Brain Restoration in Alzheimer's Disease: Deep Brain Stimulates Reversal of Brain Shrinkage

BRAIN shrinkage in people with Alzheimer's disease can be reversed in some cases - by jolting the degenerating tissue with electrical impulses. Moreover, doing so reduces the cognitive decline associated with the disease. _NS

NS
Alzheimer's disease is an increasingly common cause of total disability in the ageing population. One of the manifestations of Alzheimer's is a shrinking and shutting down of activity in multiple centres of the brain which are critical to memory function. Cells die and crucial brain tissue is lost, as part of the disease process. Now scientists at Toronto Western Hospital in Ontario, believe they may have found an effective approach -- for some.

The group inserted electrodes into the brains of six people who had been diagnosed with Alzheimer's at least a year earlier. They placed the electrodes next to the fornix - a bundle of neurons that carries signals to and from the hippocampus - and left them there, delivering tiny pulses of electricity 130 times per second.

Follow-up tests a year later showed that the reduced use of glucose by the temporal lobe and posterior cingulate had been reversed in all six people (Annals of Neurology, DOI: 10.1002/ana.22089).

The researchers have now begun to investigate the effects on the hippocampus. At the Society for Neuroscience annual meeting in Washington DC last week they announced that while they saw hippocampal shrinking in four of the volunteers, the region grew in the remaining two participants.

"Not only did the hippocampus not shrink, it got bigger - by 5 per cent in one person and 8 per cent in the other," says Lozano. It's an "amazing" result, he adds.

Tests showed that these two individuals appeared to have better than expected cognitive function, although the other four volunteers did not.

Though Lozano is not sure exactly how the treatment works, his team's recent work in mice suggests that the electrical stimulation might drive the birth of new neurons in the brain. Deep brain stimulation in mice also triggers the production of proteins that encourage neurons to form new connections _NS

This approach is worth pursuing further. It is too invasive to be used on a wide scale, but it is likely that there will be no shortage of volunteers for the procedure. What is learned from this research can be used to devise less invasive approaches which will be more appropriate for use in larger populations.

In the meantime, research into the use of pharmaceuticals, growth factors, and stem cell therapies for Alzheimer's will continue.

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.