Proof of Concept for Rejuvenating Effect of Stem Cells: Pregnancy

Stem cell research has been controversial for decades. But we are beginning to learn that stem cell rejuvenation therapy experiments have been taking place for as long as humans have walked the Earth.

In earlier articles, we explained how pregnancy can make a woman younger due to the transfer of certain molecules -- hormones, growth factors etc -- from the fetus to the mother. In another article we learned that pregnancy can help make women's brains work better. Now we learn that pregnant women's bodies can be regenerated via embryonic stem cell rejuvenation treatments from the fetus.

These findings come from research in mice done at Mount Sinai School of Medicine in New York:

Mouse fetuses will give up stem cells to repair their mother's heart. The discovery could explain why half the women who develop heart weakness during or just after pregnancy recover spontaneously.

Hina Chaudhry of the Mount Sinai School of Medicine in New York City mated normal female mice with males genetically engineered to produce a green-fluorescing protein in all their body cells. Half the resulting fetuses also produced the protein, making it easy to spot any fetal tissue in the mother.

Chaudhry's team inflicted a heart attack on the pregnant mice and killed them two weeks later to take a look at their hearts. They found some fluorescent cells in the mothers' damaged heart tissue, where they had accelerated repair by changing into new heart cells, including beating cardiomyocytes and blood vessel cells.

Chaudhry says that the phenomenon is an evolutionary mechanism: the fetus promotes its own survival by protecting its mother's heart. Because the cells are easy to obtain from the placenta and unlikely to cause immunological reactions, they could provide a new and potentially limitless source of stem cells for repairing damaged hearts.

"The study is the first to show conclusively that fetal cells contained in the placenta assist in cardiac tissue repair," says Jakub Tolar, director of stem-cell therapies at the University of Minnesota in Minneapolis. _NewScientist

All the debate that has gone on over embryonic stem cell treatments, and we discover that it has been going on in mammals from the beginning.

Now it is a matter of learning how to maximise the positive effects of pregnancy, and to compensate for the potential negative effects.

Of course, in the long run, artificial wombs will relieve most women of the burden of gestation. But for those stylishly retro women who will wish to carry their own -- the advantages continue to build.

Above cross-posted from Al Fin, You Sexy Thing!

A One-Two Gene Knockout Makes Mice Stronger and Faster

Swiss scientists have discovered that knocking out the nuclear receptor corepressor 1 (NCoR1) gene in the muscles of mice allow the animals to run farther, and faster. Knocking out the same gene in fat cells eliminated the problem of diabetes in the mice. And those are only two tissues, of the many types of tissues in a mouse's body. I wonder if knocking out the NCoR1 gene in human muscles would create a super athlete?

Knocking out a particular gene in muscle lets mice run twice as far as normal. Knocking out the same gene in fat cells allows the animals to put on weight without developing type-2 diabetes.

The discoveries could lead to new treatments for diabetes or for invigorating muscles in elderly people and in those with wasting diseases, say Johan Auwerx of the Federal Polytechnic School of Lausanne, Switzerland, and colleagues.

...Auwerx and his colleagues used a targeted virus to knock out the gene that makes a protein called nuclear receptor corepressor 1 (NCoR1) in the muscle of mice. Without NCoR1, mitochondria, which power cells, keep working at full speed. "Effectively, the mice go further, faster, on the same amount of gas," says Auwerx.

"The treated mice ran an average of 1600 metres in 2 hours, compared with 800 metres for untreated mice," he says.

...Auwerx warns athletes not to try to grow their muscles and stamina illicitly by somehow targeting the NCoR1 protein, however.

"We only know what happens if it's knocked out either in fat or muscle, and it could have serious side effects on other organs," he says. Also, he points out that without NCoR1, all fetuses perish, so it plays a vital but undiscovered role in fetal development. _NewScientist

Right. As if Auwerx' warnings would have any effect on a determined athlete's plans. And there are likely several other ways for athletes to tweak their muscles' genes, to gain an advantage.

