Aging Biomarkers plus Importance of Lysosomes

Researchers are looking for biomarkers which would reveal the state of aging in an organism. Given the relationship between telomere length and cell reproductive capacity, researchers at Rockefeller University looked for biomarkers of telomere shortening.

Telomere dysfunction limits the proliferative capacity of human cells by activation of DNA damage responses, inducing senescence or apoptosis. In humans, telomere shortening occurs in the vast majority of tissues during aging, and telomere shortening is accelerated in chronic diseases that increase the rate of cell turnover. Yet, the functional role of telomere dysfunction and DNA damage in human aging and diseases remains under debate. Here, we identified marker proteins (i.e., CRAMP, stathmin, EF-1α, and chitinase) that are secreted from telomere-dysfunctional bone-marrow cells of late generation telomerase knockout mice (G4mTerc−/−). The expression levels of these proteins increase in blood and in various tissues of aging G4mTerc−/− mice but not in aging mice with long telomere reserves. _PNAS_via_NBF

It will be interesting to determine if the same markers are present in humans.

Scientists at Albert Einstein College of Medicine have managed to "stop the aging process" by boosting cellular protein clearance.

"Many of these diseases [of aging AF] are due to 'misbehaving' or damaged proteins that accumulate in neurons. By preventing this decline in protein clearance, we may be able to keep these people free of symptoms for a longer time."

If the body's ability to dispose of cell debris within the cell were enhanced across a wider range of tissues, she says, it could extend life as well.

In healthy organisms, a surveillance system inside cells called chaperone-mediated autophagy (CMA) locates, digests and destroys damaged proteins...Specialised molecules, the "chaperones", ferry the harmful material to membrane-bound sacs of enzymes within the cells known as lysosomes...Once the cargo has been "docked", a receptor molecule transfers the protein into the sac, where it is rapidly digested.

With age, these receptors stop working as well, resulting in a dangerous build-up of faulty proteins that has been linked, in the liver, to insulin resistance as well as the inability to metabolise sugar, fats or alcohol.

The same breakdown of the cell's cleaning machinery can also impair the liver's ability to remove the toxic build-up of drugs at a stage in life when medication is often part of daily diet.

In genetically modified mice, Cuervo compensated for the loss of the receptors in the animals by adding extra copies...."That was enough to maintain a clean liver and to prove that if you keep your cells clean they work better," she says. _Source_via_NextBigFuture

Cleaning up cellular debris buildup is part of Aubrey de Grey's SENS program of engineered anti-senescence.

Anti-aging research proceeds along several fronts. It is important to be able to monitor a person's state of aging, if anti-aging therapy is to be put upon a sound scientific basis. And it is vital to produce many safe and effective therapies against as wide a range of aging mechanisms as possible.

Dimebon Improves All 5 Alzheimer's Measures

183 Russian Alzheimer's patients were studied for a year to compare the safety and efficacy of Dimebon, an obscure antihistamine that is not on the market anywhere in the world. The study was conducted by Baylor College of Medicine researchers, and published in the Lancet.

In the study, the authors noted that Dimebon is the first drug for Alzheimer's disease that demonstrated continued improvement in patients over a 12 month period. Other approved drugs do not have this effect.

Half of the 183 patients in the Russian study received Dimebon; the other half were given a placebo or an inactive pill. Clinicians at the study sites then monitored the patients' progress over the next year on five different outcomes. All of those in the study had mild to moderate Alzheimer's disease.

"What we saw in the clinical trial is that people on the medication continued to improve over time," Doody said. "Those on placebo continued to decline."

Researchers believe the medication works by stabilizing mitochondria, the cellular components that produce energy, and possibly by inhibiting brain cell death. Researchers evaluated patients' thinking and memory ability, overall function, psychiatric and behavioral symptoms, and ability to perform daily activities.

"Usually at this point in a drug's development, we are happy to see improvement in one of the outcome measures," Doody said. "We saw improvement in all five." _SD

The study was reportedly well-designed and conducted. The significant and ongoing improvement of the drug group over the placebo group for at least a year, is quite impressive. Rights for the drug are owned by Medivation, Inc. (Nasdaq: MDVN), which has enjoyed a recent boost in stock price.

