Brain Cell Regeneration Using Reprogrammed Astroglia

The brain consists of two major cell types: neurons, which transmit information, and glial cells, which support and protect neurons. Interestingly, evidence suggests that some glial cells, including astroglia, can be directly converted into neurons by specific proteins, a transformation that may aid in the functional repair of damaged brain tissue. However, in order for the repaired brain areas to function properly, it is important that astroglia be directed into appropriate neuronal subclasses. In this study, we show that non-neurogenic astroglia from the cerebral cortex can be reprogrammed in vitro using just a single transcription factor to yield fully functional excitatory or inhibitory neurons. We achieved this result through forced expression of the same transcription factors that instruct the genesis of these distinct neuronal subtypes during embryonic forebrain development. Moreover we demonstrate that reactive astroglia isolated from the adult cortex after local injury can be reprogrammed into synapse-forming excitatory or inhibitory neurons following a similar strategy. Our findings provide evidence that endogenous glial cells may prove a promising strategy for replacing neurons that have degenerated due to trauma or disease. _PLOS

Scientists from the Helmholtz Center and Ludwig-Maximilians University in Munich, have used a virus to reprogram brain helper cells -- astroglia -- into actual neurons. They were able to convert astroglia from early post-natal and adult mouse brains into either excitatory or inhibitory neurons, depending upon the transcription factors which were introduced.

The study adds to growing evidence that certain cell types can be transformed directly into other cell types without first being converted into stem cells. Researchers have previously transformed skin cells into neurons, and one type of pancreatic cell into another. Marius Wernig, a coauthor of the skin cell study and a stem cell biologist at Stanford University, says there's a growing awareness that it may not be necessary to erase a cell's existing identity before giving it a new one.

...this latest study "means that these astroglial cells could be converted in the brain" without the need for a transplant. Berninger says that one of the next challenges is to determine whether these reprogrammed neurons can survive and function in a living brain.

Fortunately, the brain seems to have a ready source of astroglia. When the brain is injured, these cells proliferate, similar to the way the skin repairs itself after a wound. The researchers found they could also derive neurons from injury-induced astroglia taken from the brains of adult mice. _TechnologyReview

More:

we first aimed at a more potent neuronal reprogramming by inducing higher and more persistent expression of neurogenic fate determinants in astroglial cells. This allowed us not only to obtain fully functional neurons that also establish synapses from astroglial cells in vitro but also to demonstrate that distinct neurogenic transcription factors, such as on the one hand Neurog2 and on the other Dlx2 alone or in combination with Mash1, can indeed instruct the selective generation of different neuronal subtypes, such as glutamatergic and GABAergic neurons, respectively. Moreover, we found that the reprogramming efficiency of postnatal cortical astroglia towards GABAergic neurons by Dlx2 could be enhanced by first expanding the astroglial cells under neurosphere conditions prior to forced expression of Dlx2. Given that following brain injury reactive astroglia from the adult cerebral cortex de-differentiate, resume proliferation, and can give rise to self-renewing neurospheres in vitro [16], we finally show that neuronal reprogramming and subtype specification are not restricted to postnatal stages but can also be achieved from adult cortical astroglia responding to injury. _PLOS

The findings are a striking reminder that nature offers us many more possibilities than we can presently conceive of. But perhaps we will grow in our conceptual capacity, over time.

The possibility of regenerating brain tissue in situ -- without the need for inserting new cells from elsewhere -- offers new hope for brain trauma, infection, infarct, atrophy, and senility. But it also offers a distinctly new possibility which most observors are not quite ready to think about -- much less discuss.

I am referring to the possibility of growing entirely new neural networks in situ, from astroglia. The possibility that humans can induce their own brains to create entirely new brain centers and pathways, using more advanced forms of such techniques, should not be overlooked.

There is currently a race between biological methods of repairing and enhancing human organs, and technological methods of compensating for organ damage or loss -- the cyborg approach. A cyborg may utilise nano-technological enhancement, and thus manifest no outward sign of distinction from standard normal humans. The same would be true for most biological enhancements or remediation.

This lack of overt differences between ordinary persons and enhanced persons is quite important to most military uses of enhanced individuals, and to virtually all covert uses by government and other organisations.

But these tools of transformation are not likely to remain limited to deep pocketed groups and individuals. Garage biohackers are not as uncommon as you might think, and are performing a similar service for bio-hacking as the garage techno-hackers performed for microcomputers in the early days. And it is also extremely likely that persons involved in expensive and large scale research into bio-transformation technologies will set off on their own as they discover the ability to profit from their technical knowledge and skills.

Cross-posted at Al Fin

Tricks of Epigenetic Memory

It is common knowledge that a person's memory tends to get a bit foggy as he ages. A young person's memory tends to be crisper and quicker than that of a person in senescence. But it is possible that there is a means within our grasp by which we can turn back the clock in the aging brain -- back to a time of quicker and clearer recall, and a stronger grasp of new knowledge.

A new study published in Science sheds some light on how “memory disturbances” in an aging mouse brain are associated with altered “hippocampal chromatin plasticity” — the combination of DNA, histones, and other proteins that make up the chromosomes associated with the hippocampus. Specifically, the study describes an acetyl genetic switch that produces memory impairment in aging 16-month-old mice. Because the acetyl wasn’t present in young 3-month-old mice, the study concludes that it acts as a switch for a cluster of learning and memory genes.

...Dr. Fischer’s research shows that when young mice are learning, an acetyl group binds to a particular point on the histone protein. The cluster of learning and memory genes on the surrounding DNA ends up close to the acetyl group. This acetyl group was missing in the older mice that had been given the same tasks. By injecting an enzyme known to encourage acetyl groups to bind to any kind of histone molecule, Fischer’s team flipped the acetyl genetic switch to the “on” position in the older mice and their learning and memory performance became similar to that of 3-month-old mice. _hplus

More:

Dr Fischer, of the European Neuroscience Institute in Goettingen, Germany, pinpointed a tiny protein called H4K12 that controls genes key to memory and learning in the mouse brain.