One gene, for example, called MYH16, contributes to the development of large jaw muscles in other apes. In humans, MYH16 has been deactivated. (Puny jaws have marked our lineage for as least 2 million years.) Many people have also lost another muscle-related gene called ACTN3. People with two working versions of this gene are overrepresented among elite sprinters while those with the nonworking version are overrepresented among endurance runners. _Slate

More muscle boosting genes:

CNTF 1357 G → A polymorphism and the muscle strength response to resistance training Jnl Appl Physio 2009

Follistatin Gene Delivery Enhances Muscle Growth and Strength in Nonhuman Primates Sci Transl Med 2009

Long-term enhancement of skeletal muscle mass and strength by single gene administration of myostatin inhibitors PNAS 2008

Increased muscle PGC-1α expression protects from sarcopenia and metabolic disease during aging PNAS 2009

Genetically boosted athletes are inevitable, once stealth techniques of controlling gene expression and transfer are developed. But that also means that viable means of strengthening the muscles, bones, and other tissues that normally weaken with ageing, will also be within reach. So it's best not to complain too loudly about the athletes who tweak themselves for advantage, so long as the rest of us can win in the game of life.

Abstract from Cell:

Transcriptional coregulators control the activity of many transcription factors and are thought to have wide-ranging effects on gene expression patterns. We show here that muscle-specific loss of nuclear receptor corepressor 1 (NCoR1) in mice leads to enhanced exercise endurance due to an increase of both muscle mass and of mitochondrial number and activity. The activation of selected transcription factors that control muscle function, such as MEF2, PPARβ/δ, and ERRs, underpins these phenotypic alterations. NCoR1 levels are decreased in conditions that require fat oxidation, resetting transcriptional programs to boost oxidative metabolism. Knockdown of gei-8, the sole C. elegans NCoR homolog, also robustly increased muscle mitochondria and respiration, suggesting conservation of NCoR1 function. Collectively, our data suggest that NCoR1 plays an adaptive role in muscle physiology and that interference with NCoR1 action could be used to improve muscle function. _Cell

Would You Trade Places With a Naked Mole Rat?

the naked mole rat has what could be the most extraordinary set of natural defenses ever found in a mammal. A mouse's life is short and terrible—even in the lab, with plenty of food and a steady thermostat, it lasts for just three or four years at the most. A naked mole rat shows no sign of aging until it's a quarter of a century old. Blind and plump, it skitters around in a hazmat suit of its own creation. _Slate

Naked mole rats appear impervious to radiation and carcinogens of all kinds. These naked mole rats are incredibly reluctant to get cancer. And that is not the half of it:

In 2004, Buffenstein and her students tried one of these shortcuts. They placed some mole rats in a gamma chamber and blasted their pale, pink bodies with ionizing rays. The animals were unimpressed. When I visited Buffenstein’s lab this past July, many were still alive, skittering through the plastic tubes of their basement habitat at the Barshop Institute for Longevity and Aging Studies.

Four years later, Buffenstein...infected cells from a naked mole rat with a virus designed to corrupt their nuclei with the cancer-causing genes SV40 TAg and Ras. Then she slipped those cells into a live mouse, under the skin behind its ear. If you do the same using infected material from a mouse or a rat, or even a cow or a human, the transplant quickly grows into a deadly tumor, invading nearby fat and muscle tissue. But when Buffenstein and her colleagues used cells from a naked mole-rat, nothing happened.

...Earlier this year, one of Buffenstein's graduate students tried smearing the skin of half a dozen naked mole rats with a pair of vicious carcinogens: A synthetic compound called DMBA and an inflammatory agent known as TPA. When the same toxic pairing was applied to regular Black-6 lab mice as an experimental control, a cluster of tumors popped up within weeks. Every single mouse had cancer, and every single mouse died. The naked mole rats went on skittering through their tubes.

...Her latest assault involves pouring carcinogens down the mole rats' throats in a last-ditch effort to induce liver or mammary cancer. But that may not work, either. For years, Buffenstein's laboratory Rasputins have been irradiated, poisoned, and heated up; their cells dosed with every imaginable pollutant—chemotherapies, oxidative stressors, and heavy metals—with little or no effect. "You name it," the professor says, "we tried all the kinds of toxins that are out there, and the naked mole rat seems to be very resilient and resistant."

