The Mystery of Epigenetic Heredity, and Its Possible Impact on Longevity

The basic mechanisms of life and inheritance function much the same in worms, fruit flies, mice, and humans. That is one reason why lower life forms are used so often in longevity research. Much shorter lifespans is another reason. A recent Stanford study on worms provides a hint at an epigenetic method of inheritance which may eventually prove useful for extending lifespans in human offspring.

The study used Caenorhabditis elegans worms with very low levels of the SET-2 enzyme. The SET-2 enzyme normally adds methyl molecules onto DNA's protein packaging material. In doing so, the enzyme opens up the packaging material, allowing the genes to be copied and expressed. Some of those genes appear to be pro-aging genes, says Brunet. Her team knocked out SET-2 by removing genes that code for it. This had the effect of significantly lengthening the worms' lifespan, presumably because those pro-aging genes were no longer expressed.

Next, the long-lived, enzyme-lacking worms mated with normal worms. The offspring had the regular genes for making SET-2, and even expressed normal amounts of the enzyme, but they lived significantly longer than control worms whose parents both had regular lifespans. The life-extending effect carried over into the third generation, but returned to normal by the fourth generation (in the great-grandchildren of the original mutant worms). For the first few generations, having a long-lived ancestor increased life expectancy from 20 days to 25, extending a worm's life by 25 to 30 percent on average.

Brunet and her team haven't yet determined the exact mechanism for the lifetime extension, or which molecules are at work. This is one of the study's imperfections, says David Katz, who researches epigenetic transcriptional memory at Emory University. Regardless, "the effect is clearly epigenetic," he says, "and it's probably one of the most complicated traits that has been linked to epigenetic inheritance."

...The results, published October 19 in Nature (Scientific American is part of Nature Publishing Group), provide the first evidence that some aspects of lifespan length can be passed from parent to offspring, independent of the direct influence DNA. _SciAm

Contrary to what Dr. Katz asserts above, the fact that the research team hasn't determined the exact mechanism for the lifetime extension is one of the study's great promises.

Remember, it is often the questions that a study raises which causes the study to become frequently cited, and immortalised -- not necessarily the questions the study answers. Studies that raise good questions often act as springboards for entire new developments in science. Such may be the case here.

What Supplements Should Be Taken to Preserve the Brain?

A recent study published in the Journal of Intelligence looked at the effects on IQ of a proprietary combination of nutritional supplements, called Ceretrophin, vs. placebo. The combination is made up of Huperzine A, Vinpocetine, Acetyl-l-carnitine, R. Rosea and Alpha-lipoic acid, all readily available over the counter in the US. The researchers tested the subjects on Ravens Advanced Progressive Matrices (APM) prior to treatment and after 4 weeks of treatment or placebo.

A significant study visit (time) treatment condition interaction was found: F (1, 57) = 7.279, p = 0.009, partial 2 = .113, with paired samples t-tests revealing a significant improvement in mean APM score from baseline to retest (week 4) (t(34) = 4.045, p < .001) for the Ceretrophin group. Improvements in APM scores could be attributed to the active intervention over the placebo, indicating that the treatment improved general intelligence. Implications for improving our understanding of the biological basis of intelligence and pharmacologically improving human cognition are discussed. _Intelligence_via_Inductivist

Ron Guhname at the Inductivist blog suggests that this improvement in Ravens APM scores represents an increase in IQ score of 6 points (see comment at link).

The assortment of supplements included in "Ceretrophin" provides a wide spectrum of effects on neural tissues, including anti-inflammatory, stimulant, vascular, and neuroreceptor effects.

In addition to the supplements listed, there are a number of others which should be considered, including curcumin and omega 3 fatty acids. It would be easy to go overboard on taking supplements, so make sure that you find a good justification for each supplement that you choose to take. Also keep in mind possible interactions between supplements, between supplements and any drugs you may take, an any potential of supplements to exacerbate a pre-existing condition you may have.

In general, the doses of supplements and herbs available OTC in pills and capsules in western nations, should not represent significant risk to most individuals.

Al Fin gerontologists and cognitive scientists do not dispute the findings in the study, although they feel the sample size was too small for definitive conclusions. Nevertheless, the study suggests that similar research with larger sample sizes and a variety of supplement combinations could be justified.

Brain Implants are Coming: Can They Repair Stroke Damage?

Recent research on rats at Tel Aviv University is offering hope that we may soon have access to brain implants which could help to bypass damaged areas of brain, and allow relatively normal functioning after stroke and other types of brain damage.

Matti Mintz of Tel Aviv University in Israel and his colleagues have created a synthetic cerebellum which can receive sensory inputs from the brainstem - a region that acts as a conduit for neuronal information from the rest of the body. Their device can interpret these inputs, and send a signal to a different region of the brainstem that prompts motor neurons to execute the appropriate movement.

"It's proof of concept that we can record information from the brain, analyse it in a way similar to the biological network, and return it to the brain," says Mintz, who presented the work this month at the Strategies for Engineered Negligible Senescence meeting in Cambridge, UK.

...The team analysed brainstem signals feeding into a real cerebellum and the output it generated in response. They then used this information to generate a synthetic version on a chip that sits outside the skull and is wired into the brain using electrodes.

To test the chip, they anaesthetised a rat and disabled its cerebellum before hooking up their synthetic version. They then tried to teach the anaesthetised animal a conditioned motor reflex - a blink - by combining an auditory tone with a puff of air on the eye, until the animal blinked on hearing the tone alone. They first tried this without the chip connected, and found the rat was unable to learn the motor reflex. But once the artificial cerebellum was connected, the rat behaved as a normal animal would, learning to connect the sound with the need to blink.

...The next step is to model larger areas of the cerebellum that can learn a sequence of movements and test the chip in a conscious animal - a much greater challenge. "This is very demanding because of the decrease of [neural] signal quality due to artefacts caused by movement," says Robert Prueckl of Guger Technologies in Graz, Austria, who is working with Mintz. He thinks this can be achieved, though, by developing improved software to tune out noise and better techniques for implanting the electrodes. Ultimately, the goal is to build chips that can replicate complex areas of the brain _NewScientist

Yes, the implant used by the researchers was only able to substitute for a small part of the cerebellum -- which is only one part of the brain. Still, it is a start. The challenge is to enlarge and consolidate this understanding of the motor system. Then we can move beyond these early victories to the far more complex and difficult challenges of substituting for more complex signaling that occurs in the cortical and subcortical tissues.

And yet it would be best not to underestimate this achievement. The cerebellum helps to control and coordinate body movement, which is a very important function of being human. Those who have lost the ability to initiate, control, coordinate, and terminate basic movements, understand how important the motor system is to quality of life.

Cyborg brain part replacement is not the end goal, of course. We really want to re-grow any damaged brain parts or nerve connections which have been lost. But cyborg replacements will be an important bridge between where we are now and where we would like to go.

IPS Stem Cells Are Looking More Promising for Regenerative Medicine

George Church is a professor of genetics at Harvard Medical School. He is becoming more and more deeply involved in the field of regenerative medicine, using induced pluripotent stem cells (IPS). Church was interviewed recently on how he sees the field of IPS regenerative medicine progressing.

A pioneer in developing DNA sequencing technologies, and in researching everything from epigenetics and microbiomics to synthetic biology, Church has co-founded or advises over 20 companies. He also has launched the Personalized Genome Project with a goal of sequencing the complete genomes of 100,000 volunteers.

When I asked Church what he was most excited about right now, he answered without hesitation: "I'm thinking a lot about using regeneration as the key to treatments and keeping people healthy."

TR: You mean regeneration using stem cells?

Church: Yes, induced pluripotent stem (IPS) cells (see, "Growing Heart Cells Just for You"). This is where I'm putting almost all of my chips these days, because it combines many of my interests--genomics, sequencing, epigenetics, synthetic biology, stem cells. I don't think people have fully appreciated how quickly adult stem cells and sequencing and synthetic biology have progressed. They have progressed by orders of magnitude since we got IPS. Before that, they basically weren't working.