...In an accompanying article, Professor David Sweatt , a U.S. neurobiologist, said that turning on H4K12 was likely to help with both Alzheimer's and age-related memory loss.
He said the German results 'provide important proof of principle that this might be a viable approach to therapeutic interventions in ageing'.
'These studies will hopefully lead to more effective prevention strategies to improve quality of life in the aged, as well as contribute to a better understanding of memory function,' he added.
The treatment of other brain conditions, such as schizophrenia and Parkinson's disease, could be improved by finding other switches that act in a similar way.
Dr Marie Janson, of the Alzheimer's Research Trust, said: 'Although in mice, this research gives us clues about how memories are formed and function in the brain.
'We now need to find out if the same processes happen in the human brain.
'This understanding is vital if we are to develop ways to protect the ageing brain from cognitive decline.
'Alzheimer's and other dementias are complex, with many things happening in the brain, so it's likely that we'll need several drugs to treat them effectively._DailyMail

Brain function is inextricably tied to genetic function. The relationship is certainly of a circular nature. If we are to learn to live long and fulfilling lives, we will need to undertand ourselves better, at a much deeper level than we once thought possible.

Stem Cells to Restore Your Hearing, Your Heart, Your Teeth

Stanford University researchers have developed a way to grow replacement "hair cells" for the inner ear, in mice. The hair cells are responsible for hearing, and the cumulative loss of hair cells over a lifetime result in permanent hearing loss. If humans could learn to regenerate the hair cells in the inner ear, hearing loss could be reversed without the need for electronic devices such as cochlear implants or hearing aids. Source via Brian Wang

Geron scientists have demonstrated the safety of GRNCM1 (cardiomyocites or stem cells) for replacing damaged heart tissue. This treatment, once approved, is likely to be used to treat chronic heart failure -- a significant cause of death and disability worldwide.
Source 1 (via Brian Wang), Source 2

Columbia University researchers are developing a method for growing replacement teeth "in place", inside the actual socket of the lost tooth. The method utilises stem cells to re-grow the tooth along with accompanying soft tissue support. This approach will do away with the need to use hardware implants, or to grow teeth outside the body in culture media.
Source via Brian Wang

The re-growth of body organs in place -- using the original tissue matrix as a scaffolding -- is a safer approach than re-growing organs outside the body, then surgically implanting them. Both approaches will probably become common, but in circumstances where in situ stem cell replacement is effective, most persons will likely opt for that approach.

Stem Cells from Endometrial Tissue Reverse Parkinson's?

Scientists at the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), have injected endometrial stem cells into the brains of mice with an induced form of Parkinson's Disease. The injected stem cells began producing dopamine -- the neurotransmitter that is deficient in Parkinson's.

The finding raises the possibility that women with Parkinson's disease could serve as their own stem cell donors. Similarly, because endometrial stem cells are readily available and easy to collect, banks of endometrial stem cells could be stored for men and women with Parkinson's disease.

"These early results are encouraging," said Alan E. Guttmacher, M.D., acting director of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the NIH Institute that funded the study. "Endometrial stem cells are widely available, easy to access and appear to take on the characteristics of nervous system tissue readily."

Parkinson's disease results from a loss of brain cells that produce the chemical messenger dopamine, which aids the transmission of brain signals that coordinate movement. This is the first time that researchers have successfully transplanted stem cells derived from the endometrium, or the lining of the uterus, into another kind of tissue (the brain) and shown that these cells can develop into cells with the properties of that tissue. The findings appear online in the Journal of Cellular and Molecular Medicine. _SD

An optimal form of brain regeneration would likely combine the use of exogenous growth factors and stem cells, along with the stimulation of endogenous stem cell and growth factor production. There is a lot to be learned about how the brain works normally, and what goes wrong in degenerative conditions, trauma, ischemia, and aging.

Even an Old Hippocampus Continues Making New Neurons

The brain maintains neuronal stem cells throughout life, according to scientists at Max Planck Institute who studied the phenomenon of lifelong neurogenesis in mouse brains.

The precise factors that influence the reactivation of dormant stem cells are not yet clear. The cells can, however, be stimulated to divide again. The scientists observed more newborn hippocampal neurons in physically active mice than in their inactive counterparts. "Consequently, running promotes the formation of new neurons," says Verdon Taylor. Pathological brain activity, for example that which occurs during epileptic seizures, also triggers the division of the neuronal stem cells.

...The presence of neurons that are formed over the course of life has also been demonstrated in the human hippocamus. Therefore, scientists suspect that different types of active and inactive stem cells also arise in the human brain. It is possible that inactive stem cells in humans can also be activated in a similar way to inactive stem cells in mice. _Physorg

If increased physical activity can stimulate new nerve cell generation, a strong argument could be made for encouraging a more active physical regimen throughout a person's lifetime. Such a finding argues for the importance of physical rehabilitation as a treatment for neurodegenerative diseases, and after a stroke or other necrotising brain injury.

Making new neurons is not the same thing as being sure the neurons are healthy and optimally functioning. Scientists are learning more about the micro-differences between healthy neurons and those that are not so healthy. The delicate micro-structures called dentritic trees or arbours, are important to good communication within the neuronal networks. And the health of these dendritic trees depends upon optimal quantities of certain cell proteins -- which are under genetic control.

And that genetic control is of course under the control of transcription factors which are influenced by a number of other things -- some under genetic control, and some influenced by the evironment.

Finding more ways that a person can optimise the generation of healthy new neurons -- and to maintain the health of those in existence -- will be worth all the time it will take.