...The very thing that makes naked mole rats so interesting to Buffenstein—an astonishing vitality that lasts for decades—only makes her research more difficult. "You're caught between a rock and a hard place, because they live so long that your grandchildren have to finish the studies you start." Still, slow science may have rich rewards, and the decisions we make today—on whether to invest in new model organisms or build out the ones we already have—are sure to have profound effects on the (human) generations to come. _Slate

The above Slate article by Daniel Engber is an excellent example of good science writing. We learn about the things that make the naked mole rat intriguing as an object of study, then we learn why the biomedical funding establishment is so biased against funding studies using naked mole rats. The life of science is full of such conflicts, which can drive scientists out of the lab entirely if they cannot learn to deal with the frustrating politics and grant grubbing.

No human would want to trade places with a naked mole rat, even if it meant living 10 times longer -- and in better health -- than the average human. But we might want some of the naked rats resistance to cancer and degenerative change.

Human gerontologists are not trying to discover the path to immortality. They are not even trying to give humans the relative advantage in life span that the naked mole rat has over other rodents. What human scientists are trying to achieve is fairly modest -- they want to find a way to delay the signs of aging for roughly seven years beyond the average:

THE TARGET What we have in mind is not the unrealistic pursuit of dramatic increases in life expectancy, let alone the kind of biological immortality best left to science fiction novels.20 Rather, we envision a goal that is realistically achievable: a modest deceleration in the rate of aging sufficient to delay all aging-related diseases and disorders by about seven years.21 This target was chosen because the risk of death and most other negative attributes of aging tends to rise exponentially throughout the adult lifespan with a doubling time of approximately seven years.22 Such a delay would yield health and longevity benefits greater than what would be achieved with the elimination of cancer or heart disease.23 And we believe it can be achieved for generations now alive.

If we succeed in slowing aging by seven years, the age-specific risk of death, frailty, and disability will be reduced by approximately half at every age. People who reach the age of 50 in the future would have the health profile and disease risk of today’s 43-year-old; those aged 60 would resemble current 53-year-olds, and so on. Equally important, once achieved, this seven-year delay would yield equal health and longevity benefits for all subsequent generations, much the same way children born in most nations today benefit from the discovery and development of immunizations.

A growing chorus of scientists agrees that this objective is scientifically and technologically feasible. How quickly we see success depends in part on the priority and support devoted to the effort. Certainly such a great goal – to win back, on average, seven years of healthy life – requires and deserves significant resources in time, talent and treasury. But with the mammoth investment already committed in caring for the sick as they age, and the pursuit of ever-more expensive treatments and surgical procedures for existing fatal and disabling diseases, the pursuit of the Longevity Dividend would be modest by comparison. In fact, because a healthier, longer-lived population will add significant wealth to the economy, an investment in the Longevity Dividend would likely pay for itself. _"TheScientist"_via_NR

Can we learn anything toward that end, from the naked mole rat? Quite possibly. But we have to be willing to put in the time and expense to learn how to transfer the lessons from that exceptional rodent to the human species.

Cognitive Enhancers In Health and Disease

Cognitive enhancer	Neuromodulatory mechanism	Cognitive functions improved	Known brain systems most affected	Currently recommended clinical use
Methylphenidate, amphetamine	Dopamine and noradrenaline reuptake inhibitors	Response inhibition, working memory, attention, vigilance	Frontoparietal attentional systems, striatum, default mode networks	ADHD, wake-promoting agent
Caffeine	Non-selective adenosine receptor antagonist	Vigilance, working memory, incidental learning	Frontal lobe attentional systems	–
Nicotine	Nicotinic cholinergic receptor agonist	Working memory, episodic memory, attention	Fronto-parietal attentional systems, medial temporal lobe, default mode networks	–
Modafinil	Unknown, but effects on dopamine, noradrenaline and orexin systems proposed	Working memory, episodic memory, attention	Frontal lobe attentional systems	Wake-promoting agent
Atomoxetine, reboxetine	Noradrenaline reuptake inhibitors	Response inhibition, working memory, attention	Frontoparietal attentional systems	ADHD, depression
Donepezil, galantamine, rivastigmine (AChEI)	Blocks enzymatic breakdown of acetylcholine	Episodic memory, attention	Frontal lobe attentional systems	Alzheimer's disease, PDD, DLB
Memantine	Noncompetitive, low-affinity, open channel blocker of the NMDA receptor	Episodic memory, attention	Frontal and parietal lobe	Alzheimer's disease

Table SourceThe ongoing process of ageing in all advanced societies around the world presents the unhappy prospect of a veritable global epidemic of Alzheimer's and other neurodegenerative conditions. Such an ominous prospect makes the quest for cognitive enhancers somewhat urgent, for all modern nations. We will look at the nature of current cognitive enhancers, and consider the prospects for future enhancers of cognition. The focus will be on long-term enhancement and neuroprotection, rather than the short-term performance enhancers which are popular on college campuses.