Is this because IPS cells are relatively easy to create and to engineer?

You can use them to reprogram genomes--not sequence them, but to reprogram them genetically and epigenetically. In other words you make the minimum changes it takes to get them where you want them to be genetically and epigenetically and then you program the cells into tissues.

What do you mean?

Let's use stem cells in bone marrow as an example. They are easy to use and to get to work when you implant them in bone marrow. You might one day have three choices. You can have bone marrow from someone else that is matched to you, or that is from you, or bone marrow that is matched to you and comes to you, but is better than you. This better bone marrow might be [engineered to be] resistant to one virus, or to all viruses. It could have a bunch of alleles that you picked out of super centenarians, alleles that you have reason to believe are at least harmless and possibly helpful. So now you have choice, a patient who can take a good bone marrow that he might reject and you'll be on immunosuppressants your whole life. Or you might use your own, or your own that might fix the cancer, or your own enhanced bone marrow. And you will be able to do that for almost every stem cell population. Some of them are a little bit harder to replace, though.

Does IPS really work to accomplish this regeneration?

We have good evidence that you can create an entire mouse from IPS cells.

Has this been done?

This has been done. They have used IPS cells to grow a mouse, and they made IPS cells from that mouse. They're totipotent [able to make an entire organism], not merely pluripotent. We haven't done this for humans for obvious ethical reasons, but we will do it. As far as I know the mice have done fine.

But haven't there been some problems with mutations occurring with IPS-generated tissue?

We have a recent paper in Nature that shows that when you make human induced pluripotent stem cells you actually do get mutations in coding regions at a slightly elevated level. But I think this is temporary. We're going to use this information as an assay to make the process work better, to correct problems. You will be able to use this to improve the quality of gene therapy because that's been the problem with gene therapy the last ten years.

How far are we from testing that in humans?

Almost everything I've described has been done in rodents, so we're talking about years, not decades. It's shorter than the Human Genome Project [which took 13 years], not less expensive, but definitely shorter. _TechnologyReview

Scientists at the University of Toronto have recently made a breakthrough in the control of IPS cells' pluripotency:

Scientists have found a control switch that regulates stem cell “pluripotency,” the capacity of stem cells to develop into any type of cell in the human body. The discovery reveals that pluripotency is regulated by a single event in a process called alternative splicing.

Alternative splicing allows one gene to generate many different genetic messages and protein products. The researchers found that in genetic messages of a gene called FOXP1, the switch was active in embryonic stem cells but silent in “adult” cells—those that had become the specialized cells that comprise organs and perform functions.

“It opens the field to the fact that alternative splicing plays a really important role in stem cell pluripotency,” said Prof. Benjamin Blencowe, principal investigator on the study and a Professor in the University of Toronto’s Departments of Molecular Genetics and Banting and Best Department of Medical Research. “We’re beginning to see an entirely new landscape of regulation, which will be crucial to our understanding of how to produce more effective pluripotent stem cells for therapeutic and research applications.”

The findings were published in the current online edition of the scientific journal Cell. _Source

These are some fascinating developments, which will eventually lead to advanced therapies for diseases which are currently untreatable, such as cancers and end stage degenerative diseases of the heart, lungs, liver, kidneys, and brain.

The ability to grow replacement organs from stem cells is already being proven in animals. The ability to regenerate a badly degenerated organ in situ, using stem cells, is also being proven. According to George Church, stem cells are also the best method for making genetic improvements to organs and organisms.

BioHeart's clinical stem cell trials in Mexico

ThermoGenesis an early commercial entrant into the human stem cell regenerative medicine industry

Molecular Circuits Learn to Trigger Targeted Cancer Cell Death

Discover
An international team of researchers has learned to use micro-RNA circuits to trigger targeted cell death in HeLa cells, widely used cultured cervical cancer cells, orginally taken from a woman who died long ago. Although it is too late for this information to help Henrietta Lacks, it is possible that this approach -- or something like it -- may be used to trigger the large-scale suicide of a wide range of cancer cells eventually.

Xie has developed a genetic “logic circuit” that prompts cells to kill themselves if the levels of five molecules match those of a cancer cell. Yaakov Benenson, who led the study, says, “In the long term, the circuits’ role is to act like miniature surgeons that can identify and destroy cancer cells.” That is a very long way off, but the study is a promising step in the right direction.

Xie worked with HeLa cells, a common line of cervical cancer cells taken from a tobacco farmer called Henrietta Lacks in 1951. Since then, they have become one of the most important tools in modern medicine. Xie identified five small molecules called microRNAs that act as a signature for HeLa cells, separating them from healthy ones. Two of the microRNAs are unusually common in HeLa; three are unusually rare.

Next, Xie created five genetic switches that would only flip if their respective microRNAs were found at the right levels. The switches control a gene called Bax, an executioner that compels a cell to kill itself. If the circuit is introduced into a cell that carries the molecular signature of HeLa, all five switches flip, Bax is roused into action, and the cell automatically self-destructs.

Xie rigged his circuit so that Bax could be restrained by each of the three microRNAs found at low levels in HeLa cells. The gene would only activate if all three molecules were largely absent; any one of them could stay the executioner’s hand. Meanwhile, the two microRNAs that are common in HeLa actually lift restraints on Bax, by blocking genes that keep it in check. Again, the circuit needs high levels of both of these molecules. If either is absent, Bax is held back.

This clever set up means that all five switches must to be flipped before the executioner carries out it bloody work. The cell only dies if it meets every one of five conditions. And Xie found that his circuit worked in practice. It activated Bax at far higher levels in HeLa cells and selectively killed them while leaving other lineages of laboratory cells unharmed. _Discover

Article abstract from Science

More from ArsTechnica

More from ETH Zurich via Nanowerk

Al Fin research oncologists and molecular biologists feel that Benenson's approach is more than a bit awkward and prone to breaking down. But he is working at a level of gene regulation which should prove relatively safe, as it moves closer to clinical research. And he is working at a level of complexity which should prove fertile for learning more about the molecular networks of cancer.

Expect some fascinating developments to come from this line of research.

Why Do Old Brains Prefer Young Blood?

A paper published today in Nature finds that when younger mice are exposed to the blood of older mice, their brain cells behave more like those found in aging brains, and vice versa. The researchers who carried out the work also uncovered chemical signals in aged blood that can dampen the growth of new brain cells, suggesting that the decline in brain function with age could be caused in part by blood-borne factors rather than an intrinsic failure of brain cells. _TechnologyReview

Many things change in the human body as we age. Our cells lose their ability to repair incidental damage, and produce less and less energy for our ever-less efficient muscles. We produce lower levels of hormones which help us, and higher levels of chemicals that cause inflammation and cellular damage.

It has been found that young blood can reverse certain signs of aging in the circulatory systems of old mice. Now there is evidence that young blood can help rejuvenate old brains.

To arrive at the discovery, the researchers studied pairs of old and young mice that were literally joined at the hip. They used a technique called parabiosis, in which two mice are surgically joined together along the flank, which causes them to develop a shared circulatory system. The technique has been used to study the development of the blood system, and more recently has been used to investigate the effects of age by joining old and young mice.

Lead author Tony Wyss-Coray, a neuroscientist at Stanford University, says that five weeks after creating these May-December pairings, "we found striking effects both on the young and old brains." The young mice had a reduction in the production of new neurons (neurogenesis), an increase in brain inflammation, and less activity in synapses connecting neurons.

The older mice, in contrast, had an increase in new neurons, less inflammation, and greater activity at synapses. "You could almost call this a rejuvenation effect," Wyss-Coray says.

...To see whether the effect could influence behavior, they injected, in separate experiments, young mice with plasma from older mice and vice versa, and found that old plasma impaired the younger animals' ability to perform learning and memory tasks, whereas young plasma improved the abilities of older mice.