A Second Level of Gene Transcription Control

Controlling gene expression is an important key to controlling ageing, cancer, diseases of degeneration and autoimmunity, and virtually any other mechanism of human health and pathology. As scientist learn more about the mechanisms of gene expression, they also discover new ways of intervening to prevent or treat disease. The following article discusses the ongoing clarification of an important added complexity of gene expression that will certainly be exploited for good effect before long.

A new study published online today (April 29) in Cell helps drive home just how widespread this second level of gene control is, and implicates a cancer-causing transcription factor as a major player in the process.

"This is another piece in the puzzle that demonstrates controlling the elongation phase of transcription" -- the production of messenger RNA as the transcriptional apparatus propagates down the gene -- "is one of the more important control mechanisms," said biochemist David Price of the University of Iowa, who was not involved in the study. "[This] paper is going to help convince the field that this is just the way it is."

Scientists once believed that transcription factors promoted gene expression simply by recruiting RNA polymerase II (Pol II) machinery to the promoter region of their target genes, and letting the Pol II take over from there. But over the last 20 years, several lines of evidence indicated that once bound to the promoter, Pol II pauses, or stalls, just a little ways down the transcript, and needs another signal (such as a transcription factor) to continue transcribing the gene. Recent evidence suggests that this pause is a widespread phenomenon in the genome, but "there's been some reluctance in the transcription community to accept that there are these polymerases poised [just past the start site] all throughout the human genome," Price said.

Exploring the role of this mechanism of gene control in mouse embryonic stem cells (ESCs), molecular biologist Richard Young of the Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology and his colleagues have all but eliminated that doubt. They found evidence of paused polymerases on the vast majority of genes -- both those actively being transcribed and those that remained silent.

"We're thinking now that at all genes where RNA polymerase II initiates transcription, there is a pause step," Young said. "So even genes that are being currently and actively transcribed, polymerase initiates [transcription], but must go through this pause checkpoint before it's allowed to proceed to elongation."

The team further showed that the well-studied transcription factor c-Myc, which is involved in cell self-renewal and proliferation and has been implicated in 15-30 percent of human cancers, is an example of the additional factor needed to push Pol II past the pause. Instead of promoting gene expression by recruiting Pol II to the genes, c-Myc appears to release already-initiated polymerases from this paused stage. It does so by recruiting a protein known as positive transcription elongation factor b (P-TEPb) to release the Pol II to finish what it started.

Understanding the details of this mechanism of gene control could thus have important implications for the treatment of a variety of ailments, said molecular biologist and clinician B. Matija Peterlin of the University of California, San Francisco, who also did not participate in the research. "I think it brings a whole new aspect to not just cancer [research] but" other diseases as well, Peterlin said. "If you attenuate the activity of P-TEFb, you might be able to [develop] a non-gene-modifying way treat a lot of human diseases."

P.B. Rahl, et al., "c-Myc regulates transcriptional pause release," Cell:141,1-14,2010.

Read more: More support for transcription trick - The Scientist - Magazine of the Life Sciences http://www.the-scientist.com/blog/display/57384/#ixzz0malxMCbC _the-scientist

Nano-Magnets Lead Stem Cells to Damaged Heart

A promising way of healing damaged heart tissue involves combining stem cells with nano-magnets.  The magnetised stem cells are then steered to the site of damage, using magnetic fields.

"Stem cell therapies show great promise as a treatment for heart injuries, but 24 hours after infusion, we found that less than 10 percent of the stem cells remain in the injured area," said Eduardo Marbán, M.D., director of the Cedars-Sinai Heart Institute. "Once injected into a patient's artery, many stem cells are lost due to the combination of tissue blood flow, which can wash out stem cells, and cardiac contraction, which can squeeze out stem cells. We needed to find a way to guide more of the cells directly to the area of the heart that we want to heal."
Marbán's team, including Ke Cheng, Ph.D. and other researchers, then began a new animal investigation, loading cardiac stem cells with micro-size iron particles. The iron-loaded cells were then injected into rats with a heart attack. When a toy magnet was placed externally above the heart and close to the damaged heart muscle, the stem cells clustered at the site of injury, retention of cells in the heart tripled, and the injected cells went on to heal the heart more effectively.
"Tissue viability is enhanced and heart function is greater with magnetic targeting," said Marbán, who holds the Mark Siegel Family Foundation Chair at the Cedars-Sinai Heart Institute and directs Cedars-Sinai's Board of Governors Heart Stem Cell Center. "This remarkably simple method could easily be coupled with current stem cell treatments to enhance their effectiveness." _Physorg

Image Source

The combination of stem cells with nanotechnology provides another synergistic surprise, loaded with hope for future cures and life extension potential.

Tomorrow's medical treatments will be more individualised, more targeted to specific systems and tissues. As a result, the collateral damage will be lessened, interventional dosing and exposure can be moderated, and a desired outcome can be made more likely.

Switching Off Cancer Using Nanoparticles

Cuanas
Scientists at Cal Tech in Pasadena have used targeted nanoparticles to alter the gene expression of cancer cells in human cancer patients. Their phase 1 clinical trial established the efficacy of their targeting approach and was published in the 21 March advanced online Nature.

Lead author Dr Mark E Davis, the Warren and Katharine Schlinger Professor of Chemical Engineering at Caltech, told the press that in principle:

"Every protein now is druggable because its inhibition is accomplished by destroying the mRNA."

"And we can go after mRNAs in a very designed way, given all the genomic data that are and will become available," he added.

However, as is often the case, what looks straightforward in theory is fraught with obstacles when you try and apply it in practice. One such difficulty, when trying to apply RNAi technology to humans is, how do you deliver such tiny, fragile molecules, the small interfering RNAs (siRNAs), to the tumors?

Senior author Dr Antoni Ribas, an associate professor of medicine and surgery and a researcher at UCLA's Jonsson Comprehensive Cancer Center, said:

"There are many cancer targets that can be efficiently blocked in the laboratory using siRNA, but blocking them in the clinic has been elusive."