More information on this study and other new research on Alzheimer's Disease at WaPo:.

The study was done in Russia because dimebon had been approved there as an antihistamine. Dimebon is made by the San Francisco-based biopharmaceutical company Medivation. Doody is on the Scientific and Clinical Advisory Board of Medivation and has stock options in the company.

Another phase III trial has just started, Doody said. This six-month trial is being conducted in the United States, Europe and South America and is now in the process of recruiting several hundred patients, she noted.

"We are anxiously awaiting the completion of the next study, so that we can see if this drug could potentially be approved for treating Alzheimer's patients," Doody said.

Gandy said the drug does appear to be superior to the currently approved medicines for Alzheimer's.

"This is the first new promising symptomatic therapy in a long time," Gandy said. "This drug could potentially add to the effects of other drugs such as Aricept, Namenda and Exelon," he said. "I think it's a pretty exciting development."

Partially excerpted from a previous posting at Al Fin

Methionine Restriction and QOD Feeding

The latest issue of Rejuvenation Research contains some articles dealing with dietary restriction strategies for extending lifespan.

The latest issue of Rejuvenation Research is online. You'll find a few more esoteric items on calorie restriction biochemistry, but one paper on methionine restriction is more accessible and interesting. By way of a reminder, recall that there's a fairly good argument for the beneficial effects of calorie restriction to largely stem from lowering the intake of methionine, one of the eight essential amino acids in your diet.

On Methionine Restriction, Suppression of Mitochondrial Dysfunction and Aging

Rats and mice, when subjected to methionine restriction (MetR), may live longer with beneficial changes to their mitochondria. Most explanations of these observations have centered on MetR somehow suppressing the effects of oxygen free radicals.

The other paper that caught my attention is a nice demonstration that the benefits of calorie restriction don't necessarily have anything to do with insulin-like growth factor 1, IGF-1. For those who have been following research into IGF-1 metabolism and aging, a field with at least as much interest as investigations into mitochondria and aging, that might be a counterintuitive result.

Effect of Every Other Day Feeding on Mitochondrial Free Radical Production and Oxidative Stress in Mouse Liver

It is known that dietary restriction (DR) increases maximum longevity in rodents, but the mechanisms involved remain unknown. Among the possible mechanisms, several lines of evidence support the idea that decreases in mitochondrial oxidative stress and in insulin signaling are involved but it is not known if they are interconnected.

It has been reported that when C57BL/6 mice are maintained on an every other day (EOD) feeding their overall food intake is only slightly decreased and plasma insulin-like growth factor (IGF)-1 is even somewhat increased. In spite of this, their maximum longevity is increased, analogously to what occurs in classic DR. Thus, this model dissociates the increase in longevity from the decrease in IGF-1 observed in classic DR.

...

These results support the possibility that EOD DR increases maximum life span at least in part through decreases in mitochondrial oxidative stress which are independent from insulin/IGF-1-like signaling.

_FightingAging

Various manipulations of diets in animal models should provide us with more information about aging mechanisms, as research designs become more sophisticated to tease out effective manipulations, and as collection and analysis of animal response data delves more deeply into the actual molecular mechanisms that are altered.

Update on "Understanding Aging" at UCLA

After working in obscurity and semi-respectability for almost a decade, Aubrey de Grey is finally getting the recognition he deserves. The Understanding Aging conference at UCLA is wrapping up after a full weekend of presentations.

Probably the most famous presentation of the weekend to hit the news so far, is the potential "cancer cure" being studied by Wake Forest researcher Zheng Cui, who gave a presentation yesterday at the meetings. Zheng's study involves screening 500 healthy young (under 50) adult volunteers for cancer resistance, then selecting the 100 volunteers with the strongest measured cancer resistance and taking white blood cell (WBC) donations from the 100. These WBC's would then be transfused into cancer patients to determine safety and efficacy of the treatment. The approach has proved very successful in mice. More information here and here.

Another interesting presentation was given by Trevor Marshall reporting on studies linking stem cells, cancer, and bacterial infection.

This comprehensive overview from Brian Wang allows a busy non-attendee to briefly sample the research fare of the busy weekend conference. By doing an internet search using a science search engine, you can often find full text articles by participating authors, which should give considerable background on their current research.

