Sirtris Resveratrol SRT501 To Be Used To Study Mitochondrial Deficiency Diseases

Resveratrol--a phyto-antioxidant found in grapeskins--is not only being studied for its possible anti-aging effects, it is also being studied for its potential for treating degenerative diseases of several types.

For the Rochester study, published in the March issue of Advances in Experimental Medicine and Biology, the research team wanted to examine if resveratrol had a negative effect on cancer cells. In this case, they chose pancreatic cancer cells. Pancreatic cancer is particularly hard to treat with chemotherapy, because the pancreas, a gland located deep in the abdomen, pumps powerful digestive enzymes into the intestines. This pumping process clears the gland of chemotherapy doses, making treatment difficult.

The team, lead by Dr. Paul Okunieff, the chief of radiation oncology at the University’s cancer center, prepared two sets of pancreatic cancer cells and added pure resveratrol to one. After treating both sets with chemotherapy, they found that the resveratrol had "depolarized" the cell membranes of 35 percent of the mitochondria, shutting down the organelles and exposing the cells to radiation treatment.

...Sirtris is supplying their resveratrol, called SRT501, to a team of scientists at England's Newcastle University to conduct clinical trials on ailments related to a mitochondrial-related illness, called MELAS—mitochondrial myopathy, encephalopathy, lactic acidosis, strokelike episodes. MELAS is caused by mutated mitochondria and is a progressive and fatal disease that normally surfaces when the patient is between five and 15 years old. Strokelike episodes may lead to impaired muscular function and dementia.

...Chinnery's team will study if resveratrol can improve the functioning of the mitochondria and hopefully diminish the symptoms. If the research is successful, the FDA will then consider approving SRT501, with Sirtris as the sole marketer, for a seven-year period. "Many diseases of aging, such as type 2 diabetes, exhibit impaired mitochondrial function," said Peter Elliot, vice president of development at Sirtris. "We hope to develop new therapies." CheckBiotech

That is fascinating news, given the humble origins of resveratrol. Other related stilbenes found in berries and grapes may prove to be even more useful therapeutically (eg pterostilbene).

Phase I Trials: Prodarsan for Cockayne's Syndrome

Prodarsan is a combination of small protein molecules devised by Pharming NV[PHGUF.PK] for treatment of premature aging including Cockayne's Syndrome.

Leiden, The Netherlands, April 23, 2008. Biotech company Pharming Group NV (Pharming) (NYSE Euronext: PHARM) announced today that its wholly owned subsidiary DNage has started a Phase I clinical study to evaluate the pharmacokinetics and tolerability of Prodarsan(R) in humans.

Premature ageing, the primary target of Prodarsan(R), is a group of rare genetic diseases which manifests itself in several forms that are genetically and clinically similar although not identical. Dependent on the specific form of the disease, patients have a strongly reduced life expectancy and exhibit many ageing-related diseases early on in their lives. There is currently no effective therapy available for these patients.

Pharming has demonstrated that Prodarsan(R) as an oral, liquid formulation has significant effects in animal models for Cockayne Syndrome (CS). CS is one of the more common forms of premature ageing and is characterized, amongst others, by growth failure, mental retardation, eye abnormalities and a reduced life expectancy. The positive effects of Prodarsan(R) in preclinical testing on life expectancy in general and more specifically on the eye abnormalities are promising for further development of the product and its testing in humans.

The Phase I trial that is now being conducted consists of a combined single and multiple dose escalating clinical study in healthy volunteers. By studying the pharmacokinetics and tolerability of Prodarsan(R) and the effects of food intake on the absorption and elimination of the product, an oral dosing scheme will be determined that targets the pharmacological effective concentration range effectively. It is expected that following a successful completion of this trial the first clinical studies in patients will start later in 2008. Source

Prodarsan's proposed mechanism of action is via the DNA repair mechanism of the cell.

CKN1 is caused by a defect in the Cockayne syndrome type A gene (CSA or ERCC8) located on chromosome 5. Affected persons inherit 2 mutant genes, one from each parent. Cells carrying ERCC8 mutations are hypersensitive to UV light. They do not recover the ability to synthesize ribonucleic acid (RNA) after exposure to UV light. In addition, the cells cannot remove and degrade deoxyribonucleic acid (DNA) lesions from strands that have active transcription.

Mutations in the DNA excision repair gene ERCC6 located on band 10q11 cause CS type 2 (MIM number 133540; CSB). This gene encodes helicase, a protein that is presumed to have DNA unwinding function. Mutations include a deletion of exon 4, an amino acid substitution at the 106th glutamine to proline (Q106P) in the WD-40 repeat motif of the CSA protein, and large deletion in the upstream region, including exon 1 of the CSA gene. The Q106P mutation could alter the propeller structure of the CSA protein, which is important for the formation of the CSA protein complex. Additionally, a missense mutation (A205P) and a nonsense (E13X) mutation have been identified, as well as a new common single nucleotide polymorphism in CKN1. No genotype-phenotype correlation exists. _EMedicine

We can hope that experience in augmenting DNA repair in the tragic accelerated aging syndromes may be helpful in devising strategies to augment DNA repair in helping to delay normal aging.