Davis and colleagues had a solution: they had already been working on ways to deliver nucleic acids into cells before RNAi was discovered. They eventually came up with a method featuring four components, one of which is a unique polymer that can assemble itself into a targeted nanoparticle that carries siRNA.

Davis explained that their nanoparticles can take the siRNAs into the targeted site within the body, and when they reach their target, the cancer cells inside the tumor, the nanoparticles enter the cells and release the siRNAs.

The researchers used a new method developed at Caltech to find and image the nanoparticles inside cells biopsied from the tumors of several patients taking part in the trial.

They also found that the more nanoparticles a patient was given, the more were present in the tumor cells: thus establishing there was a dose-dependent response.

But what was even better, said Davis, was they found evidence the siRNAs had done their job: in the cells they analyzed, which had been targeted to prevent production of the cell-growth protein ribonucleotide reductase, they found the corresponding mRNA had been degraded. Thus effectively the siRNAs had silenced the gene that was fuelling cancer growth.

Davis explained that this was the first time that anyone has found an RNA fragment from patient cells showing that the RNAi mechanism had severed the mRNA at exactly the correct base:

"It proves that the RNA interference mechanism can happen using siRNA in a human," said Davis.

Ribas said:

"This research provides the first evidence that what works in the lab could help patients in the future by the specific delivery of siRNA using targeted nanoparticles."

"We can start thinking about targeting the untargetable," he added. _MedicalNews

As the authors say, this is just the beginning. Silencing gene expression by targeting the mRNA is only a temporary approach. If such treatment kills all of the cancer cells -- and leaves normal cells alone -- then being only temporary will not be an impediment.

But in many types of cancer -- and other disease -- it will not be enough merely to block the offensive mRNA. You will want to alter the DNA itself to put a permanent stop to the flow of a particular unwanted mRNA. That will require a different approach altogether.

The challenge is vast and seemingly unending. But it is worthwhile.

H/T Cuanas

New Hope for Treating Autoimmune Diseases

Cell
The autoimmune diseases cause untold pain, misery, and hardship -- not to mention expense -- throughout the human lifespan. When the person's immune system attacks other cells in his own body, treatment options are generally limited and sub-optimal. But now, researchers at the University of Alberta, Calgary, have devised a treatment (and prevention) for Type 1 diabetes which may lead to a revolution in the treatment and prevention of autoimmune diseases -- such as multiple sclerosis, rheumatoid arthritis, lupus, and many more.

Researchers from the University of Calgary in Alberta, led by Dr. Pere Santamaria, were looking to halt the autoimmune response that causes type 1 diabetes, but do so without damaging the immune cells that control and regulate the immune system or that protect against infections. So the team focused on developing a highly targeted antigen-specific immunotherapy - one, they explained, that could address the "internal tug-of-war between aggressive T cells that want to cause the disease and weaker T cells that want to stop it from occurring."

The researchers produced a unique vaccine comprising nanoparticles, which are thousands of times smaller than the size of a cell. They coated the particles with type 1 diabetes-relevant peptides, or protein fragments, that were bound to certain molecules that play a critical role in immune cell communication (called MHC molecules).

In the mice, the nanoparticle treatment expanded a type of regulatory T cell -- these cells ultimately suppressed the aggressive immune attack that destroys the insulin-producing beta cells of the pancreas. The researchers noted that the expanded cells shut down the immune attack by preventing autoreactive immune cells from being stimulated, either by the peptide contained in the vaccine or by any other diabetes autoantigen presented simultaneously by antigen-presenting cells. With the immune response that causes diabetes blocked, mice with type 1 diabetes regained normal blood sugars. And those that would have contracted the disease didn't.

The study also provides important - and promising - insight into the ability to translate these findings into therapeutics for people: Nanoparticles that were coated with molecules specific to human type 1 diabetes were able to restore normal blood sugar levels in a humanized mouse model of diabetes (that is, a mouse that has been genetically altered to biologically simulate type 1 diabetes in people). _ jdrf

Article abstract from Cell

H/T Brian Wang

Science is slowly but surely decoding the complex signaling involved in life, disease, and ageing. With the better tools being provided by advanced genetics, nanotechnology, immunology, and information technology, it is easy to feel that there are no secrets of life that will not be unwrapped and decoded sooner or later.

Human Cell Aging Reversed by Biotime

Biotime researchers report the successful resetting of the "age clock" of mature human cells back to the embryonic age. This was apparently accomplished using telomeric technology similar to what Geron has been working on.

In the article, BioTime and its collaborators demonstrate the successful reversal of the developmental aging of normal human cells. Using precise genetic modifications, normal human cells were induced to reverse both the "clock" of differentiation (the process by which an embryonic stem cell becomes the many specialized differentiated cell types of the body), and the "clock" of cellular aging (telomere length). As a result, aged differentiated cells became young stem cells capable of regeneration.
_NextBigFuture

More links, videos, and information from Brian Wang and at the BioTime website.

Hydrogen Sulfide Suspended Animation Video

Roth's technique replaces inhaled oxygen with hydrogen sulfide. Normally toxic, hydrogen sulfide has the curious ability to alter the mammalian metabolism when applied in a cold environment. Using this technique, Roth has already managed to place lab animals into suspended animation, and safely bring them back. When in a suspended state, the body can better cope with the deadly oxygen deprivation that results from shock, massive blood loss, and heart attacks.
Source

The 1000 Year Old Brain? Can They Last?

Aubrey de Grey claims that the first person to live 1,000 years is alive right now. Perhaps. But would anyone alive right now wish to live 1,000 years with a senile brain? Probably not. That is why it is so important to learn all we can about our brains, so that we can make the necessary improvements that will allow us to stay sharp, clear, and responsive to the many changes that the next 1,000 years will bring.

A World of Manics, Where No One is Depressed?

University of Maryland researchers have taken mice and knocked out PKCI/HINT1 genes -- resulting in mice that do not get depressed or anxious.