It would probably be fair to say that we are still in the first generation of studies to examine the potential for cognitive enhancement in humans. In both healthy individuals and many patient groups, the overall effects of drugs generally seem to be modest. However, there is evidence that there might be more significant effects in subgroups, such as those whose baseline performance is poorest or individuals with a particular genotype. Moreover, new drugs aimed at enhancing the phasic response of neurotransmitter systems, such as direct nicotinic agonists for the cholinergic system [34], might prove to have greater effects than existing modulators that globally increase levels of a neurotransmitter in a tonic fashion. The neurobiology underpinning the effects of cognitive enhancers and the mechanisms that determine responsiveness across individuals promise to be the focus of research in health and brain disorders in the future. _Source

The ongoing study of current cognitive enhancers such as those in the table above, have given us scattered hints as to what future therapies might offer. Here is a short list of possible future targets for cognitive therapies:

Among targets under investigation, cholinergic receptors have received much attention with several nicotinic agonists (α7 and α4β2) actively in clinical trials for the treatment of AD, CIAS and attention deficit hyperactivity disorder (ADHD). Both glutamatergic and serotonergic (5-HT) agonists and antagonists have profound effects on neurotransmission and improve cognitive function in preclinical experiments with animals; some of these compounds are now in proof-of-concept studies in humans. Several histamine H3 receptor antagonists are in clinical development not only for cognitive enhancement, but also for the treatment of narcolepsy and cognitive deficits due to sleep deprivation because of their expression in brain sleep centers. Compounds that dampen inhibitory tone (e.g., GABAA α5 inverse agonists) or elevate excitatory tone (e.g., glycine transporter inhibitors) offer novel approaches for treating diseases such as schizophrenia, AD and Down syndrome. In addition to cell surface receptors, intracellular drug targets such as the phosphodiesterases (PDEs) are known to impact signaling pathways that affect long-term memory formation and working memory. Overall, there is a genuine need to treat cognitive deficits associated with many neuropsychiatric conditions as well as an increasingly aging population. _Source

It is important for us, at the outset, to take as realistic a viewpoint toward the possibility of meaningful cognitive enhancement as possible. The Likelihood of Cognitive Enhancement (Lynch et al 2011 PDF) is a useful introduction to many of the practical issues that need to be faced from the very beginning of this enterprise. Cognitive Enhacement: Promises and Perils (Hyman 2011 PDF) is a less technical introduction to the topic, perhaps more accessible to most laymen.

Cognitive Enhancement as a Pharmacotherapy Target for Stimulant Addiction (Sofuoglu 2010) looks at the use of cognitive enhancers as possible treatments for cocaine and methamphetamine addictions. Long term and heavy use of these drugs leads to cognitive deficits which make it even more difficult for a person to stop using these drugs and lead a "normal" life. The restoration of cognitive function is likely to provide a certain amount of "mental fortification" to allow at least some addicts to turn away from the dead end lifestyle. Similarly, restoration of cognitive function in persons suffering from age-related neurodegeneration is more likely to allow the person to participate in normal social interaction, and to undertake some level of responsibility, and perhaps productive activity.

Emerging Pharmacotherapies for Neurodevelopmental Disorders (Wetmore et Garner 2010) looks at the use of cognitive enhancers for persons who suffer from neurodevelopmental disorders such as Down's Syndrome, Fragile X, autism, etc. Given the overlap of mechanisms between some of the cognitive deficits in developmental disorders and ageing-related cognitive deficits, some of the coming developments in this area of pharmacotherapy should also prove quite helpful for treating age-related dementias.

