2 replies to this topic

[DR01D]

Sciencedaily: How Calorie Restriction Influences Longevity: Protecting Cells from Damage Caused by Chronic Disease

Oxidative stress occurs as cells use oxygen to produce energy, but this activity also releases other potentially toxic molecules, known as free radicals. As cells age, they become less effective in clearing these free radicals -- leading to cell damage, oxidative stress and the effects of aging.

However, Dr. Verdin and his team found that βOHB might actually help delay this process. In a series of laboratory experiments -- first in human cells in a dish and then in tissues taken from mice -- the team monitored the biochemical changes that occur when βOHB is administered during a chronic calorie-restricted diet. The researchers found that calorie restriction spurs βOHB production, which blocked the activity of a class of enzymes called histone deacetylases, or HDACs.

Normally HDACs keep a pair of genes, called Foxo3a and Mt2, switched off. But increased levels of βOHB block the HDACs from doing so, which by default activates the two genes. Once activated, these genes kick-start a process that helps cells resist oxidative stress. This discovery not only identifies a novel signaling role for βOHB, but it could also represent a way to slow the detrimental effects of aging in all cells of the body.

"This breakthrough also greatly advances our understanding of the underlying mechanism behind HDACs, which had already been known to be involved in aging and neurological disease," said Gladstone Investigator Katerina Akassoglou, PhD, an expert in neurological diseases and one of the paper's co-authors. "The findings could be relevant for a wide range of neurological conditions, such as Alzheimer's, Parkinson's, autism and traumatic brain injury -- diseases that afflict millions and for which there are few treatment options."

Edited by DR01D, 06 December 2012 - 11:38 PM.

[DR01D]

So if CR/Ketogenic diets are a potent HDAC inhibitor what might that help?

Epigenetic targets of HDAC inhibition in neurodegenerative and psychiatric disorders

Recent years have witnessed an explosion in the development of new HDAC inhibitors [7]. HDAC inhibitors can be classified into four main chemical families, the short-chain fatty acids (e.g., sodium butyrate, phenylbutyrate and valproic acid), the hyroxamic acids (e.g., trichostatin A and suberoylanilide hydroxamic acid (SAHA)), the epoxyketones (e.g., trapoxin) and the benzamides. Of these, the most widely studied are sodium butyrate, phenylbutyrate, trichostatin A and SAHA. The butyrates are known to cross the blood-brain barrier [7,8]. The initial interest in these inhibitors came from studies linking HDACs to a wide variety of human cancers. HDAC inhibitors arrest growth, induce differentiation and, in some cases, apoptosis and have potent anit-cancer activities, with remarkable tumor specificity [7,8]. For this reason, inhibitors of class 1 and 2 HDACs are in phase I/II clinical trials for cancer therapy and potentially cancer prevention. In the nervous system, the anticonvulsant and mood-stabilizing drug valproic acid was identified as an inhibitor of HDAC1, thereby linking its anti-epileptic effects to changes in histone acetylation. As described below, more recent work has revealed that inhibitors of class 1 and 2 HDACs represent novel therapeutic approaches to treat neurodegenerative disorders, depression and anxiety and the cognitive deficits that accompany many neurodevelopmental disorders.

I don't want to cut and paste everything in this paper but it contains a lot of good info on how HDAC inhibitors may treat many different neurological diseases including Huntington’s disease, Parkinson’s disease, Alzheimer’s disease, Ischemic stroke, Depression, Anxiety disorders, Schizophrenia, Rubinstein-Taybi Syndrome, Rett Syndrome, Fragile X syndrome.

Edited by DR01D, 07 December 2012 - 02:50 AM.

[DR01D]

Last but not least HDAC inhibitors are being tested for autoimmune diseases.

New cancer drugs could help in autoimmune disease

A new class of drugs used to treat cancer might be effective at suppressing overactive immune systems in patients with autoimmune diseases like Crohn's disease, U.S. researchers said on Sunday.

Rationale for HDAC inhibitor therapy in autoimmunity and transplantation.

While there are currently more than 70 ongoing clinical trials of inhibitors of so-called classical HDACs (HDACi) as anticancer therapies, given their potency as antiproliferative and angiostatic agents, HDACi also have considerable therapeutic potential as anti-inflammatory and immunosuppressive drugs. The utility of HDACi as anti-inflammatory agents is dependent upon their proving safe and effective in experimental models. Current pan-HDACi compounds are not well suited to this role, given the broad distribution of target HDACs and their complex and multifaceted mechanisms of action. In contrast, the development of isoform-selective HDACi may provide important new tools for therapy in autoimmunity and transplantation. This chapter discusses which HDACs are worthwhile targets in inflammation and progress toward their therapeutic inhibition, including the use of HDAC subclass and isoform-selective HDACi to promote the functions of Foxp3+ T regulatory cells.