Wang said, "Although we don't yet know why the deletion of the gene altered the mood status of the mice, what we have learned about the importance of this gene in mood function and its involvement in human mental disorders is interesting. The protein encoded by this gene could be a potential drug target for development of diagnostic or therapeutic agents that one day might be used for depression, bipolar or schizophrenia disorders. In addition, the knockout mice might be useful as a model to study mania, as there is no other animal model available yet. __MNT

When thrown in the deep end of the pool, these PKCI/HINT1 knockout mice never gave up in despair, when all other mice simply rolled over and drowned. They were literally "never say die" mice. Imagine a world of such people.

Excitable Nerves, They All Said

Sometimes nerves can "excite themselves to death." This over-excitation of NMDA glutamate receptors may lead to Alzheimer's, Parkinson's, and multiple sclerosis -- among other neurodegenerative diseases.

....the N-methyl-D-aspartate receptor belongs to a family of cellular receptors that mediate excitatory nerve transmission in the brain.


Excitatory signals represent the majority of nerve signals in most regions of the human brain. One theory of causation in Alzheimer's, Parkinson's and multiple sclerosis posits that excessive amounts of the excitatory neurotransmitter, glutamate, can cause an overstimulation of glutamate receptors, including the NMDA receptor. Such excitotoxicity, the theory holds, can cause nerve-cell death and subsequent neurological dysfunction.


...The search is well under way for molecules that can shut down the NMDA receptor with much greater specificity. _MNT

Memories to Last 1000 Years?

Humans have short term memories (STMs) and long term memories (LTMs). Short term memory is necessary for maintaining a train of thought, or for remembering why you tied that string around your finger an hour or two ago. Long term memory is for remembering things that happened to you more than a day or so ago. These memories are formed and farmed out by the hippocampus, and the system usually works well for a lifespan of 70 or 80 years. But what happens when we live 1,000 years, and desperately need to remember something that happened 899 years ago?

Scientists have known that memories first form in the hippocampus and are later transferred to long-term storage in other parts of the brain. For some amount of time the memory resides both in the hippocampus and elsewhere in the brain. What’s not been known is how, after a few months or years, the memory is gradually cleared from the hippocampus.


Researchers have also debated the role of neurogenesis in learning and memory. The hippocampus is one of only two places in the adult brain where scientists know that new neurons form. On the basis of previous studies, many researchers think new neurons stabilize memory circuits or are somehow otherwise necessary to form new memories.


The new study suggests the opposite: Newborn neurons weaken or disrupt connections that encode old memories in the hippocampus.


Kaoru Inokuchi, a neuroscientist at the University of Toyama in Japan, and his colleagues used radiation and some genetic tricks to block neurogenesis in rats and mice that had been trained to fear getting a mild electric shock when placed in a particular cage. Control animals, with normal neurogenesis, eventually were able to bypass their hippocampi and retrieve the fear memory directly from long-term storage. But animals in which neurogenesis had been blocked still depended on the hippocampus to recall the fear memory, the researchers found.


Running on an exercise wheel, which boosts neurogenesis, also sped the rate at which old memories were cleared from the hippocampus. __Wired

Surviving the Addiction Bottleneck

The human brain has to survive through the treacherous years of childhood, adolescence, and early adulthood in order to gain the wisdom and experience to know how to live, and what to avoid like the plague. Children, adolescents, and young adults are prone to experimenting with drugs, alcohol, and high-risk / low reward behaviours. If the child becomes a crack whore or even an adolescent drunk or pothead like the US president, the 1,000 year prognosis can be very grim.

We need good ways of reversing the brain warp induced by early and habitual drug use.

Medical researchers led by Stephen Dewey at The Feinstein Institute for Medical Research and Dr. Jonathan Brodie of New York University School of Medicine recruited parolees who were cocaine dependent, each using an average of two grams of cocaine daily for nine years.


While half the participants in the study received a placebo powder mixed into their juice each day, half got a powder containing vigabatrin. After three months, 14 of the 50 study participants who got vigabatrin each day were able to abstain from cocaine use during the final three weeks of the study, compared with only 4 of the 53 who received the placebo. _MoneyTimes

It's a start. And in animals, the same drug reduces drug use for most every addictive substance. Of course, it will be harder to make up for the psychological neotenisation caused by poor childraising, abominable educational practises, and a horrifically dumbed down popular culture.

Does Evolution's Arrow Point to Smaller Human Brains?

Human populations that evolved nearer the equator ended up with generally smaller brains, and typically with lower IQ, than human populations that evolved farther from the equator. Anthropologist John Hawks says that the future may be bringing yet smaller brains to the entire global population.

“We know the brain has been evolving in human populations quite recently,” University of Wisconsin-Madison (UWM) paleoanthropologist John Hawks explains, quoted by LiveScience.

“When it comes to recent evolutionary changes, we currently maybe have the least specific details with regard [to] the brain, but we do know from archaeological data that pretty much everywhere we can measure – Europe, China, South Africa, Australia – that brains have shrunk about 150 cubic centimeters, off a mean of about 1,350. That's roughly 10 percent. As to why is it shrinking, perhaps in big societies, as opposed to hunter-gatherer lifestyles, we can rely on other people for more things, can specialize our behavior to a greater extent, and maybe not need our brains as much,” the expert adds. _Softpedia

Modern cultures of hyper-specialisation may lead to even greater shrinking of the human brain. That could be bad for that 1,000 year lifespan.

Smaller brains are typically less intelligent, and will probably be less able to adapt to the lightspeed changes that will hit human populations like truckloads of bricks, every few years to every few dozen years.

Cross-posted at Al Fin

Stem Cell Advances

Any adult cell can become a stem cell. This is a striking finding from the Cambridge, Mass. researchers.