Blood cells from one mouse cannot travel into the brain of the other because of the blood-brain barrier, so the team concluded that free-floating molecules in the blood, capable of passing through, must be responsible for the effects. By comparing more than 60 chemokines—chemical messengers secreted by cells that circulate in the blood—the researchers identified several associated with the detrimental effect of old blood. Administering one of these chemicals, called CCL11, to young mice dampened neurogenesis and impaired learning and memory. CCL11 has been studied for its role in allergies and asthma, but it's not clear how it influences neurons. _TechnologyReview

Does this mean that those of us who wish to stay young will have to prey on our young like vampires, sucking their life's blood for our own sustenance? No. For we are learning how to take our old cells and make them young again, in vitro -- in the test tube. The goal is to do the same thing, only better, and in vivo.

Such cellular rejuvenation treatments are likely to excellent stopgap methods of anti-aging, with significant -- but limited -- effects. The lifespans we live will be lived as younger, more vital monkey-men. And that is worth a very great deal.

But if we wish to live significantly longer lives, at significantly higher levels of awareness, intellect, and invention, we will need to go deeper than cellular replacement and humoral replacement therapies of this type.

Extending Brain Plasticity and Learning into Later Life

Dendrites integrate synaptic inputs to neurons, and their branching is thought to be related to their representational capacity [24]. Branching patterns of dendritic trees are related to the degree of compartmentalization of inputs to the cell and a stronger potential for compartmentalization (i.e. more complex branching) has been proposed to increase the representational power of the cell resulting in greater learning and memory capacity [24]. Dendritic structure appears to be regulated during development in part by calcineurin [26]. Dendritic spines, which comprise the post synaptic element of over 90% of cortical excitatory synapses, are thought to be particularly important for learning and memory [18]. _ScienceDirect

ScienceDirect
An international team of researchers from Yale, University of Zagreb, and VU University in Amsterdam, have discovered that plasticity and pruning of dendritic spines in the human prefrontal cortex continues well into adulthood, throughout the 20s.

Pasko Rakic at Yale University and colleagues at the University of Zagreb, Croatia, and the VU University Medical Center in Amsterdam, the Netherlands, have now found that the brains of adults in their 20s are still subject to synaptic pruning.

Rakic's team analysed post-mortem tissue from a brain region called the prefrontal cortex (PFC) in 32 people aged between 1 week old and 91 years. Specifically, they calculated the density of dendritic spines – the tiny projections that protrude from the neuron's long dendrites, each of which facilitates communication with other neurons through a synapse.

As expected, Rakic's team found that spine density increased rapidly during infancy, reaching a peak before the 9th birthday. It then began to fall away as pruning began. Intriguingly, though, spine density did not plateau after adolescence, as might have been expected, but continued to fall gradually until the late 20s.

Rakic says the result could be good news for those hoping to gain new skills in their third decade. The period of pruning is associated with a heightened ability to learn – whether that is in picking up language skills or understanding new concepts, he says. "You should not give up learning just because you're in your 20s – it isn't too late," he says. _NewScientist

Abstract for PNAS paper

It has been shown that in rats, age related loss of normal dendritic density in prefrontal cortical neurons, occurred at the same time as loss of experience-related dendritic plasticity.

The goal of researchers is to develop ways to extend the optimal periods of brain learning well beyond young adulthood, into middle age and beyond. A Harvard - Mass General study published in Neuroscience Letters in Jan. 2011, discusses the use of a calcineurin inhibitor -- FK 506 -- to effectively increase dendritic density in cortical pyramidal neurons (all sites) of adult rats.

Such drugs provide clues as to how dendritic plasticity in the brain is regulated, and are likely to help lead to effective ways of beating back the growing impact of Alzheimer's disease and other dementias. Interestingly, calcineurin upregulation has been implicated in Alzheimer's Disease models as being responsible for amyloid related loss of glutamate receptors and decreased dendritic spine density. In such conditions, the inhibition of calcineurin (as in FK506) might well partially reverse the Alzheimer-like effects.

The mechanisms of brain development, plasticity, and disease are highly complex. We will need to learn as much as possible about signaling pathways, genetic and epigenetic mechanisms, cytoskeletal dynamics, and a number of other cellular and intercellular activities, before we will be ready to intervene in a definitive way. But things look promising, if a bit slower than we would like.

Brain Overclocking: Living a More Intense Life

Neurons recruited for local computations exhibit rhythmic activity at gamma frequencies. The amplitude and frequency of these oscillations are continuously modulated depending on stimulus and behavioral state. This modulation is believed to crucially control information flow across cortical areas....by rapidly balancing excitation with inhibition, the hippocampal network is able to swiftly modulate gamma oscillations over a wide band of frequencies. _ScienceDirect

SPIE
Besides finding ways to prolong one's life, it would be worthwhile to find ways to live one's life more intensely. We have discussed ways in which we might reduce the amount of time spent in sleep, without suffering from diminished mental or physical health. There are also everyday ways in which a person can intensify his experience of his waking time. Some examples are listed at the end of this piece.

From the neurocognitive standpoint, the concept of the controlled "overclocking" of the brain -- speeding up the functioning of brain processes so that more can be experienced and accomplished in less time -- is just coming into the realm of possiblity. The concept, once developed, will rest upon a sound understanding of brain processing and inter-brain communications.

Brain activity changes between different brain states, whether awake, asleep, drugged, etc. Besides the activation of different centers in the brain according to brain state, the actual speed (frequency) of brain activity varies with different brain states.

It is thought that synchronous oscillations involving gamma carrier waves (30 to 100 Hz) modulated by theta frequencies (4 to 8 Hz) allow multiple brain processes to occur, including the transfer of working memory to long-term memory, and the binding of different sensory or other inputs into a coherent mental image of an object or idea. In other words, the way the oscillations of the brain are organised on a moment to moment basis, is what allows us to "think" and remember. (see Working Memory: The Importance of Theta and Gamma Oscillations, Lisman, Current Biology Vol 20 No 11)

Gamma oscillations are thought to transiently link distributed cell assemblies that are processing related information1, 2, a function that is probably important for network processes such as perception1, 2, 3, attentional selection4 and memory5, 6. This 'binding' mechanism requires that spatially distributed cells fire together with millisecond range precision7, 8; _Nature

The idea of a synchronous oscillator, or "clock", involved in thinking and memory suggests the possibility of "speeding up the clock" or "overclocking," analogous to the overclocking of a computer processor to achieve higher computing speeds. In reality, of course, things work much differently in the brain, and no central processing unit is available for safe and controlled overclocking.

But we do know that the top end of the gamma "carrier wave" frequency can vary between types of animals. Some kinds of insects, for example, exhibit brain synchrony at frequencies up to 200 Hz in certain circuits. (Kirschfeld PNAS USA Vol. 89, pp. 4764-4768, May 1992 Neurobiology)

Different frequencies of gamma oscillation serve to connect different brain centers, in practise. This allows for simultaneous parallel activity between multiple circuits. Therefore, when "overclocking," one must be sure not to "step on" the frequencies used by different brain circuits.

There are a number of other cautions, assuming that one had a good idea how to begin to go about ramping up gamma oscillation carrier wave frequencies in the first place. The intricacy of neuronal signaling of brain circuits should discourage any attempts to permanently alter neuronal oscillatory activity. For example, gamma frequencies are closely controlled and modulated by inhibitory interneurons. You cannot change the timing of one type of cell and expect to maintain a system of smooth communication between brain nuclei. Rather, multiple keys that control the timing of networks across the brain will have to be discovered and mastered.

Why should we bother to attempt something which will require so much work? It is possible, after all, to intensify the experience of everyday life without resorting to the extremes of genetic modification of the brain.

