Blocking an enzyme which makes stress hormones improves memory in old mice. Perhaps blocking this enzyme would slow the rate of brain decay with age?
Such memory loss has been linked with high levels of 'stress' steroid hormones known as glucocorticoids which have a deleterious effect on the part of the brain that helps us to remember. An enzyme called 11beta-HSD1 is involved in making these hormones and has been shown to be more active in the brain during ageing.
In a study published today in the Journal of Neuroscience, the team reports the effects of a new synthetic compound that selectively blocks 11beta-HSD1 on the ability of mice to complete a memory task, called the Y maze.
Professor Jonathan Seckl from the University of Edinburgh, who discovered the role of 11beta-HSD1 in the brain, described the findings: "Normal old mice often have marked deficits in learning and memory just like some elderly people. We found that life-long partial deficiency of 11beta-HSD1 prevented memory decline with ageing. But we were very surprised to find that the blocking compound works quickly over a few days to improve memory in old mice suggesting it might be a good treatment for the already elderly."
The effects were seen after only 10 days of treatment.
I tend toward skepticism about compounds that might slow aging. Short term beneficial effects often come at the cost of assorted longer term harms. The way metabolism works usually as a constructive reason. That even holds for many metabolic changes in an aging body. For example, cells divide less as you age. Efforts to up-regulate stem cells might enable those stem cells to do more repair and slow the rate of aging. But stimulating old cells to divide faster probably will increase the incidence of cancer. More often than not intervention with drugs has costs and those costs can outweigh the benefits.
The researchers have previously found that carbenoxolone improves memory in heath elderly men and also people with insulin-resistant diabetes.
Professor Brian Walker and Dr Scott Webster from the University of Edinburgh are leading the drug development programme. Professor Walker added: "These results provide proof-of-concept that this class of drugs could be useful to treat age-related decline in memory. We previously showed that carbenoxolone, an old drug that blocks multiple enzymes including 11beta-HSD1, improves memory in healthy elderly men and in patients with type 2 diabetes after just a month of treatment, so we are optimistic that our new compounds will be effective in humans. The next step is to conduct further studies with our preclinical candidate to prove that the compound is safe to take into clinical trials, hopefully within a year."
I expect drugs for revving up and adjusting our metabolism to lessen the effects of aging will become much more useful once we have great ways to cure cancer. More generally, medical science and biotechnology will supply ways to better manage side effects. So interventions with drugs will become more likely to yield a net benefit.
In order to manage drug side effects and manipulate the metabolism for a net benefit we need much more complicated and complete models of human genomes, cells, and metabolism. Since side effects do not fall equally on all people who use a drug the development of ways to individualized prediction of side effects will open up the possibility of much more aggressive drug use with fewer side effects and more benefits.
Scientists have discovered a compound that restores the capacity to form new memories in aging rats, likely by improving the survival of newborn neurons in the brain's memory hub. The research, funded in part by the National Institutes of Health, has turned up clues to a neuroprotective mechanism that could lead to a treatment for Alzheimer's disease.
"This neuroprotective compound, called P7C3, holds special promise because of its medication-friendly properties," explained Steven McKnight, Ph.D., who co-led the research with Andrew Pieper, M.D., Ph.D., both of University of Texas Southwestern Medical Center, Dallas. "It can be taken orally, crosses the blood-brain barrier with long-lasting effects, and is safely tolerated by mice during many stages of development."
a drug like this carries some risks. Most notably, by preventing cell death the drug increases the risk that mutated pre-cancerous cells will manage to survive and even start replicating. Brain cancer might be a real risk. This is the problem with any drug that improves cell replication and growth in old organisms. The most likely reason the stem cells become less able to replicate is a mechanism selected for by evolution to lower cancer risk.
Neurogenesis in the dentate gyrus is key to new memory formation.
Physical activity, social, or other enriching experiences promote neurogenesis – the birth and maturation of new neurons. This growth takes place in the dentate gyrus, a key area of the brain's memory hub, the hippocampus. But even in the normal adult brain, most of these newborn neurons die during the month it takes to develop and get wired into brain circuitry. To survive, the cells must run a gauntlet of challenges. Newborn hippocampus neurons fare much worse in aging-related disorders like Alzheimer's, marked by runaway cell death.
Neuron formation was tripled in the dentate gyrus.
To find out if P7C3 could similarly stem aging-associated neuronal death and cognitive decline, the researchers gave the compound to aged rats. Rodents treated with P7C3 for two months significantly outperformed their placebo-treated peers on a water maze task, a standard assay of hippocampus-dependent learning. This was traced to a threefold higher-than-normal level of newborn neurons in the dentate gyrus of the treated animals. Rats were used instead of mice for this phase of the study because the genetically engineered mice could not swim.
Then the researchers developed a derivative drug that is even more potent. Imagine a black market in A20 for people in college.
The researchers pinpointed a derivative of P7C3, called A20, which is even more protective than the parent compound. They also produced evidence suggesting that two other neuroprotective compounds eyed as possible Alzheimer's cures may work through the same mechanism as P7C3. The A20 derivative proved 300 times more potent than one of these compounds currently in clinical trials for Alzheimer's disease. This suggested that even more potent neuroprotective agents could potentially be discovered using the same methods. Following up on these leads, the researchers are now searching for the molecular target of P7C3 – key to discovering the underlying neuroprotective mechanism.
Dr. McKnight was one of the first 12 recipients of the NIH Director's Pioneer Award, which is designed to allow researchers to pursue risky experiments that have the potential for producing highly innovative results.
"When I received the award, I thought 'I'm not going to waste it on something safe – I'm going to go for it. That's what the NIH expected of me and my team,' " Dr. McKnight said. "I'd like to give the NIH credit for betting on 'cowboy' science. If this pans out, it will be the most useful contribution of my career."
The discovery, made after researchers systematically and painstakingly infused each of 1,000 different chemicals into the brains of live mice, could point the way to a new type of neuroprotective drug for people with Alzheimer's or other neurodegenerative diseases, according to the report in the July 9th issue of the journal Cell, a Cell Press publication.
"We really didn't know if the screen would turn up a favorable compound or not," said Steven McKnight of the University of Texas Southwestern. "It was blind luck."
"Our chances were slim," added Andrew Pieper, also of UT Southwestern. "But we knew if we did find something, we would already have evidence that it worked in a living animal." Promising candidates landed in cell culture too often don't pan out.
We need the ability to rejuvenate the immune system in order to slash cancer risk. We can't turn up cell replication in aged stem cells without a way to prevent the rise in cancer risk that higher rate of cell division will otherwise bring.
Thanks to Lou Pagnucco for the heads up. Here's the open access research paper for this report: "Discovery of a Proneurogenic, Neuroprotective Chemical".