“Essentially, all cells have the potential to become pluripotent. It is something that seems to happen to the cells under these conditions stochastically — that is, in a continuous, but probabilistic fashion,” Jaenisch explains. _Softpedia

Stem cell treatment restores limb function in rats with cervical spine injuries. The UCI team used human embryonic stem cells (pre-oligodendrocytes) that "rebuilt myelin, stopped tissue death and triggered nerve fiber regrowth".

Patients with advanced leukemia successfully treated with stem cells. Of the 58 patients, 35% survived 3 years -- an exceptionally good result for patients at such an advanced stage.

New technique developed to separate "safe" from "unsafe" stem cells before therapy. Stem cells vary in their likelihood to grow out of control and cause malignancies. "Undifferentiated" stem cells are more likely to lose control of growth.

Scientists from Invitrogen and the Buck Institute for Age Research, located in Novato, California, collaborated in developing this innovative solution that depletes greater than 99% of undifferentiated human embryonic stem cells from differentiated populations. They are presenting data on this new technology at the International Society for Cellular Therapy Meeting in San Diego. __LabmateOnline

Stem cells provide the bricks and mortar for constructing human tissues and organs. We are just beginning to learn how to create them, and to use them safely and efficaciously. In ten years -- if the US biomedical system has not been completely destroyed by government intervention -- we will look back to the present, amazed that human medicine was ever so primitive and hopelessly ineffective.

SENS4 Conference in Cambridge England Underway

Kristen Fortney from Ouroborus blog is covering the 4th Strategies for Engineered Negligible Senescence conference, presently underway in Cambridge, England. Below are some excerpts of Kristen's coverage, courtesy of Fight Aging:

SENS4, Session 1: Combating oxidation

Cathy Clarke tested an original and interesting approach to avoiding free radical damage to poly-unsaturated fatty acids, or PUFAs: isotope reinforcement. ... The basic idea here, explained in an earlier paper, is very simple: heavier isotopes make stronger bonds, so isotope-reinforced PUFAs will be more resistant to free radical attack. Will these results transfer to higher organisms? Is there any chance that the deuterium could get incorporated into other molecules, stabilizing proteins that we want to degrade? The authors plan to follow up this study in worms and mice.

SENS4, Session 3: Optimising metabolism against aging

Stephen Spindler described his (ongoing) project to screen a large number of potential lifespan-affecting compounds in mice - so far, several candidates look promising. Interestingly, he also argued that the majority of previous studies measuring the effects of various compounds on rodent life expectancy suffer from serious flaws. In particular, he argued that many of them were confounded by a possible calorie restriction effect: mice are picky eaters, and if you change their diet by adding some compound to it, they will often eat less of it.

SENS4, Session 4: Adult regenerative capacity

Brandon Reines presented a counterintuitive result on regeneration: sometimes old animals have a higher regenerative capacity than young animals. In particular, if you punch a hole in the ear of a young mouse, then it won’t heal; but in a middle-aged mouse it will heal completely. He argued that this happens because mouse ear connective tissues never fully differentiate, and suggested that other neural-crest-derived connective tissues might show similar properties.

SENS4, Session 5: Eliminating recalcitrant intracellular molecules: the lysosome

John Schloendorn discussed ongoing work at the SENS Foundation Research Center to develop new enzymes that can degrade harmful intracellular junk that accumulates with age. So far, they have discovered enzymes that can degrade A2E and 7-ketocholesterol, which are implicated in macular degeneration and osteoporosis, respectively. Their next step will be to construct a drug delivery system to get these enzymes to lysozomes ... On the lighter side, Schloendorn also described some of the Center’s methods for building functional lab equipment on the cheap, all good examples for aspiring DIY biologists.

SENS4, Session 6: Eliminating recalcitrant intracellular molecules: other

Claude Wischik spoke about preventing aggregation of tau protein, which is implicated in Alzheimer’s disease. Clinical trials of their aggregation-inhibiting drug Rember are promising: it seems to slow the down the rate of cognitive decline in patients with mild to moderate Alzheimer’s disease.

SENS4, Sessions 9 and 10: Rejuvenating extracellular material

Kendall Houk gave a very interesting talk on computationally designing enzymes from scratch. They plan to apply their recently published protocol to develop enzymes that can reverse the formation of Advanced Glycation End-products (AGEs) - sugar-modified proteins that accumulate with age and are implicated in several age-related diseases. _links to more information

Ouroborus is updating Kristen's coverage as it comes in.

Twitter updates

Aubrey de Grey's SENS initiative has achieved prominence in scientific gerontology, thanks to financing from the Methuselah Foundation. Under most government health care and pension systems, long life is a bad thing, since the longer you live, the longer the government has to support your existence. That may be why so little progress was made under government financed gerontology research.

With private funding via SENS, expect much more progress. The same applies to private financing of space launch, and other crucial innovations. The private sector is all about getting results. The government is all about soaking up as many resources as possible, growing as large as possible, and employing as many public sector union members as possible.

Cross posted at Al Fin

Giving Babies Healthy Mitochondria

Scientists at the Oregon National Primate Center have succeeded in producing healthy rhesus infants using the egg nucleus from one female transplanted into the enucleated cytoplasm of another female. The mitochondria from the cytoplasmic component reproduced normally alongside the nuclear material from the nuclear component, without contamination of mitochondria from the nucleus donour.

For their experiments, Mitalipov and his colleagues extracted DNA from the nucleus of monkey eggs; the nucleus contains the genes for most of a creature's traits. The researchers then transplanted that DNA into eggs from other females that had healthy mitochondrial DNA but from which the nuclear DNA had been removed.

They then fertilized the eggs in the laboratory and transferred 15 of the resulting embryos into the wombs of nine females. Two twins were born -- named Mito and Tracker -- along with two other offspring, Spindler and Spindy. So far, all the offspring appear to be healthy. _WaPo_via_ImpactLat

This research shows the way to new techniques for using cytoplasmic donour eggs to assure healthy offspring for mothers who may carry deficiencies for mitochondria -- which have their own DNA, for the most part.