Aubrey de Grey's excellent introduction to SENS anti-aging research, Ending Aging, was published in 2007, but the information in parts of the book is already becoming obsolete by the rapid progress in research labs. Thanks to the energy, ideas, and fund-raising by de Grey and his colleagues, anti-aging research is finally coming out of the closet into the daylight.

Stem Cell Rejuvenation: Overcoming the Impediments of Aging and Disease

As individuals age, their stem cell pools tend to shrink. Likewise in the presence of many diseases, stem cells are less readily available. Even worse, the tissue response to stem cell supplementation is less successful under conditions of aging or disease. Researchers at the University of Frankfurt and Harvard Medical School have discovered ways of replenishing stem cell pools in aging and disease, as well as means of pre-treating diseased tissues for more successful stem cell supplementation.

In addition to age, which is known to affect stem cells functions, risk factors for coronary artery disease (CAD) and heart failure diminish the capacity of the bone marrow–derived cell to contribute to functional repair (Figure 1). Although patients usually are exposed to more than one risk factor, the next paragraph will discuss the impact of the individual risk factors and disease entities on endogenous bone marrow–derived and circulating cells.

...Similar to the impaired function of circulating or bone marrow–derived cells by diabetes, other risk factors such as hypercholesterolemia26 and hypertension26,27 also were associated with reduced and dysfunctional circulating EPCs. In addition, circulating CD34+KDR+ or CD34+CD133+ KDR+CD45low cells were inversely correlated with smoking,7,28 and this reduction was reversed by smoking cessation.28

...In old rats, chronological age leads to telomeric shortening in CPCs, which by necessity generate a differentiated progeny that rapidly acquires the senescent phenotype.5 The daughter cells inherit the shortened telomeres of the maternal CPCs and, after a few rounds of division, express the senescence-associated protein p16INK4a. The pool of old cardiomyocytes progressively decreases and ventricular function is impaired. However, telomerase competent CPCs with long telomeres are present in the regions of storage in the atria and apex and these cells, after activation by growth factors, migrate to areas of damage where they create a population of young myocytes reversing to some extent the aging myopathy structurally and functionally. The senescent heart phenotype is partially corrected and the improvement in cardiac hemodynamics results in prolongation of maximum lifespan in the rat model.5 __Source__via__Ouroborus

The article goes on to discuss ways of pre-treating the stem cells to be injected to enhance survival, and ways of pre-treating the target tissue to improve homing, engraftment, survival, and differentiation.The researchers demonstrate that despite the handicaps acting against successful stem cell treatment in disease and aging, that specific therapeutic pre-treatments for the stem cells and the target tissue should be able to counteract these deficiencies, and allow successful stem cell treatment.

Much interesting and useful information at the linked--free access article.

Chronic Stress, Chronic Infections, and Telomeres

Ouroborus has an interesting post looking at the telomere-shortening effect of chronic infections and chronic stress.

Chronic stress has been associated with decreased telomere length in lymphocytes. The association is robust and has been observed in multiple studies, including one that looked at stress in addition to other risk factors for cardiovascular disease (CVD), so it appears that lymphocyte telomeres are a useful biomarker for some convolution of age and lifetime stress level. The question still remains, however, whether the relationship is correlative or causative.

...To the extent that telomere shortening is a causative force in aging (an idea consistent with correlative data showing an association between critically short telomeres and extreme old age, and bolstered by evidence that telomere length is a heritable determinant of lifespan), this study implies that infection itself contributes to the aging process, at least within the hematopoietic lineage — and that we already have one biomarker, just a PCR away from a peripheral blood sample, to measure the extent of that contribution. __Ouroborus

The article discusses a study that appears to strengthen the connection between infection and telomere shortening.

Geron and other research groups have studied telomerase with the intent of blocking the enzyme in cancer, but also with the possibility that a telomerase form or analog might be useful in regenerating senescent cells.

Until science can separate the connection between cancer and old age, progress on this front may be slow. Then again, breakthroughs often occur just when you'd given up hope.

New Polymer Cell Organelles Hold Promise for Cell Repair and Rejuvenation

New research from the University of Basel offers the hope of replacing or supplementing an aging or dysfunctional cells organelles with polymer replacements. The Swiss researchers were able to upgrade human cells in a petri dish, using the polymer organelles.