Below are some of the everyday means by which some persons provide themselves with temporary experiences of high intensity consciousness:

Pharmacological brain stimulants have been used for this purpose for centuries, but in general they extract a steep price from the user who does not exercise prudence. Veterans of combat can attest to the consciousness-intensifying effect of the life-or-death experience. But we are looking for something more sustainable and less risky. Sky-diving, hang gliding, scuba diving, whitewater kayaking, etc. are less risky than combat, but provide a temporary aura of intensity which lingers after the experience. In occupational settings, life or death emergencies attended to by firefighters, police officers, EMS personnel, medical personnel in hospitals, etc. provide temporary "fixes" of intensity. And under the category of "not to be recommended," the commission of a crime and the attendant risk of being caught supplies the outlaw with a feeling of intensity which can become addictive to some. Similarly, committing acts which may be legal but which are socially or occupationally frowned upon, can sometimes provide a touch of that "outlaw intensity," that accompanies risk.

Perhaps the most dangerous method of intensifying experience is to fall in love. The fallout from such a turn is apt to be fatal to any number of persons involved and in the immediate vicinity. ;-)

As for using brain science to overclock the brain, I will be exploring some of the ideas that might be tried eventually in short works of fiction on another Al Fin blog.

New Findings in the Control of Stem Cell Differentiation

Nodal Activin Pathways Image Source
Researchers from the Genome Institute of Singapore have helped to untangle how stem cells might be controlled with a single signaling pathway -- the nodal activin pathway.

Morphogens are secreted signaling molecules that orchestrate the spatial distribution and sequence of cellular differentiation events throughout embryonic development. The specific cell types, their localization and order of induction from recipient stem cell populations are determined by the concentration gradient of morphogens diffusing from the source of secretion. Previous studies have proposed some of the models by which morphogen gradients are initiated, established and stabilized including the level of receptor occupancy, positive/negative feedback and feed forward mechanisms [1]–[3]. However, little is understood about the transcriptional mechanisms responding to variable receptor activation and how they permit pluripotent stem cells to interpret signaling levels and direct the appropriate differentiation programs during mammalian development....

Nodal and Activin are morphogens of the TGFbeta superfamily of signaling molecules that direct differential cell fate decisions in a dose- and distance-dependent manner. During early embryonic development the Nodal/Activin pathway is responsible for the specification of mesoderm, endoderm, node, and mesendoderm. In contradiction to this drive towards cellular differentiation, the pathway also plays important roles in the maintenance of self-renewal and pluripotency in embryonic and epiblast stem cells. The molecular basis behind stem cell interpretation of Nodal/Activin signaling gradients and the undertaking of disparate cell fate decisions remains poorly understood. Here, we show that any perturbation of endogenous signaling levels in mouse embryonic stem cells leads to their exit from self-renewal towards divergent differentiation programs. Increasing Nodal signals above basal levels by direct stimulation with Activin promotes differentiation towards the mesendodermal lineages while repression of signaling with the specific Nodal/Activin receptor inhibitor SB431542 induces trophectodermal differentiation. To address how quantitative Nodal/Activin signals are translated qualitatively into distinct cell fates decisions, we performed chromatin immunoprecipitation of phospho-Smad2, the primary downstream transcriptional factor of the Nodal/Activin pathway, followed by massively parallel sequencing, and show that phospho-Smad2 binds to and regulates distinct subsets of target genes in a dose-dependent manner. Crucially, Nodal/Activin signaling directly controls the Oct4 master regulator of pluripotency by graded phospho-Smad2 binding in the promoter region. Hence stem cells interpret and carry out differential Nodal/Activin signaling instructions via a corresponding gradient of Smad2 phosphorylation that selectively titrates self-renewal against alternative differentiation programs by direct regulation of distinct target gene subsets and Oct4 expression. _PLoS Genetics

This finding has profound implications for experimental approaches to guided stem cell differentiation and / or stem cell self renewal. The ability to control multiple distinct sets of genes by titrating the dose of signaling molecules is likely to prove a very powerful tool for geneticists, stem cell researchers, and bio-developmental scientists.

In other longevity news, a team of scientists from multiple universities has helped elucidate how cryoprotectant molecules protect proteins from freezing. Future research should enlarge the scope of study to discover optimal cryoprotectants for cells, tissues, organs -- and eventually for entire organisms.

It is quite possible that different types and levels of cryoprotectant will prove optimal for different organs and tissues, so that in order to viably freeze and thaw an entire organism -- say, a human being -- a complex process of multiple simultaneous organ infusion with several cryoprotectants would be necessary.

Restoring Lost Memories: Hope for Long-Lived Brains?

Our brains were not really meant to last for 80, 90, 100 years. Metabolic debris accumulates, DNA repair mechanisms break down, and function tends to degenerate at variable rates -- depending upon the individual's lifestyle and genetic complement. Now scientists at USC in Los Angeles are learning how to restore lost memories -- at least in rats.

Theodore Berger at the University of Southern California in Los Angeles, and colleagues, used electrodes implanted within the hippocampus to record patterns of brain activity while rats learned how to operate a sequence of levers to gain a reward.

Next, the team obliterated the memory of the task by injecting chemicals into the hippocampus that block the signalling between neurons needed to access long-term memories. When tested, the rats could no longer perform the task.

However, when the team used the electrodes to stimulate the brain with the same pattern of activity recorded when the rats first learned the task, their ability to operate the levers in the correct sequence was restored. The rats could temporarily access the original memory, even though the chemical blockade was still in place. When fed scrambled versions of the code, the rats could no longer perform the task.

Ultimately, the researchers hope to create implants that contain codes for 20 to 30 simple tasks, enabling people with brain damage to recover basic abilities that have been lost, such as speaking or dressing themselves.

Berger says that encoding these tasks will be very difficult. "These are very basic capabilities that we are investigating, and it has taken us a lot of effort to get this far," he says. _NewScientist

It is unlikely that the USC team actually encoded rat brain activity with any accuracy. Rather, the team was able to encode a sufficient "hint" so as to allow the rats to internally re-assemble or approximate their former memories. Even in a rat's brain, mental codes are more difficult than even the best scientists understand.

But it is a promising beginning that provides hope for the long-lived brains of the future.

Article Abstract from Jnl of Neural Engineering

More on Sleep, ATP, and Adenosine

Sleep Phases and Progression

Levels of adenosine triphosphate (ATP), the energy currency of cells, in rats increased in four key brain regions normally active during wakefulness. Shown here is the energy surge measured in the frontal cortex, a brain region associated with higher-level thinking. Credit: Courtesy, with permission: Dworak et al. The Journal of Neuroscience 2010.
We spend roughly 1/3 of our lives in the state of sleep. Researchers are beginning to learn why we must do this, and are gleaning hints of possible technologies for bypassing at least part of the sleep imperative, and doing well on less sleep.

“For a long time, researchers have known that sleep deprivation results in increased levels of adenosine in the brain, and has this effect from fruit flies to mice to humans.” Abel said. “There is accumulating evidence that this adenosine is really the source of a number of the deficits and impact of sleep deprivation, including memory loss and attention deficits. One thing that underscores that evidence is that caffeine is a drug that blocks the effects of adenosine, so we sometimes refer to this as ‘the Starbucks experiment.’”

Abel’s research actually involved two parallel experiments on sleep-deprived mice, designed to test adenosine’s involvement in memory impairment in different ways.

One experiment involved genetically engineered mice. These mice were missing a gene involved in the production of glial transmitters, chemicals signals that originate from glia, the brain cells that support the function of neurons. Without these gliatransmitters, the engineered mice could not produce the adenosine the researchers believed might cause the cognitive effects associated sleep deprivation.

The other experiment involved a pharmacological approach. The researchers grafted a pump into the brains of mice that hadn’t been genetically engineered; the pump delivered a drug that blocked a particular adenosine receptor in the hippocampus. If the receptor was indeed involved in memory impairment, sleep-deprived mice would behave as if the additional adenosine in their brains was not there.

...To see whether these mice showed the effects of sleep deprivation, the researchers used an object recognition test. On the first day, mice were placed in a box with two objects and were allowed to explore them while being videotaped. That night, the researchers woke some of the mice halfway through their normal 12-hour sleep schedule.

