of the impaired mice. Despite the fact that there was a comparable amount of brain atrophy in the mice exposed to an enriched environment (EE) as in those not so treated, the results were that the EE-treated mice showed markedly increased associative and spatial learning when compared to the nonenriched mice. Moreover, “levels of synaptic proteins and synaptophysin and MAP-2 immunoreactivity were significantly higher in EE-treated CK-p25 Tg mice when compared to nonenriched CK-p25 mice. This result indicates that EE promoted growth of new dendrites and synapses in CK-p25 mice. [Emphasis added] Thus, despite the substantial loss of neurons, EE induced the refinement of the synaptic network, which may be the cause of improved learning in the CK-p25 Tg mice.”

Could Memories Be “Misplaced” Rather Than Totally Lost in Neurodegenerative Disease?

The authors proposed a hypothesis: “Notably, it was not clear whether memories were lost or whether they became inaccessible owing to synaptic and neuronal loss. In the latter case, it might be possible to re-establish access to such memories if sufficient refinement of the neuronal network can be achieved by the remaining neurons. . . . The fact that long-term memories [of fear-inducing stimuli and Morris water maze spatial information] can be recovered by EE supports the idea that the apparent ‘memory loss’ is really a reflection of inaccessible memories. These findings are in line with the phenomenon known as ‘fluctuating memories,’ in which demented persons experience temporary time periods of apparent clarity.”

Histone Modification in Associative Learning

The authors hypothesized that the acetylation and methylation of histone proteins that control whether DNA segments are “on” or “off” (transcriptional regulation of gene expression) could be involved in the synaptic plasticity and learning behavior revealed in the EE-treated CK-p25 Tg mice. In fact, they found that EE induced hippocampal and cortical acetylation and methylation of histones 3 and 4 as soon as 3 hours after treatment. “In addition, intraperitoneal and intracerebroventricular injections of the histone deacetylase (HDAC) inhibitors sodium butyrate or trichostatin A significantly facilitated associative learning in wild-type mice. To investigate whether inhibition of HDACs mimics the effects of EE, we administered SB [sodium butyrate] into wild type mice for four weeks. The in vivo effect of SB was confirmed by a robust increase in H3 and H4 acetylation in the hippocampus.”

The authors concluded, “Thus, chronic injections of SB led to the recovery of memories in CK-p25 Tg mice that had developed severe neuronal loss.”

Increasing Your Intake of Butyrate

Fortunately, getting increased amounts of butyrate into your body is as simple as eating more foods high in dietary fiber. Butyrate is one of the short-chain fatty acids made by colonic microbes from resistant starch and dietary fiber. The fermentation of barley fiber by these microbes is a particularly good source of butyrate (as compared to other short-chain fatty acids). Other dietary inhibitors of type I and II HDAC enzymes include diallyl disulfide (found in garlic and other Allium vegetables) and sulforaphane (found in cruciferous vegetables).2

Sulforaphane from Cruciferous Vegetables

As reported in the March 15, 2006 Journal of the National Cancer Institute (pp. 377–379), “Histone deacetylase inhibitors sit at crossroads of diet, aging, cancer,” Roderick Dashwood, Ph.D., chief of the cancer chemoprevention program at the Linus Pauling Institute, and his colleagues Drs. Emily Ho and Melinda Myzk, are studying compounds found in the diet that can inhibit histone deacetylases moderately at biologically relevant concentrations. They found sulforaphane to be one such agent. “Normal cells are being exposed to these agents like sulforaphane every day,” said Dashwood. “They are modulating HDAC activity maybe 20% or 25%. . . . We still don’t know what concentrations are achieved in people,” he said. But he added that (in the reporter’s words), “a study just completed demonstrated that when volunteers are fed sulforaphane-rich broccoli sprouts, highly significant inhibition of HDAC can be measured in peripheral blood mononuclear cells—in some cases within 3 hours of consumption.”


  1. Fischer et al. Recovery of learning and memory is associated with chromatin remodeling. Nature 447:178-82 (2007).
  2. Davis and Ross. Dietary components impact histone modifications and cancer risk. Nutr Rev 65(2):88-94 (2007).

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