The artificial organelle's membrane can be chemically tuned to control which chemicals can pass through it and regulate the reactions inside, according to Wolfgang Meier, one of the researchers. "We call it a 'nanoreactor'," he says...At 200 nanometres across, the organelles are 400 times smaller in width than a human hair.

...Artificial organelles might .. be able to treat conditions caused by a deficit of a particular enzyme. For example, someone with lactose intolerance could have their digestive cells given artificial organelles containing lactose-digesting enzymes.

In the far future, it might be possible to introduce non-human metabolic functions into human cells. "We could, in principle, bring in a nanoreactor that [lets] your skin do something like photosynthesis. So if you are hungry, you just lie in the Sun," says Meier. __NS_via_Kurzweilai.net

These polymer organelles are reminiscent of the polymer "red blood cells" invented by Joseph DeSimone at the University of North Carolina.

He has created tiny sacks of the polymer polyethylene glycol just 8 micrometres across – in the range of human red blood cells – that are capable of deforming in a way that allows them to pass through the tiniest capillaries.

Polyethylene glycol is biologically benign, but binds easily with other substances, which makes it ideal for carrying cargo through the blood, says DeSimone.

For example, a haemoglobin-type molecule carried inside the bag could deliver oxygen to the body and carry away carbon dioxide. The bags could also deliver drugs instead, or help as contrast agents for scans such as magnetic resonance imaging, PET or ultrasound. __NS_suggested by Will Brown

The ability to create tiny organs and organelles to replace malfunctioning or deficient human cells and cell components offers a more profound level of therapy than medical practice has been accustomed to. Over time, a more full array of uses for these polymer replacements will no doubt be devised.

Aging 2008 at UCLA

The Methuselah Foundation announces "Aging2008" at UCLA Friday June 27th.

The speakers at Aging 2008 will argue that the near-term consequences of intense research into regenerative medicine could be the development of therapies that extend healthy human life by decades, even if the therapies are applied in middle age. Peter Thiel, president of Clarium Capital, initial investor in Facebook, and lead sponsor of Aging 2008, said, "The time has come to challenge the inevitability of aging. This forum will provide an excellent opportunity to look at the scientific barriers that must be overcome to substantially extend healthy human life, as well as the sociological implications of doing so."

Aging 2008 also serves as the free opening session for the technically focused Understanding Aging Conference, which will run at UCLA on June 28th and 29th.

What: Aging: The Disease, The Cure, The Implications, hosted by Methuselah Foundation

When: Friday, June 27, 2008, Drinks 4pm, Presentations 5pm, Dinner 8pm

Where: Royce Hall, 405 Hilgard Ave, Los Angeles, CA 90024 __Source

Canadian Neuro-Arm Robot Surgeon Precision

To achieve radically longer lives, we will need to engineer ourselves to be more resilient to damage and disease, but we will always need the ability to intervene safely with radical surgical tools.

Canadian researchers developed the Neuro-Arm robot, a robot compatible of MRI imaging so that a surgeon can operate on a tumour with real-time feedback.

A surgeon is able to control the robot using levers at a computer workstation in a room next to the surgery. Sutherland said human ability to manipulate robotic surgery techniques can be credited, at least in part, to the explosion in popularity of video games.

"We would all agree that our young children who have become immersed in video games represent the future generation of surgeons," he said. "[They] will be experienced in the integration of hand controllers with images and …will have enhanced hand-eye co-ordination with highly developed spatial orientation."

The technology works in conjunction with real-time magnetic resonance imaging, or MRI, to provide surgeons with unprecedented detail and the control to manipulate tools at a microscopic scale for operations ranging from repairs of blood vessels to removal of brain tumours. __Source

The successful MRI-guided removal of a brain tumour in Calgary by Neuro-Arm suggests that robotic surgeons will gain more and more use over time.

Even if our bodies are modified to last for hundreds of years, we will always be subject to accidents and "break-through disease" which is somehow resistant to our life extension programming. In those situations, we will need the best medical and surgical care possible.