On the second day, the mice were placed back in the box, where one of the two objects had been moved, and were once again videotaped as they explored to see how they reacted to the change.

“Mice would normally explore that moved object more than other objects, but, with sleep deprivation, they don’t,” Abel said. “They literally don’t know where things are around them.”

Both sets of treated mice explored the moved object as if they had received a full night’s sleep.

“These mice don’t realize they’re sleep-deprived,” Abel said.

Abel and his colleagues also examined the hippocampi of the mice, using electrical current to measure their synaptic plasticity, or how strong and resilient their memory-forming synapses were. The pharmacologically and genetically protected mice showed greater synaptic plasticity after being sleep deprived than the untreated group.

Combined, the two experiments cover both halves of the chemical pathway involved in sleep deprivation. The genetic engineering experiment shows where the adenosine comes from: glia’s release of adenosine triphosphate, or ATP, the chemical by which cells transfer energy to one another. And the pharmacological experiment shows where the adenosine goes: the A1 receptor in the hippocampus. _MedicalXpress

Abel's is a sophisticated experiment which covers a lot of possiblities. Combining the findings of this experiment with findings of previous experiments gives one a fuller picture of what is going on.
The brain has evolved certain activity in N2 sleep (sleep spindles) which apparently promotes the production of ATP from adenosine and phosphate groups. As ATP levels rise in N2 sleep, adenosine levels drop. So the sound sleeper receives both the benefits of higher ATP energy levels and the improved learning that results from lower hippocampal free adenosine levels.

More on sleep spindles (PDF)

Adenosine is a potent pharmacological agent, powerfully affecting heart rhythms. It also affects central nervous system activity in a largely inhibitory function, and also exhibits anti-inflammatory effects.

Adenosine and deep brain stimulation (DBS)

Why Do We Sleep? A brief look at stages of sleep, and possible benefits of sleep.

Cross posted to Al Fin, the Next Level

How could we manage on less sleep? The fastest route to achieving high-functioning sleep reduction would seem to involve electromagnetic brain stimulation or inhibition over particular brain areas at specific pulse frequencies. The aim would be to reduce adenosine levels -- and increase ATP levels -- in specific areas of the brain including the hippocampus.

Pharmacological methods for blocking adenosine's effect, such as used in the experimental mice in the study above, offer another possiblity -- although a time delay before approval for a new drug of at least 10 years is to be expected.

Genetic techniques for modifying adenosine production or re-uptake and ATP synthesis, are another likely approach -- eventually. At the present time, genetic (and epigenetic) treatment methods are far too primitive and clumsy to risk for such an objective as sleep reduction, for most people.

Other neuromolecules are likely involved in this puzzle, but at least this information offers a place to start.

Refurbishing the Brain, Making Humans Smarter and Happier

“I think we’re getting closer to harnessing neurogenesis to improve cognition and mood in humans. This research may also help explain a bit of a mystery in the field, which we still don’t understand, regarding how the hippocampus can be involved with both cognition – which is its classic function – and in mood and anxiety-related functions. Perhaps the fact that pattern separation affects both the cognitive and mood domains is the beginning of an answer to that paradox,” said Dr. Hen. _StemCells

René Hen, PhD, professor of Neuroscience and Pharmacology, in the Departments of Neuroscience and Psychiatry at Columbia University and the New York State Psychiatric Institute, has discovered a possible escape hatch by which some members of society might escape the Idiocracy. It involves the use of chemicals called "BAX inhibitors." Particular members of that class of drugs have the potential to preserve newborn stem cells in the brain's hippocampus. And doing that could make all the difference in the course of a person's life success and happiness.

After boosting the number of neurons in the hippocampus, an area of the brain involved in memory and mood, the researchers tested the mice in both learning and mood-related tasks and looked for changes in behavior. The researchers found specific effects on learning tasks that involve a process called pattern separation, which is the ability to distinguish between similar places, events and experiences.

“This process is crucial for learning because it enables us to know whether something is familiar or novel,” said Dr. Hen. “If it is familiar, you move on to the next bit of information; if it’s novel, you want to be able to recognize that it’s new and give it meaning. These mice, with just more adult-born neurons, and no other changes in the brain, basically learn better in tasks where they have to discriminate between similar contexts.”

Earlier strategies for manipulating neurogenesis, according to the investigators, were broader and less specific. “In addition to stimulating neurogenesis, these earlier methods exerted many other effects on the brain. As a result, you never knew with these older manipulations what’s due to neurogenesis, or what’s due to the other effects that these manipulations cause, and, indeed, what we find is that when you stimulate just adult neurogenesis, you actually get a subtle effect. Unlike broader manipulations, it does not affect all forms of learning, it’s very specific to tasks that require pattern separation,” said Dr. Hen.

Pattern separation is not only important for learning; it may also be important for anxiety disorders, including post traumatic stress disorder (PTSD) and panic disorder. People with PTSD, say the researchers, have a more generalized fear response, so that when they are placed in a situation that reminds them of even one aspect of their trauma, they frequently have a full fear response.

...The researchers say that the genetic strategy used to stimulate neurogenesis in their experiments can be mimicked pharmacologically, potentially leading to the development of new drugs to reverse pattern separation deficits. One such class of drugs the investigators are currently testing – BAX inhibitors – works by blocking cell death.

“These drugs are basically doing the same thing that we did with our genetic manipulation-namely, increasing the survival of the young neurons which normally undergo a process of cell death that eliminates at least half of these neurons. Now instead of dying, the neurons will go on to survive,” said Dr. Sahay.

Some BAX inhibitors have been developed for stroke research, where the goal has also been to prevent neurons from dying. The Columbia researchers plan to begin testing the BAX inhibitors in mice shortly. And if they produce cognitive benefits, the testing will be extended to clinical trials to determine if there’s also a beneficial effect in humans. _StemCells

This is all related to the length of time required before antidepressants are able to bring about a full "antidepressive response." The full effect of modern antidepressants requires new stem cell production in the hippocampus -- but that takes time to achieve. Drugs capable of rapid and prolonged increases of hippocampal stem cells could conceivably keep anxiety and depression at bay, while improving a person's cognitive capacity.

No, this is not NZT. As mentioned here previously, a drug that could achieve the effect of the fictional NZT would have to stimulate changes in gene expression on multiple levels, and across a wide range of brain centers.

Smart drugs alone will not achieve the goal of smarter, better-rounded, and happier humans. Educational and environmental interventions would also be necessary, to blunt the Idiocratic brainwashing effect of modern media, modern academia, and modern popular culture, while allowing the brain to develop newer, more functional pathways.

Realistically, it will take 15 years at the earliest to see the early promise of this type of medication come to fulfillment. But a single ray of hope in the distance is worth a lot to a person immersed in the modern rush to Idiocracy.

More 5April2001: An example of rapid brain plasticity in human adults
The PNAS Abstract from the actual study

Previously published at Al Fin

As noted here before, improved neurogenesis in the hippocampus is associated with antidepressant and anti-anxiety behaviours in animal studies -- and probably in humans. It does no good to live longer with younger brains if we are unable to enjoy our added time and brainpower.

Inflammation Kills! Blocking the Inflammation After MI, CVA

Blocking Complement
A person may survive a severe heart attack (MI) or stroke (CVA) only to succumb to the effects of devastating inflammation which tends to occur after blood supply is restored to tissue that was damaged from temporary loss of perfusion. An effective treatment for preventing such re-perfusion inflammation could save many hundreds of thousands of lives a year.