As more is learned about the time-course of dysfunction in NDDs [neurodevelopmental disorders], targeting of therapies to the existing brain state may be improved. Moreover, individuals with NDDs have multiple cognitive and behavioral disabilities, and a particular drug therapy may improve only a subset of cognitive functions. Thus, a combination of complementary drugs may offer the most benefit by addressing deficits in attention, arousal, information processing, or depression.
...
The NDDs discussed here are phenotypically diverse yet linked by common mechanisms of dysfunction, including abnormal gene dosage, imbalance among neurotransmitter systems, and local protein translation (Fig. 2). A particular NDD can be caused by mutations in multiple genes, underscoring the convergence of dysfunction in key biochemical pathways. _Source

Finally, I would like to append to this entry some material from an earlier Al Fin article, which provides a few hints of future drug targets, as well as links to related material:

AMPAkines
CREB
PDE Inhibitors(4,10)
Nicotinic Alpha-7 agonists
mGluR antagonists
5HT6 antagonists

Frontrunners in the pharmaceutical race for smarter, better memory drugs include Memory Pharmaceuticals, Cortex Pharmaceuticals, Saegis Pharmaceuticals, Helicon, Lilly, Pfizer, Wyeth, Merck, Sention and many others. The precedent of approving drugs for erectile dysfunction (ED)--a lifestyle drug--suggests that smart drugs will eventually be approved for drooping memories as well.

Further Reading:

Molecules for Memory

Nootropics

Smart Drugs: What Are the Prospects?

Shaping the Brain with Smart Drugs (Gazzaniga)

CREB and Memory (basic neuroscience)

CREB, Synapses, and Memory Disorders

Hat tip Advanced Nano and Kurzweilai.net

Stem Cell Research Starting to Pay Off

A total of 23 patients took part in the ''Scipio'' trial, all of whom had suffered heart failure due to a previous heart attack. Sixteen were assigned to the stem cell therapy while the other seven received standard care.

...The ground-breaking new treatment involved extracting cardiac stem cells (CSCs) - self-renewing cells that rebuild hearts and arteries - from patients during bypass surgery.
The cells were purified and grown in the laboratory before being injected back into damaged regions of the patients' hearts four months later.

A million CSCs were infused into each patient via a balloon catheter, an expandable device used to open up arteries.

Heart pumping efficiency is assessed by measuring the fraction of blood expelled or ''ejected'' from the left ventricle with each beat.

At the start of the study, the patients had an average left ventricular ejection fraction (LVEF) of 40% or lower. Normal LVEF is 50% or higher.

Over a period of four months patients who underwent the treatment saw an 8.5% improvement in LVEF. After one year, this increased to 12.3%. LVEF did not change in the seven ''control'' patients who did not receive the therapy.

The findings were published today in an online edition of The Lancet medical journal. They were also presented at the American Heart Association's Scientific Sessions meeting in Orlando, Florida.

Magnetic Resonance Imaging (MRI) scans conducted on a number of patients showed that scarring in their hearts had been reduced.

The small Phase I study was primarily designed to assess safety rather than effectiveness. _Telegraph

As noted, the study was a "Phase I" clinical study meant to determine the safety of the treatment. In later, Phase II studies, efficacy will be looked at more closely. The results from this trial are quite encouraging -- modest but significant -- allowing a greater range of activity for the treatment group, post trial.

More from Genetic Engineering News:

Stage A of the ongoing open-label Phase I SCIPIO (Stem Cell Infusion in Patients with Ischemic cardiOmyopathy) study, by investigators at the University of Louisville and Brigham and Women’s Hospital, is evaluating CSC transplantation in patients with severe heart failure secondary to ischemic cardiomyopathy. The target population includes patients who underwent coronary artery bypass grafting (CABG), had LV ejection fraction (EF) of less than or equal to 40%, and a previous myocardial infarction.

Treated patients were administered with about a million autologous CSCs by intracoronary infusion, at a mean of 113 days after CABG. To generate the cardiac stem cells, tissue from the right atrial appendage was harvested from the patients at the time of CABG, and CSCs were isolated and expanded at the Brigham and Women’s Hospital.

...The trial has been led by Roberto Bolli, M.D., at the University of Louisville and Piero Anversa, Ph.D., at Brigham and Women's Hospital/Harvard Medical School in Boston. "The results are striking," Dr. Bolli states. "While we do not yet know why the improvement occurs, we have no doubt now that ejection fraction increased and scarring decreased. If these results hold up in future studies, I believe this could be the biggest revolution in cardiovascular medicine in my lifetime."