In the new robo-surgeons, we can see the nascent form of a future "robo-doc" that is capable of operating far from human medical experts. If humans are to be able to travel and live in the remotest outposts of our solar system, we will necessarily have communities inaccessible to the full range of highly trained human specialists. In such situations, robotic surrogates will be a vital part of the team.

Sirtris Resveratrol SRT501 To Be Used To Study Mitochondrial Deficiency Diseases

Resveratrol--a phyto-antioxidant found in grapeskins--is not only being studied for its possible anti-aging effects, it is also being studied for its potential for treating degenerative diseases of several types.

For the Rochester study, published in the March issue of Advances in Experimental Medicine and Biology, the research team wanted to examine if resveratrol had a negative effect on cancer cells. In this case, they chose pancreatic cancer cells. Pancreatic cancer is particularly hard to treat with chemotherapy, because the pancreas, a gland located deep in the abdomen, pumps powerful digestive enzymes into the intestines. This pumping process clears the gland of chemotherapy doses, making treatment difficult.

The team, lead by Dr. Paul Okunieff, the chief of radiation oncology at the University’s cancer center, prepared two sets of pancreatic cancer cells and added pure resveratrol to one. After treating both sets with chemotherapy, they found that the resveratrol had "depolarized" the cell membranes of 35 percent of the mitochondria, shutting down the organelles and exposing the cells to radiation treatment.

...Sirtris is supplying their resveratrol, called SRT501, to a team of scientists at England's Newcastle University to conduct clinical trials on ailments related to a mitochondrial-related illness, called MELAS—mitochondrial myopathy, encephalopathy, lactic acidosis, strokelike episodes. MELAS is caused by mutated mitochondria and is a progressive and fatal disease that normally surfaces when the patient is between five and 15 years old. Strokelike episodes may lead to impaired muscular function and dementia.

...Chinnery's team will study if resveratrol can improve the functioning of the mitochondria and hopefully diminish the symptoms. If the research is successful, the FDA will then consider approving SRT501, with Sirtris as the sole marketer, for a seven-year period. "Many diseases of aging, such as type 2 diabetes, exhibit impaired mitochondrial function," said Peter Elliot, vice president of development at Sirtris. "We hope to develop new therapies." CheckBiotech

That is fascinating news, given the humble origins of resveratrol. Other related stilbenes found in berries and grapes may prove to be even more useful therapeutically (eg pterostilbene).

Phase I Trials: Prodarsan for Cockayne's Syndrome

Prodarsan is a combination of small protein molecules devised by Pharming NV[PHGUF.PK] for treatment of premature aging including Cockayne's Syndrome.

Leiden, The Netherlands, April 23, 2008. Biotech company Pharming Group NV (Pharming) (NYSE Euronext: PHARM) announced today that its wholly owned subsidiary DNage has started a Phase I clinical study to evaluate the pharmacokinetics and tolerability of Prodarsan(R) in humans.

Premature ageing, the primary target of Prodarsan(R), is a group of rare genetic diseases which manifests itself in several forms that are genetically and clinically similar although not identical. Dependent on the specific form of the disease, patients have a strongly reduced life expectancy and exhibit many ageing-related diseases early on in their lives. There is currently no effective therapy available for these patients.

Pharming has demonstrated that Prodarsan(R) as an oral, liquid formulation has significant effects in animal models for Cockayne Syndrome (CS). CS is one of the more common forms of premature ageing and is characterized, amongst others, by growth failure, mental retardation, eye abnormalities and a reduced life expectancy. The positive effects of Prodarsan(R) in preclinical testing on life expectancy in general and more specifically on the eye abnormalities are promising for further development of the product and its testing in humans.

The Phase I trial that is now being conducted consists of a combined single and multiple dose escalating clinical study in healthy volunteers. By studying the pharmacokinetics and tolerability of Prodarsan(R) and the effects of food intake on the absorption and elimination of the product, an oral dosing scheme will be determined that targets the pharmacological effective concentration range effectively. It is expected that following a successful completion of this trial the first clinical studies in patients will start later in 2008. Source

Prodarsan's proposed mechanism of action is via the DNA repair mechanism of the cell.