The lectin pathway is responsible for the potentially devastating inflammatory tissue response that can occur when any bodily tissue or organ is reconnected to blood supply following ischaemia – a temporary loss of that blood supply and the oxygen that it carries. This excessive inflammatory response is, in part, responsible for the morbidity and mortality associated with myocardial infarction (heart attack) and cerebrovascular accidents (CVAs or strokes). Moreover, the work succeeded in finding a way to neutralise this enzyme by raising a therapeutic antibody against it. A single antibody injection in animals has been shown to be sufficient to disrupt the molecular process that leads to tissue and organ destruction following ischaemic events, resulting in significantly less damage and markedly improved outcomes.

"This is a fascinating new achievement in the search for novel treatments to significantly reduce the tissue damage and impaired organ function that occur following ischaemia in widespread and serious conditions such as heart attacks and strokes," said Professor Schwaeble. "This new potential therapy was also shown in animals to significantly improve outcomes of transplant surgery and may be applicable to any surgical procedure where tissue viability is at risk due to temporary interruption of blood flow. _Eurekalert

Of course Professor Schwaeble is correct. Not only would such a treatment be a potential blockbuster drug for preventing complications from MI and CVA, but it would also be immensely useful for surgical procedures where blood supply is temporarily interrupted, or for treating cases of trauma where blood supply is interrupted by the trauma itself and/or by a lifesaving procedure such as a tourniquet or MAST suit used to prevent fatal exsanguination.

The University of Leicester led an international team whose research has been published today in the Early Online Edition of the Proceedings of the National Academy of Sciences (PNAS).

Professor Wilhelm Schwaeble of the Department of Infection, Immunity and Inflammation at the University of Leicester, initiated and co-ordinated research collaborations with King's College London, the Medical University of Fukushima, Japan and the State University of New York, to achieve the present breakthrough findings, which were published today in PNAS.

Professor Schwaeble and collaborators identified an enzyme, Mannan Binding Lectin-Associated Serine Protease-2 (MASP-2), that is found in blood and is a key component of the lectin pathway of complement activation, a component of the innate immune system. _Eurekalert

Total Brain Network Imaging Reveals Efficiency Loss w/ Ageing

“While particular brain regions are important for specific functions, the capacity of information flow within and between regions is also crucial,” said study leader Scientia Professor Perminder Sachdev from UNSW’s School of Psychiatry.

“We all know what happens when road or phone networks get clogged or interrupted. It’s much the same in the brain.

“With age, the brain network deteriorates and this leads to slowing of the speed of information processing, which has the potential to impact on other cognitive functions.” _Science Alert

University of New South Wales researchers have utilised advanced diffusion tensor imaging (PDF research article) along with powerful computational tools to assess the efficiency of the total brain network of white matter, and watched overall brain processing speeds as they slow due to ageing.

The research team, led by Scientia Professor Perminder Sachdev from the UNSW School of Psychiatry, has mapped the network of fibres or ‘white matter’ for the first time, allowing them to examine the strength of connections between different cortical regions, or ‘grey matter’, which are responsible for specific functions. In the past, most research has focused on the more complicated grey matter without looking at how information flows between separate regions.

A new type of magnetic resonance imaging (MRI) called diffusion tensor imaging (DTI) combined with powerful computers allowed the team to create the map and see the whole network in great detail.

“Using a mathematical theory you can see how strongly the different regions are connected to each other,” Professor Sachdev said. “You can basically look at the efficiency of the network and with ageing, we can see a reduction in the efficiency of these networks.”

“What we wanted to see is how this relates to cognitive function, and we found that the best relationship was with processing speed, which makes sense because we’re talking about strength of information connections.”

Other areas strongly affected by the efficiency of neural networks were executive functions that manage other brain processes and the ability to navigate in space, known as visuospatial function.

Sachdev said the findings could help to some extent with dementia research, by offering another way of looking at the condition, but had already helped explain what happens in the brain when physical reaction time slows down in older people.

“It’s not that they can’t do the task, it just takes longer, and we have shown that this is related to structural changes in the brain, in terms of its neural networks.”

“The next step is looking at what determines the efficiency of these networks. We want to see if they are flexible or plastic, and whether maybe we can intervene.”

...The results of the study, which was based on a sample of 342 healthy people aged between 72 and 92, have been published in the January edition of the Journal of Neuroscience. _AustralianAgeingAgenda

Here is more from science alert Australia:

In the study, the researchers performed magnetic resonance imaging (MRI) scans on 342 healthy individuals aged 72 to 92, using a new imaging technique called diffusion tensor imaging (DTI).

Using a mathematical technique called graph theory, they plotted and measured the properties of the neural connectivity they observed.

“We found that the efficiency of the whole brain network of cortical fibre connections had an influence on processing speed, visuospatial function – the ability to navigate in space – and executive function,” said study first author Dr Wei Wen.

“In particular greater processing speed was significantly correlated with better connectivity of nearly all the cortical regions of the brain.”

Professor Sachdev said the findings help explain how cognitive functions are organised in the brain, and the more highly distributed nature of some functions over others. _Science Alert

It is important to stress the difference between speed of nerve transmission and speed of information processing for the brain. The two are related, and both are measurable (or calculable) using the DTI computational techniques, but information processing is a much higher order process than mere nerve conduction velocities. Knowing processing speeds -- particularly being able to compare whole brain processing and subsystem processing speeds and efficiencies -- provides more information.

Diffusion Tensor Imaging (DTI) can be used to assess several aspects of brain functioning, including general intelligence and executive function. It can also be used to assess multiple types of brain pathology, including schizophrenia.

Better brain imaging techniques provide clinicians and researchers with better information with which to form theories and plan therapies. As brain ageing comes to be seen more as a reversible pathology, more advanced diagnostic tools and therapeutic methods will be made available more widely.

Are We Closer to Viable Long-Term Freezing for Organs and People?

Once we are able to viably freeze and thaw living organs and whole animals, without damage or injury, we will be able to plan for the targeted freezing and thawing of living humans for purposes of extended survival.

A technology that has come from the frozen sushi industry in Japan is being studied for possible application to living animals and human organs such as hearts, livers, lungs, and kidneys.

A technology used to freeze sushi is solving a dilemma for organ storage. By borrowing tech used to preserve high-end food delicacies, a Hiroshima University research group proved it possible to safely freeze whole teeth and their delicate attaching tissues. As long as the freezer stays cold, the folks at Hiroshima U. think your teeth could be stored for 40 years, no problem.

But the sushi-storage system isn’t a one trick pony: internal organs could be next thanks to the magic of supercooling. In typical cryo-storage, fast freezing of organs requires poisonous levels of anti-freeze, and let’s face it, no one wants a poisoned kidney transplanted into their body. But slower freezing causes cell popping ice crystals to form.

So, what do you do to prevent ice crystals during slow freezing? Use magnets. ABI is the Japanese company producing the freezer system. ABI’s “Cells Alive System” (CAS) vibrates water with magnetic fields, preventing freezing, even at supercool temperatures of -10 degrees Celsius (According to the Patent.) When the field is turned off, the water in the food instantly freezes. No time for ice growth means no Freddy Krueger action on frozen organs.

...The transition of this tech from food to longevity science is slowly evolving, but the steps forward are real. You can, right now, pay to store your teeth. Hiroshima University tested the cooling technology for teeth, and uses ABI CAS freezer tech at The Teeth Bank, the world’s first commercial tooth bank. Dr. Toshitsugu Kawata, a Hiroshima University professor who has done extensive research at the Teeth Bank, helped prove that CAS is a viable technology to preserve teeth. Spare teeth used to be worthless medical waste. Now, removed wisdom teeth aren’t garbage, they can be frozen and re-implanted at any point during your life.