Assuring mitochondrial health is one of the most important bases for overall health and longevity.

While this technique will only work for animals at the egg stage, there is no reason not to believe that advanced forms of mitochondrial culturing and transplant will not occur. Eventually, interventional genetic therapies will be developed which will move most of the genetic material from the mitochondria -- where it is subjected to extreme mutagenic oxidative stress -- to the nucleus where it would be better protected. That is one of the foundations of the SENS approach to longevity.

Hope for the Aging Brain

An intriguing finding from the University of South Florida offers new hope for rejuvenating aged and amyloid-clogged brains.

GCSF is a blood stem cell growth factor or hormone routinely administered to cancer patients whose blood stem cells and white blood cells have been depleted following chemotherapy or radiation. GCSF stimulates the bone marrow to produce more white blood cells needed to fight infection. It is also used to boost the numbers of stem cells circulating in the blood of donors before the cells are harvested for bone marrow transplants. Advanced clinical trials are now investigating the effectiveness of GCSF to treat stroke, and the compound was safe and well tolerated in early clinical studies of ischemic stroke patients.

....The researchers showed that injections under the skin of filgrastim (Neupogen®) — one of three commercially available GCSF compounds — mobilized blood stem cells in the bone marrow and neural stem cells within the brain and both of these actions led to improved memory and learning behavior in the Alzheimer’s mice. “The beauty in this less invasive approach is that it obviates the need for neurosurgery to transplant stem cells into the brain,” Dr. Sanchez-Ramos said.

Based on the promising findings in mice, the Alzheimer’s Drug Discovery Foundation is funding a pilot clinical trial at USF’s Byrd Alzheimer’s Center. The randomized, controlled trial, led by Dr. Sanchez-Ramos and Dr. Ashok Raj, will test the safety and effectiveness of filgrastim in 12 patients with mild to moderate Alzheimer’s disease _Biosingularity

As noted, the reversal of Alzheimer's brain damage occurred in research mice -- a mouse "Alzheimer's model" involving 52 aged study mice. If the trial involving 12 human patients shows promise, expect several larger human studies.

In my opinion, Alzheimer's Disease is every bit the crisis that AIDS represents, and the search for therapies for Alzheimer's should be given at least as much funding and regulatory impetus as the research effort into HIV and AIDS has been given. Unfortunately, President Obama and his administration are sending signals that advanced medical care for the aged will be given an extremely low priority under Obamacare.

Another stem cell growth factor -- EGFL7 -- may play a large role in therapies for a wide array of conditions involving brain degeneration and damage.

The findings of Schmidt and Dikic offer a plethora of medical applications. Maturation of adult stem or precursor cells is significant for the development of multiple tissues, e.g. in the central nerve system or in the heart. Moreover, cancer stem cells have been described, which are important for the formation of tumors, especially in the human brain. EGFL7 might also be applied as a neuronal differentiation factor in ischemic insults or neurodegenerative diseases such as Alzheimer or Parkinson predict both researchers. Future work will unravel in which diseases EGFL7 can unfold its therapeutic potential. _Biosingularity

We are likely to find dozens of growth factors and differentiation factors that will come into play in the reversal of degenerative, traumatic, and age-related diseases of the brain. It will take time, investment, and long hours of dedicated research by an army of bright and well-trained researchers with open minds.

It is also important to eat the right foods, and to get plenty of exercise. Thinking "young" can also keep the brain more vital. Seek out new experiences and adventures. Try new foods, travel within your means, renew old friendships and make new ones.

It is easy to tell the difference between people who have given up, and those who will be scrapping right up to the end. Try to be a scrapper.

Will This Metallomolecule Help to Extend Life?

Perhaps it will extend life. It can kill cancer, kill deadly resistant microbes, and may become a key part of the SENS anti-aging platform. Here is how:

The compound [Fe2L3]4+ is an iron triple helicate with three organic strands wrapped around two iron centres to give a helix which looks cylindrical in shape and neatly fits within the major groove of a DNA helix. It is about the same size as the parts of a protein that recognise and bind with particular sequences of DNA. The high positive charge of the compound enhances its ability to bind to DNA which is negatively charged.

When the iron-helicate binds to the major groove of DNA it coils the DNA so that it is no longer available to bind to anything else and is not able to drive biological or chemical processes. _PO

The interesting structure known as [Fe(2)L(3)](4+) was first researched as a treatment for cancer. But University of Warwick researchers have discovered that the metallomolecule is a particularly potent killer of bacteria -- even bacteria that are resistant to conventional antibiotics.

Initially the researchers focused on the application of this useful property for targeting the DNA of cancer cells as it could bind to, coil up and shut down the cancer cell's DNA either killing the cell or stopping it replicate. However the team quickly realised that it might also be a very clever way of targeting drug-resistant bacteria.

New research at the University of Warwick, led by Dr Adair Richards and Dr Albert Bolhuis, has now found that the [Fe2L3]4+ does indeed have a powerful effect on bacteria. When introduced to two test bacteria Bacillus subtilis and E. coli they found that it quickly bound to the bacteria's DNA and killed virtually every cell within two minutes of being introduced - though the concentration required for this is high. _PO

It will be important for the researchers to learn ways that the compound can be preferentially transported across bacterial membranes, to bacterial DNA. By reducing the necessary concentrations needed to kill the bacteria, and by making the construct preferentially attracted to pathological bacteria rather than to normal human cells, the safety and the efficacy of any possible future treatment using this compound will be enhanced.