Intravenous Cord Blood Cells Rejuvenate Aging Brains, Replenish Neural Progenitor Cells

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Researchers in Florida have managed to rejuvenate the brains of aging mice with a single injection of human cord blood cells in a peripheral vein. The single cord blood cell injection resulted in new progenitor stem cells in the mouse hippocampus, and new nerve cell formation.

Neurogenesis continues to occur throughout life but dramatically decreases with increasing age. This decrease is mostly related to a decline in proliferative activity as a result of an impoverishment of the microenvironment of the aged brain, including a reduction in trophic factors and increased inflammation.

We determined that human umbilical cord blood mononuclear cells (UCBMC) given peripherally, by an intravenous injection, could rejuvenate the proliferative activity of the aged neural stem/progenitor cells. This increase in proliferation lasted for at least 15 days after the delivery of the UCBMC. Along with the increase in proliferation following UCBMC treatment, an increase in neurogenesis was also found in the aged animals. The increase in neurogenesis as a result of UCBMC treatment seemed to be due to a decrease in inflammation, as a decrease in the number of activated microglia was found and this decrease correlated with the increase in neurogenesis.

The results demonstrate that a single intravenous injection of UCBMC in aged rats can significantly improve the microenvironment of the aged hippocampus and rejuvenate the aged neural stem/progenitor cells. Our results raise the possibility of a peripherally administered cell therapy as an effective approach to improve the microenvironment of the aged brain.

...Not only do the results of this study provide novel insight into the state of the aged stem cell niche, the ability of the UCBMC to exert their effects while being administered minimally invasively may make translation to the clinical setting more likely. For this reason it will be important in future studies to determine the most efficacious dose and dosing regimen. Nevertheless, this is the first time that a systemic injection of hematopoietic cells has been shown to restore the regenerative potential of the aged brain, providing a novel insight into how the regenerative potential of the aged stem cell niches could be restored.

...The effects of UCBMC have been attributed to changes in the microenvironment of the brain, through the release of trophic factors or by reducing inflammation, and not by a direct replacement of cells [21-23]. UCBMC contains a number of cell types including B-Cells and T-Cells, as well as, mesenchymal and endothelial progenitor cells. UCBMC is also a rich source of CD34⁺ hematopoietic stem cells [24-26]. It was recently demonstrated that a systemic injection of UCBMC cells could suppress inflammation in the brain following stroke. Moreover, the effects of UCBMC cells seemed to shift the cytokine expression from a Th1 response to a Th2 response [20,23,27]. In addition to the immune modulatory effects, UCBMC cells also produce a number of trophic factors including, but not limited to, VEGF, nerve growth factor, and cytokine colony stimulating factor-1, thrombopoietin, and IL11 [20,28,29]. ___BiomedCentral__via_madscience__via__TechnutNews

It is important to understand that the cells that were injected into the peripheral veins of mice were human umbilical cord blood mononuclear cells (HUCBMCs). The results are somewhat startling, given that the injected cells were not neural stem cells, the cells were not injected directly into the brain, and the cells were given in a single dose only. It will be important for the researchers to tease out the important cellular and trophic factors present in the UCBMC's that may have led to the rejuvenatory effects.

This is a line of research that I am interested in following further.

Protecting the Brain Over the Lifespan

If humans are to extend their lifespan by 50% and more, they will need to learn to prevent accumulation of damage to the aging brain. One approach is through long-term pharmacological intervention.

Scientific work continues on the use of Ampakine drugs to treat Alzheimer's and other neurological disorders. Now it looks as if Ampakines can also serve as a prophylactic drug.

The drug, temporarily designated S18986, interacts with AMPA (short for α- Amino-3-hydroxy-5- methylisoxazole-4- propionic acid, or ampakine) receptors in the brain. These receptors transmit excitatory signals in the brain, and researchers were interested in experimental AMPA-receptor drugs (such as S18986) for their neuroprotective abilities and for the way they temporarily boost memory. But rather than investigating the compound’s short-term effects, Alfred E. Mirsky Professor Bruce McEwen and his lab members...studied the drug’s impacts on middle-aged to elderly rats and found that, when administered daily over four consecutive months, it appeared to improve memory and slow brain aging.

...When compared to control animals that had received only sugar water, the drugged rats were not only more active and better at memory tests, but their brains showed physical signs of slowed aging. Neurons in the forebrain that produce acetylcholine, a neurotransmitter known to play a role in learning and memory, had 37 percent less decline. Dopamine-producing neurons, which are responsible for sustaining activity and motivation levels, slowed their decline by 43 percent. Levels of inflammation in the brain were also significantly lower. “Every marker we chose to look at seemed to indicate there was some preservation of function during aging with chronic treatment,” Hunter says. The drug appears to slow aging’s effects throughout the entire brain.___ScienceDaily__via__FutureScanner

This particular Ampakine appears to have a protective effect on the brains of rats over a significant part of the rat's lifespan.

Ampakines are being researched as potential treatments for Alzheimer's, Depression, and other neuropathological and neuropsychiatric conditions. This research suggests an even broader potential application of Ampakines--as a neuroprotective for those at risk for neuropathology. Broadly speaking, that would be most of us, over our lifespans.