CKN1 is caused by a defect in the Cockayne syndrome type A gene (CSA or ERCC8) located on chromosome 5. Affected persons inherit 2 mutant genes, one from each parent. Cells carrying ERCC8 mutations are hypersensitive to UV light. They do not recover the ability to synthesize ribonucleic acid (RNA) after exposure to UV light. In addition, the cells cannot remove and degrade deoxyribonucleic acid (DNA) lesions from strands that have active transcription.

Mutations in the DNA excision repair gene ERCC6 located on band 10q11 cause CS type 2 (MIM number 133540; CSB). This gene encodes helicase, a protein that is presumed to have DNA unwinding function. Mutations include a deletion of exon 4, an amino acid substitution at the 106th glutamine to proline (Q106P) in the WD-40 repeat motif of the CSA protein, and large deletion in the upstream region, including exon 1 of the CSA gene. The Q106P mutation could alter the propeller structure of the CSA protein, which is important for the formation of the CSA protein complex. Additionally, a missense mutation (A205P) and a nonsense (E13X) mutation have been identified, as well as a new common single nucleotide polymorphism in CKN1. No genotype-phenotype correlation exists. _EMedicine

We can hope that experience in augmenting DNA repair in the tragic accelerated aging syndromes may be helpful in devising strategies to augment DNA repair in helping to delay normal aging.

Intravenous Cord Blood Cells Rejuvenate Aging Brains, Replenish Neural Progenitor Cells

Image Source

Researchers in Florida have managed to rejuvenate the brains of aging mice with a single injection of human cord blood cells in a peripheral vein. The single cord blood cell injection resulted in new progenitor stem cells in the mouse hippocampus, and new nerve cell formation.

Neurogenesis continues to occur throughout life but dramatically decreases with increasing age. This decrease is mostly related to a decline in proliferative activity as a result of an impoverishment of the microenvironment of the aged brain, including a reduction in trophic factors and increased inflammation.

We determined that human umbilical cord blood mononuclear cells (UCBMC) given peripherally, by an intravenous injection, could rejuvenate the proliferative activity of the aged neural stem/progenitor cells. This increase in proliferation lasted for at least 15 days after the delivery of the UCBMC. Along with the increase in proliferation following UCBMC treatment, an increase in neurogenesis was also found in the aged animals. The increase in neurogenesis as a result of UCBMC treatment seemed to be due to a decrease in inflammation, as a decrease in the number of activated microglia was found and this decrease correlated with the increase in neurogenesis.

The results demonstrate that a single intravenous injection of UCBMC in aged rats can significantly improve the microenvironment of the aged hippocampus and rejuvenate the aged neural stem/progenitor cells. Our results raise the possibility of a peripherally administered cell therapy as an effective approach to improve the microenvironment of the aged brain.

...Not only do the results of this study provide novel insight into the state of the aged stem cell niche, the ability of the UCBMC to exert their effects while being administered minimally invasively may make translation to the clinical setting more likely. For this reason it will be important in future studies to determine the most efficacious dose and dosing regimen. Nevertheless, this is the first time that a systemic injection of hematopoietic cells has been shown to restore the regenerative potential of the aged brain, providing a novel insight into how the regenerative potential of the aged stem cell niches could be restored.

...The effects of UCBMC have been attributed to changes in the microenvironment of the brain, through the release of trophic factors or by reducing inflammation, and not by a direct replacement of cells [21-23]. UCBMC contains a number of cell types including B-Cells and T-Cells, as well as, mesenchymal and endothelial progenitor cells. UCBMC is also a rich source of CD34⁺ hematopoietic stem cells [24-26]. It was recently demonstrated that a systemic injection of UCBMC cells could suppress inflammation in the brain following stroke. Moreover, the effects of UCBMC cells seemed to shift the cytokine expression from a Th1 response to a Th2 response [20,23,27]. In addition to the immune modulatory effects, UCBMC cells also produce a number of trophic factors including, but not limited to, VEGF, nerve growth factor, and cytokine colony stimulating factor-1, thrombopoietin, and IL11 [20,28,29]. ___BiomedCentral__via_madscience__via__TechnutNews

It is important to understand that the cells that were injected into the peripheral veins of mice were human umbilical cord blood mononuclear cells (HUCBMCs). The results are somewhat startling, given that the injected cells were not neural stem cells, the cells were not injected directly into the brain, and the cells were given in a single dose only. It will be important for the researchers to tease out the important cellular and trophic factors present in the UCBMC's that may have led to the rejuvenatory effects.