The prevalence of antibiotic resistance has resulted in the need for new approaches to be developed to combat previously easily treatable infections. Here we investigated the potential of the synthetic metallomolecules [Fe(2)L(3)](4+) and [Cu(2)(L')(2)](2+) as antibacterial agents.... [Fe(2)L(3)](4+) binds in the major groove and causes DNA coiling... The work described here shows that ... [Fe(2)L(3)](4+) is bactericidal for Bacillus subtilis and Escherichia coli. We demonstrate that [Fe(2)L(3)](4+) binds bacterial DNA in vivo and, strikingly, that it kills B. subtilis cells very rapidly. _IntJnlAntimicrobialAgents

Cytocidal approaches are valuable medically to the extent they can be targeted and controlled -- with only limited damage to normal cells and tissues.

One of the main pillars of the SENS anti-aging approach is the elimination of superfluous and dangerous cells that have outlived their usefulness. The more precisely that one can target cytotoxic molecules, the more useful they will be for anti-aging therapies in addition to more conventional medical disciplines such as oncology and infectious disease.

Cross-posted at Al Fin

Regenerative Medicine Gets a Boost

Blood disorders are likely to be the first targets for therapy because corrected cells can easily be transferred back to the patient via bone-marrow transplants. _TechnologyReview

Salk Institute researchers in La Jolla have demonstrated a technique that opens the door to cures for several genetic blood diseases. It involves taking a patient's skin cells, treating them genetically to correct the inherited disorder, next turning the skin cells into induced pluripotent stem cells (iPS), then differentiating those iPS into progenitor cells. These progenitor cells can be implanted into the patient to provide a supply of normal blood cells.

"This is an exciting bit of science," says Chris Mason, a professor of regenerative medicine at University College London, who was not directly involved in the research. "It's likely to be the first of a slew of similar papers that may offer hope for conditions where today there is no real therapy, let alone a cure."

So far, Belmonte's approach is applicable only to diseases in which the genetic defect that underlies the disease has been identified. "But there are quite a few of these--and the number will increase," says Mason. Blood disorders are likely to be the first targets for therapy because corrected cells can easily be transferred back to the patient via bone-marrow transplants.

Belmonte adds that in the future, the correction of more-complex genetic disorders might become possible, thereby significantly increasing the number of diseases that might be treated with altered iPS cells. _TechnologyReview

If the bone marrow can be "re-stocked" with viable normal blood progenitor cells, the inherited blood disorder may indeed be cured. The concept can be extended to other inherited and acquired genetic diseases with extensive work.

Such approaches to cell and tissue replacement open the door to significant extension of maximum life span.

Taken from an earlier post at Al Fin

Tiny Porous Nano-Spheres Carry 2 Drugs at Once

Ames Lab researchers at Iowa State University continue their work with porous silica nano-spheres as drug delivery systems. This time, they have devised nano-systems capable of delivering two different drugs simultaneously.

A boronic acid-functionalized mesoporous silica nanoparticle-based drug delivery system (BA-MSN) for glucose-responsive controlled release of both insulin and cyclic adenosine monophosphate (cAMP) was synthesized. Fluorescein isothiocyanate-labeled, gluconic acid-modified insulin (FITC-G-Ins) proteins were immobilized on the exterior surface of BA-MSN and also served as caps to encapsulate cAMP molecules inside the mesopores of BA-MSN. The release of both G-Ins and cAMP was triggered by the introduction of saccharides. The selectivity of FITC-G-Ins release toward a series of carbohydrate triggers was determined to be fructose > glucose > other saccharides. The unique feature of this double-release system is that the decrease of FITC-G-Ins release with cycles can be balanced by the release of cAMP from mesopores of MSN, which is regulated by the gatekeeper effect of FITC-G-Ins. In vitro controlled release of cAMP was studied at two pH conditions (pH 7.4 and 8.5). Furthermore, the cytotoxicity of cAMP-loaded G-Ins-MSN with four different cell lines was investigated by cell viability and proliferation studies. The cellular uptake properties of cAMP-loaded FITC-BA-MSN with and without G-Ins capping were investigated by flow cytometry and fluorescence confocal microscopy. We envision that this glucose-responsive MSN-based double-release system could lead to a new generation of self-regulated insulin-releasing devices. _ACS

The ability to release two interacting substances from separate compartments in a nano-delivery system, provides for much longer shelf life and greater potency at the time of delivery. In this case, the payoff will be stop-gap implantable blood glucose regulation.

For long term control of diabetes, working cellular systems that can synthesise their own insulin are preferable to artificial systems. In general, the same principle is valid for all replacement organs and systems.

Replacement parts that can repair themselves, and work in concert with the rest of the body, are preferable to "one trick pony" replacements that too easily give out.

Almost certainly the best use of the Ames nano-spheres will be for genetic therapies to permanently alter gene expression of cells and tissues. But for now, proving the extent of functionality of this delivery system remains important.

50 Best Anti-Ageing Blogs

The Ultrasound Technician Schools blog has put together a list of the 50 top anti-ageing blogs, for those who want to follow the broad range of online approaches to ageing and longevity.

Some of Al Fin's favourites that are on the list include Fight Aging, Ouroboros, and the Alliance for Aging Research.

Al Fin Longevity -- this blog -- finds itself on the top 50 list under the category of Longevity and Life Extension at #43.

As a side topic, I have noticed several healthcare training related blogs that provide wide ranges of lists of blogs for various topics. Some of these lists are quite useful. In fact, I would like to see a list of the top 100 list-making blogs. Wait -- what about a top 100 list of lists of top 100 list-making blogs? How about ..... Thwack!!

All righty then. My domestic android, Valerie, has just slapped me to bring me out of my list fugue. As Valerie points out, by the time you compiled the ultimate top 100 list of top 100 lists of lists of top 100 list-making blogs, the entire list would probably be obsolete. Please pardon me for the regression.

As scientific research pushes on, an extended lifespan becomes much more likely. The challenge will be not so much to keep living, but to combine the optimum mixture of enjoyable and important activities in order to fill one's life satisfactorily.

More important than improving the quantity of life is improving the quality of life. But doing both at the same time beats either one alone.