The published paper in The Lancet is titled "Cardiac stem cells in patients with ischaemic cardiomyopathy (SCIPIO): initial results of a randomised Phase I trial.” _GenEngNews

Heart muscle is relatively uncomplicated, as far as vital organs go, so it is not a great surprise that such a simple stem cell replacement therapy might work. Liver and pancreas may be similarly amenable to simple stem cell infusion. But other organs will require more clever designs for creating replacement tissue from stem cells and scaffolding.

In terms of numbers of persons potentially affected by this therapy for heart failure, the number will easily go into the millions in North America alone. Optimal therapy may require multiple infusions over time, to allow the heart to assimilate the new cells. More will be known as the research progresses into further stages.

This is just the beginning.

Rejuvenating 100 Year Old Cells: Advances in Regenerative Medicine

"Signs of aging were erased and the iPSCs obtained can produce functional cells, of any type, with an increased proliferation capacity and longevity," explains Jean-Marc Lemaitre who directs the Inserm AVENIR team....The age of cells is definitely not a reprogramming barrier. _SD

Cell Rejuvenation via IPSC
Scientists at the Functional Genomics Institute have taken cells donated by persons older than 100 years, and reprogrammed these senescent cells into pluripotent stem cells and embryonic stem cells. These stem cells can then be differentiated into specialised cells for cell, tissue, and organ replacement therapy -- once the details are worked out.

The researchers have successfully rejuvenated cells from elderly donors, some over 100 years old, thus demonstrating the reversibility of the cellular aging process.


To achieve this, they used an adapted strategy that consisted of reprogramming cells using a specific "cocktail" of six genetic factors, while erasing signs of aging. The researchers proved that the iPSC cells thus obtained then had the capacity to reform all types of human cells. They have the physiological characteristics of "young" cells, both from the perspective of their proliferative capacity and their cellular metabolisms.


Researchers first multiplied skin cells (fibroblasts) from a 74 year-old donor to obtain the senescence characterized by the end of cellular proliferation. They then completed the in vitro reprogramming of the cells. In this study, Jean-Marc Lemaitre and his team firstly confirmed that this was not possible using the batch of four genetic factors (OCT4, SOX2, C MYC and KLF4) traditionally used. They then added two additional factors (NANOG and LIN28) that made it possible to overcome this barrier.


Using this new "cocktail" of six factors, the senescent cells, programmed into functional iPSC cells, re-acquired the characteristics of embryonic pluripotent stem cells.
In particular, they recovered their capacity for self-renewal and their former differentiation potential, and do not preserve any traces of previous aging. To check the "rejuvenated" characteristics of these cells, the researchers tested the reverse process. The rejuvenated iPSC cells were again differentiated to adult cells and compared to the original old cells, as well as to those obtained using human embryonic pluripotetent stem cells (hESC).


...The results obtained led the research team to test the cocktail on even older cells taken from donors of 92, 94 and 96, and even up to 101 years old. "Our strategy worked on cells taken from donors in their 100s. The age of cells is definitely not a reprogramming barrier." He concluded. "This research paves the way for the therapeutic use of iPS, insofar as an ideal source of adult cells is provided, which are tolerated by the immune system and can repair organs or tissues in elderly patients." adds the researcher.


...Inserm's AVENIR "Genomic plasticity and aging" team, directed by Jean-Marc Lemaitre, Inserm researcher at the Functional Genomics Institute (Inserm/CNRS/Université de Montpellier 1 and 2) performed the research. The results were published in Genes & Development on November 1, 2011 _SD

The first use of this new regenerative technology is likely to be cell replacement therapy. But as the methods for growing replacement tissues and organs in the lab are perfected, the methods should be suitable for producing cells to use in growing replacement tissues and organs for purposes of disease treatment and for treating senescence.

Cross-posted from Al Fin

Two Hints of the Possibility for a Healthy Long Life

The first hint comes from the Mayo Clinic's Darren Baker. Baker has developed a way of delaying symptoms of old age in mice, and has even been able to reverse some signs of aging in already aged mice. Here's more:

Baker has developed a way of killing all of a mouse’s senescent cells by feeding them with a specific drug. When he did that in middle age, he gave the mice many more healthy years. He delayed the arrival of cataracts in their eyes, put off the weakening of their muscles, and held back the loss of their body fat. He even managed to reverse some of these problems by removing senescent cells from mice that had already grown old. There is a lot of work to do before these results could be applied to humans, but for now, Baker has shown that senescent cells are important players in the ageing process.