This is a line of research that I am interested in following further.

Protecting the Brain Over the Lifespan

If humans are to extend their lifespan by 50% and more, they will need to learn to prevent accumulation of damage to the aging brain. One approach is through long-term pharmacological intervention.

Scientific work continues on the use of Ampakine drugs to treat Alzheimer's and other neurological disorders. Now it looks as if Ampakines can also serve as a prophylactic drug.

The drug, temporarily designated S18986, interacts with AMPA (short for α- Amino-3-hydroxy-5- methylisoxazole-4- propionic acid, or ampakine) receptors in the brain. These receptors transmit excitatory signals in the brain, and researchers were interested in experimental AMPA-receptor drugs (such as S18986) for their neuroprotective abilities and for the way they temporarily boost memory. But rather than investigating the compound’s short-term effects, Alfred E. Mirsky Professor Bruce McEwen and his lab members...studied the drug’s impacts on middle-aged to elderly rats and found that, when administered daily over four consecutive months, it appeared to improve memory and slow brain aging.

...When compared to control animals that had received only sugar water, the drugged rats were not only more active and better at memory tests, but their brains showed physical signs of slowed aging. Neurons in the forebrain that produce acetylcholine, a neurotransmitter known to play a role in learning and memory, had 37 percent less decline. Dopamine-producing neurons, which are responsible for sustaining activity and motivation levels, slowed their decline by 43 percent. Levels of inflammation in the brain were also significantly lower. “Every marker we chose to look at seemed to indicate there was some preservation of function during aging with chronic treatment,” Hunter says. The drug appears to slow aging’s effects throughout the entire brain.___ScienceDaily__via__FutureScanner

This particular Ampakine appears to have a protective effect on the brains of rats over a significant part of the rat's lifespan.

Ampakines are being researched as potential treatments for Alzheimer's, Depression, and other neuropathological and neuropsychiatric conditions. This research suggests an even broader potential application of Ampakines--as a neuroprotective for those at risk for neuropathology. Broadly speaking, that would be most of us, over our lifespans.

Replacement Body Parts

Since 1967, when Christiaan Barnard successfully performed the first successful human to human heart transplant, it has been painfully obvious that there are not enough human hearts available to meet the demand. Surgeons have tried various approaches to replacing damaged and worn out hearts--including baboon hearts, refrigerator sized machine replacement hearts, and most reacently, the AbioCor totally implantable artificial heart system. While the AbioCor's batteries can be rechared through the skin, they will eventually have to be replaced. Machine hearts are subject to failure of various types, and experience with them is still only short term.

Eventually, hearts will be "printed", along with other replacement organs. Other organs, such as the urinary bladder, have already been synthetically produced and implanted. But the heart's fibrous skeleton is too complex for scientists to mimic in the lab--to this point.

So lab scientists are learning how to scavenge heart skeletons wherever they can. University of Minnesota scientists have taken dead animal hearts and removed the dead cells--leaving the fibrous infrastructure. By injecting immature heart cells into the scaffolding--in a stepwise manner--they were able to revitalize the heart to the point of beating.

The team took a whole heart and removed cells from it. Then, with the resulting architecture, chambers, valves and the blood vessel structure intact, repopulated the structure with new cells.

"We just took nature's own building blocks to build a new organ," says Dr Harald Ott, a co-investigator who now works at Massachusetts General Hospital. "When we saw the first contractions we were speechless."

The work has huge implications: "The idea would be to develop transplantable blood vessels or whole organs that are made from your own cells," said Prof Doris Taylor, director of the Centre for Cardiovascular Repair, Minnesota, principal investigator.

The method could be used to grow liver, kidney, lung and pancreas, indeed virtually any organ with a blood supply.

Telegraph

In the meantime, researchers continue to work on alternatives--including artificial hearts that spin like a turbine, producing a constant blood pressure rather than a pulse. Such turbine hearts are said to be efficient in small sizes, making it easier to fit size constraints. Such hearts would still have the problem of requiring a power supply.