...The founder of the ABI Corporation and its CAS freezer, Norio Owada (known internationally as “Mr. Freeze,”) is actively pursuing medical advances. There’s a hodgepodge of reports out there about what’s being done. According to various sources, Mr. Freeze is collaborating with 40 researchers to translate their work with teeth and sushi to hearts, nerves, and other organs. Transplant medicine could benefit tremendously. With further research, this technology could supercool, or even freeze internal organs, putting an end to the dangerously brief time frame for organ transplants. In a 2008 Forbes article, Mr. Freeze speculated on where his technology may lead. “If you could preserve a heart for three days, you could fly it anywhere.” On the late-night Japanese TV show, World Business Satellite, there was discussion of research towards using ABI’s CAS freezers to store ovaries during cancer treatment, allowing women to keep their fertility. On the ABI company webpage, photos of a rat heart transplant and undamaged cell walls of frozen wasabi are a reminder of the unusual coupling of frozen food and medicine. _SingularityHub_via_NextBigFuture

One further step is needed: a vitrification agent which can be added to the supercooled organs which would allow the electromagnetic field to be turned off without the risk of freezing. One step at a time.

The Virtues of Experience

Wikipedia
The human brain learns a lot, over time. Experience shapes the brain, determining how it will work, and which parts of the brain will be active in different circumstances. Recent Japanese brain research has determined that expert players in the Japanese chess game "Shogi" use a different part of their brain (the caudate nucleus) to play, than do amateurs of the game. The caudate nucleus is the curved purple structure in the image above.

Neuroscientists at the RIKEN Brain Science Institute in Wako, Japan, studied a group of professional and amateur shogi players. Shogi is the Japanese version of chess. With the use of real-time brain scans, the researchers discovered that the pros activated different parts of their brains than the amateurs did while studying game patterns and contemplating their next moves.

The findings were published in the Jan. 21 issue of Science.

Senior study author Keiji Tanaka, deputy director of the institute and head of the Cognitive Brain Mapping Laboratory, said the experts' unique brain circuitry enabled them to have "superior intuitive problem-solving capabilities."

Professional shogi players, who have practiced three or four hours a day for several years, "repeatedly note that the best next move comes to their mind 'intuitively,'" the authors wrote. "Being 'intuitive' indicates that the idea for a move is generated quickly and automatically without conscious search, and the process is mostly implicit."

...r brain difference occurred when the players were forced to quickly pick their next best move. The professionals' brain scans revealed activity in a portion of the basal ganglion known as the caudate nucleus, while the amateurs' scans did not.

The researchers suggest that a unique circuit between these two regions of the brain is what enables professional players to expertly recognize board game patterns and quickly choose their optimal next move.

"There was no volume difference of the caudate nucleus between professional and amateur players," said Tanaka. This suggests that "the caudate nucleus is used for other purposes in ordinary people [but] the experts have developed a unique way to use the system." _BW_via_ImpactLab

The caudate nucleus has been implicated in the development of automaticity of several types -- which places the caudate in a central, pivotal position for humans living in modern societies.

First, the caudate appears to be involved in the acquired automaticity of motor skills. This is not such a big surprise to brain researchers. But the caudate also seems to be involved in the automaticity of emotional processing, the automaticity of perceptual categorisation (PDF), automaticity of rule-based categorisation, and in switching between two languages in bilingual individuals. There are almost certainly more caudate functions to come.

Sure, there is overlap between the different caudate functions, but the brain -- and its many modular parts -- is nothing if not multi-functional. A Swiss Army knife of cognitive and emotional tools that modifies itself over a person's lifetime, adapting to the individual's experience.

That is why it is so important to the individual that the brains many potential functions be developed before their developmental windows close. And why it is so important to society that the brains of its members are well developed and long-lived.

We cannot afford to waste all of that hard-earned knowledge, experience, and savvy by dying too young. 500 year lifespans should be seen as a minimum timespan for skills acquisition and for passing these skills along to future generations.

DNA for Healthy Aging, and Rebuilding the Brain After Stroke

We will look at two studies that relate to the quest for longer, healthier, more productive and fulfilling lives. First, researchers at the University of Miami looked at an Amish population and discovered that a certain genetic pattern in the mitochondria seems to allow for a much healthier lifespan into the 80s.

On Friday they will present a paper showing that 15 percent of healthy Amish octogenarians have "haplogroup X," a genetic pattern within the mitochondria, which are the regions of cells that generate energy and help guard against deterioration. Haplogroup X is generally found in only 2 percent of Europeans, from whom the Amish descended. In the University of Miami study, only 3 percent of the control group—Amish people who had made it to 80 but suffered from significant disease or disability—had the genetic variant. The paper will be featured during a session at the American Society of Human Genetics' annual meeting in Washington, D.C.

Researchers who study aging have long suspected that mitochondria play a role in aging. Mitochondria are responsible for processing metabolized food particles into adenosine triphosphate, which fuels vital cellular processes. They're also involved in cell growth and differentiation. But the ability of mitochondria to function properly seems to decline with age.

Understanding the reason for that decline—and the genes that might control it—has been challenging. Mitochondria have their own DNA, which is passed down from the mother only. This unique chromosome has variations, called haplogroups. Nine such haplogroups have been well characterized in people of European descent, Scott says. But only haplogroup X was found to be prevalent among healthy aged people in the University of Miami study. _TechnologyReview

The second study, from UCLA researchers, looks at the ability of the brain to re-build following stroke -- or brain infarct. The team appears to have discovered a drug target with significant promise, which may lead to drugs that help the brain to re-build itself following destructive lesions.

A stroke is usually caused by a clot that blocks blood flow to an area of the brain. Tissue in that part of the brain dies from lack of oxygen unless the clot is detected immediately and is either dissolved or removed. The dead tissue cannot be revived, but often the brain can be trained to redirect nerve impulses via still-living nearby neurons. But such training is difficult, can require months to years of arduous rehab, and is often not sufficient to overcome complex disability.

The new research, by neurologist S. Thomas Carmichael and his colleagues at the University of California at Los Angeles, shows that neurons in the areas of the brain closest to the site of a stroke are impaired after it occurs. The reason for that is a buildup of an inhibitory signaling molecule called GABA that prevents the neurons from firing. When those nerves are inhibited, it's harder for the brain to recruit them into its rerouted circuits.

In studies in mice, the researchers discovered that blocking a particular piece of the GABA signaling system with an existing drug allowed the nerves to reactivate, reversing the repressed excitability, allowing them to more easily respond to other neurons, and encouraging and enhancing early recovery after a stroke by as much as 50 percent. "At face value, it's a new pharmacological target for repair and recovery in stroke," Carmichael says.

...Carmichael and his colleagues identified the piece of the GABA signaling cascade that goes awry in the area of the brain adjacent to the stroke: reduced levels of a transporter responsible for moving the inhibitory molecule out of the vicinity. Without that transporter, GABA is allowed to reach such high levels that the nearby neurons are prevented from firing.

In studies in mice, the researchers induced a stroke in the motor cortex, the movement center of the brain, and then gave them a drug that specifically reverses the post-stroke GABA uptake. The drug is not approved for use in people—it was an experimental molecule produced during the drug industry's search for memory enhancers. But just the fact that it works in mice means that stroke researchers have a new line of evidence to pursue.

"It's significant, because they're identifying a molecular mechanism that is keeping stroke survivors from recovering. And as a result, [Carmichael is] identifying targets for molecular manipulation," says Theresa Jones, a neurobiologist at the University of Texas at Austin. "Now we have potential to find drugs that aim at that target."

The scientists found that, as with other types of stroke treatments, timing was critical. During the first few days after a stroke, a brain injury is still stabilizing; prior studies have shown that any physical rehabilitation attempted during this period can aggravate the brain and actually make the damage worse. The same proved true for the drug.

But when the mice were given the drug three days later, it improved their recovery of movement by 40 to 50 percent. This implies that while the post-stroke inhibition of neurons in these areas may help with immediate recovery, but it is a harmful adaptation when it persists for weeks or months or even years after the initial injury. _TechnologyReview

Stroke is one of the major causes of death and disability in the developed world. A viable treatment for stroke rehabilitation would be a significant medical development.