Note that the mice in this study didn’t live any longer; they just spent more of their life being healthy.

Baker exploited the fact that many senescent cells rely on a protein called p16-Ink4a. He created a genetic circuit that reacts to the presence of p16-Ink4a by manufacturing an executioner: a protein called caspase-8 that kills its host cell. Caspase-8 is like a pair of scissors – it comes in two halves that only work when they unite. Baker could link the two halves together using a specific drug. By sneaking the drug into a mouse’s food, he activated the executioners, which only killed off the cells that have lots of p16-Ink4a. Only the senescent ones get the chop.

Baker tested out this system in a special strain of genetically engineered mice that age very quickly. It worked. The senescent cells disappeared, and that substantially delayed the onset of muscle loss, cataracts, and fat loss. Typically, around half of these mice show signs of muscle loss by five months of age. Without their senescent cells, only a quarter of them showed the same signs at ten months. Their muscle fibres were larger, and they ran further on treadmills. Even old mice, whose bodies had started to decline, showed improvements. _Discover

Another look at this research from the Economist:

Dr Baker genetically engineered a group of mice that were already quite unusual. They had a condition called progeria, meaning that they aged much more rapidly than normal mice. (A few unfortunate humans suffer from a similar condition.) The extra tweak he added to the DNA of these mice was a way of killing cells that produce P16INK4A. He did this by inserting into the animals’ DNA, near the gene for P16INK4A, a second gene that was, because of this proximity, controlled by the same genetic switch. This second gene, activated whenever the gene for P16INK4A was active, produced a protein that was harmless in itself, but which could be made deadly by the presence of a particular drug. Giving a mouse this drug, then, would kill cells which had reached their Hayflick limits while leaving other cells untouched. Dr Baker raised his mice, administered the drug, and watched.

The results were spectacular. Mice given the drug every three days from birth suffered far less age-related body-wasting than those which were not. They lost less fatty tissue. Their muscles remained plump (and effective, too, according to treadmill tests). And they did not suffer cataracts of the eye. They did, though, continue to experience age-related problems in tissues that do not produce P16INK4A as they get old. In particular, their hearts and blood vessels aged normally (or, rather, what passes for normally in mice with progeria). For that reason, since heart failure is the main cause of death in such mice, their lifespans were not extended.

The drug, Dr Baker found, produced some benefit even if it was administered to a mouse only later in life. Though it could not clear cataracts that had already formed, it partly reversed muscle-wasting and fatty-tissue loss. Such mice were thus healthier than their untreated confrères. _Economist

This research will require replication and a great deal of clarification, before it moves from mice to larger mammals such as humans. But it opens up a number of possible avenues of research.

The second hint of likely means to achieve healthier long lives, is research done in fruit flies at the Salk Institute, in southern California.

Although it is a well-documented fact that restricting calories during daily food intake is the easiest strategy to extend life spans for both humans and animals, little is known about biological mechanisms underlying this phenomenon.

..."Fruit flies and humans have a lot more in common than most people think," said Leanne Jones, an Associate Professor at Salk's Laboratory of Genetics and a lead scientist on the project, "There is a tremendous amount of similarity between a human small intestine and the fruit fly intestine."

The researchers found that boosting the activity of dPGC-1, the Fruit Fly version of the gene, resulted in greater numbers of mitochondria and more energy-production in flies; the same phenomenon is seen in organisms on calorie restricted diets.

When the activity of the gene was accelerated in stem and progenitor cells of the intestine, which serve to replenish intestinal tissues, these cellular changes correspond with better health and longer lifespan.

The flies lived between 20 and 50 percent longer, depending on the method and extent to which the activity of the gene was altered. _ibtimes

The fruit fly research suggests that not only healthier long lives are possible, but "longer long" lives are possible as well.

The approach taken by the SENS Foundation involves using multiple approaches to extending healthy lifespan. Destroying senescent cells -- such as Darren Baker is learning to do -- is one of the main approaches that SENS is following. Improving the function of mitochondria is another of the main tactics of SENS.

As humans in advanced societies are putting less and less energy into raising children, and putting more and more energy into raising themselves, thoughts of increased longevity and lifespan are coming more into the mainstream of respectability. The main limitation to further research into life extension is -- as always -- funding. But even with unlimited funding, moving the research from animal models into human therapeutics would take a matter of decades.

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.