Reversing Age Related Memory Loss

Researchers estimate that roughly 20 to 30 percent of people age 75 and older have elevated glucocorticoid levels (more precise figures aren't available). Most affected is so-called declarative memory, the ability to learn new facts and remember, for example, lists. People who suffer age-related memory loss are at higher risk for developing Alzheimer's and other forms of dementia, though the condition is not itself considered a form of dementia. _TechnologyReview

A research team at the University of Edinburgh have developed a new compound that appears to prevent and reverse age-related memory decline in mice. Their approach utilises a "gene knockout" approach against an amplifier of glucocorticoid effect present in brain cells.

"What's most surprising is that even short-term inhibition was able to reverse memory loss in old mice," says Jonathan Seckl, a professor of molecular medicine who was involved in the research. "I don't think people had realized this was so reversible. It takes [the animals] back to being relatively young."

The researchers hope to develop equivalent human therapies and are now more extensively studying the safety of a closely related compound in animals. They aim to begin human testing within a year.

Scientists have long known that glucocorticoids--a class of steroid hormones that mediate our response to stressful situations--play a role in age-related memory decline. Although short-term exposure to glucocorticoids enhances the formation of memories during stressful situations, chronically high levels of the hormones are linked to greater memory loss with age, both in humans and animals. The exact mechanism underlying this link is unclear, but researchers theorize that excess exposure to the hormones makes parts of the brain more vulnerable to damage.

Seckl and his collaborators focused on an enzyme called 11β-hydroxysteroid dehydrogenase type 1 (11 β-HSD1). This enzyme generates an active version of the key glucocorticoid hormone within brain cells and some other tissues, providing a target for fine-tuning the system without blocking the overall stress response. Tinkering with the enzyme seems to have little effect on blood levels of glucocorticoids, which are produced in the adrenal glands. Instead, "this enzyme acts as an intracellular amplifier of glucocorticoids," says Seckl. "If you take out the amplifier, you still have stress hormones, but they shout less loudly and cause less wear and tear."

The Edinburgh team showed that knocking out either one or both copies of the gene for this enzyme in mice preserved the animals' memory into old age. To determine whether blocking the enzyme could improve memory in already aged animals, researchers then developed a compound designed to cross into the brain and inhibit the enzyme. Just 10 days of treatment in two-year-old mice--the maximum lifespan for a typical lab mouse--was enough to improve the animals' performance on a test of spatial memory. The treatment "returned mice to the equivalent of when they were young and fully functioning," says Brian Walker, another researcher involved in the study. "It's important to emphasize that we are trying to target the pathology--the role that glucocorticoids play in age-related memory decline--not just globally improving memory." The research was published last week in the Journal of Neuroscience. _TechnologyReview

Brian Wang looks at another approach to augmenting human brainpower

Also published at Al Fin

Open Source Biotechnology: The Wonder and the Terror

As recently as a decade ago, the tools and techniques for such fiddling were confined to a handful of laboratories like those at leading research universities. Today, do-it-yourself biology clubs have sprung up where part-timers share tips on how to build high-speed centrifuges, isolate genetic material, and the like. The movement has been aided by gear that can turn a backyard shed into a microbiology lab. _WSJ

With the emergence of open-source biohacking, a number of scientists and authorities are starting to worry about the possibility that a biohacker will create some type of super-microbe which could cause a significant disease outbreak. Here you can find a zipped download introduction to biohacking.

The new fear, though, is that scientific advances that enable amateur scientists to carry out once-exotic experiments, such as DNA cloning, could be put to criminal use. Many well-known figures are sounding the alarm over the revolution in biological science, which amounts to a proliferation of know-how—if not the actual pathogens.

"Certain areas of biotechnology are getting more accessible to people with malign intent," said Jonathan Tucker, an expert on biological and chemical weapons at the James Martin Center for Nonproliferation Studies.

Geneticist Craig Venter said last month at the first meeting of a presidential commission on bioethics, "If students can order any [genetic sequences] online, somebody could try to make the Ebola virus."

Mr. Venter is a pioneer in the field whose creation of a synthetic organism this spring helped push the debate about the risks and rewards of bioscience from scientific journals to the corridors of power in Washington. "We are limited more by our imagination now than any technological limitations," Mr. Venter said.

Scientists have the ability to manipulate genetic material more quickly and more cheaply all the time. Just as "Moore's Law" describes the accelerating pace of advances in computer science, advances in biology are becoming more potent and accessible every year, experts note. _WSJ

Of all the things likely to escape from garage biohacking outposts, none are likely to bring about the end of the human species. Some of them may even be beneficial for health and long life.

Just as some of the fastest developments in personal computing emerged from basements and garages, so is it possible for home-based biohackers to make important contributions to bioscience and biomedicine. Curiosity drives most small scale hacking of all kinds -- the desire to understand how things work.

For humans who are interested in going beyond the ordinary in terms of lifespan, intelligence, sleep requirements, strength, speed, etc. the answers may well arise from small scale independent labs -- given how over-regulated and over-restricted all aspects of government sanctioned biomedicine are becoming in western countries.

Is there a danger? Yes, there is always a danger, and all of us should stay alert for persons who seem to be several cards short of a full deck. But that shouldn't stop us from pushing the limits.

Regenerative Medicine Advances

The promise of regenerative medicine involves a future where replacement organs and tissues can be re-grown in a lab from a person's own cells, then transplanted into the person as brand-new, fully functioning replacement tissue. Replacement lung tissue, replacement heart tissue, replacement ligaments and tendons, replacement skin, kidneys, muscle, intestine, bladders, and on and on. But first, scientists have to find a good way to grow millions and billions of healthy stem cells from a person's own cells, and keep them alive long enough to turn them into the proper tissue, and grow them on a proper scaffold into the proper replacement organs.

Investigators from the Massachusetts Institute of Technology (MIT) recently developed a new type of support structure for stem cells, which allows them to remain alive for weeks without using any foreign genetic material.

Generally, substrates for growing stem cells contain animal cells or tissue, but these can easily contaminate the samples themselves, which means that they can lose some of their capabilities.

This is an especially serious consequence for induced pluripotent stem cells, which are biological units that can transform into any type of tissue in the human body.

Only environmental conditions dictate whether they will turn into nerve cells, or into pancreatic tissue.

Due to this amazing differentiation ability they have, these cells hold great promise for treating a number of disorders, such as for example Parkinson's, multiple sclerosis and spinal cord injuries.

But, in order to make the best of them, researchers need to be able to grow them in sufficiently large quantities, and this is proving to be extremely difficult due to the lack of proper substrates.

One of the main issues in this field of research is the fact that human stem cells are now grown with the aid of cells or proteins derived from mice embryos. If these foreign chemicals would interact with the human body, they would definitely cause an allergic reaction.

Thanks to the MIT collaborations, which includes biologists, materials engineers and chemists, scientists now have a synthetic surface that features no material from mice or other animals.

The data the team recorded of the new surfaces show that they promote and sustain “all-natural” stem cell growth and reproduction for at least three months. Longer periods are also possible, the group says.

Another impressive feat the MIT experts achieved with their new material is the fact that it allows for researchers to separate colonies of identical cells from each other. The surface allows single cells to form colonies of cells of that type with considerable ease.

Details of the new investigation appear in the August 22 issue of the esteemed scientific publication Nature Materials, e! Science News reports. _Softpedia

Another report from ScienceDaily

“For therapeutics, you need millions and millions of cells. If we can make it easier for the cells to divide and grow, that will really help to get the number of cells you need to do all of the disease studies that people are excited about,' says MIT postdoctoral associate Krishanu Saha, one of the co-first authors of the paper. 

The work was led by MIT professors Robert Langer, Rudolf Jaenisch and Daniel G. Anderson, in collaboration with Saha and postdoctoral researcher Ying Mei. _Softpedia

This report from Brian Wang on Swiss stem cell research, suggests that mature tissue-derived stem cells can be programmed across germ layer boundaries. This finding hints at the possibility of creating virtually any type of cell or tissue from any other type of tissue -- including easily sampled tissues such as skin or blood.

Cross-posted at Al Fin