Rather than replacing the heart, methods of regenerating the existing heart are being developed. Techniques of injecting stem cells into the patient's heart have already produced positive results in some cases. Likewise, procedures that attach "sheets of muscle blasts" to the patient's heart have been successful in Japan. Clearly, it would be preferable if the patient's own heart can serve as a scaffold for cell replacement.

In several pathological processes, however, the underlying structure of the patient's heart has been rendered dysfunctional. Without extensive remodeling surgery, the heart's infrastructure has to be replaced.

In approaching heart replacement, patients, physicians, and families have to weigh the benefits and risks. With the rapid growth in viable choices for replacement, this process will necessarily become more detailed and informed.

Bioprinting organs, and other ways of regenerating or synthetically reproducing human organs, will be very expensive for a long time. That expense will push experimentation in different directions.

Originally published in Al Fin

Mainstream Media Coverage of SENS

Most readers of Al Fin blog want to live long, happy, prosperous lives. Otherwise, why read this blog? I consider Aubrey de Grey's SENS program for radical life extension to be the best ongoing approach to significant improvement in human lifespan. Now the mainstream periodical, The Economist, takes a look at de Grey's regimen:

Dr de Grey, who is an independent researcher working in Cambridge, England, is a man who provokes strong opinions. He is undoubtedly a visionary, but many biologists think that his visions are not so much insights as mischievous mirages, for he believes that anti-ageing technology could come about in a future that many now alive might live to see.

Vision or mirage, Dr de Grey has defined the problem precisely. Unlike most workers in the field, he has an engineering background, and is thus ideally placed to look into the biological repair shop. As he sees things, ageing has seven components; deal with all seven, and you stop the process in its tracks. He refers to this approach as strategies for engineered negligible senescence (SENS).

The seven sisters that Dr de Grey wishes to slaughter with SENS are cell loss, apoptosis-resistance (the tendency of cells to refuse to die when they are supposed to), gene mutations in the cell nucleus, gene mutations in the mitochondria (the cell's power-packs), the accumulation of junk inside cells, the accumulation of junk outside cells and the accumulation of inappropriate chemical links in the material that supports cells.

It is quite a shopping list. But it does, at least, break the problem into manageable parts. It also suggests that multiple approaches to the question may be needed. Broadly, these are of two sorts: to manage the process of wear and tear to slow it down and mask its consequences, or to accept its inevitability and bring the body in for servicing at regular intervals to replace the worn-out parts.

Economist

The writers at The Economist seem to understand that the key to getting anywhere in science is to "break a problem into manageable parts". Then define hypotheses which are falsifiable. Then test your hypotheses, one by one.

Because this is the approach that de Grey and his program are taking--and since no one else has attempted anything else nearly so ambitious or logical--it is to de Grey, SENS, the Methuselah Foundation etc. that most interested parties look for advances in this area. Of course, breakthroughs can occur at unexpected times and places. The radar scope must still sweep a broad circle. But reading de Grey's book, Ending Aging, and following the progress of SENS, is a good place to start.

Hat tip Brian Wang

Aubrey de Grey's Ending Aging

I recently had the opportunity to read Aubrey de Grey's briskly selling book, Ending Aging.

The book goes into more detail about the 7 approaches to anti-senescence discussed at the SENS website. Consider a progress report on a very important front of scientific research. Arnold Kling takes an economist's look at the book, and is intrigued:

Four years ago, I reported that de Grey foresees a not-too-distant future in which humans can reverse the effects of aging, raising the possibility of living healthy lives for hundreds of years. He has not backed away from that position, and this book, written by de Grey and his research associate Michael Rae, represents an update from his perspective. In brief, he says that

1. The latest scientific research indicates no flaws in the theory that aging can be eradicated.

2. However, getting the required techniques developed will require institutional changes relative to our current system for conducting medical research.

As an economist, I am most interested--and most qualified to form an opinion about--the second point.

...De Grey sees aging as a byproduct of an evolutionary process that takes place within the body. Mutations occur over time within your cells, sometimes randomly and sometimes stimulated by external events. This evolutionary process changes the balance between what I might call "good stuff" and "bad stuff" (here I am taking the technical caliber of the scientific exposition down several levels). Sometimes, the "good stuff" gets stronger, as when we develop an immunity to a disease. More often, however, the "good stuff" gets weaker and the "bad stuff" (like arterial plaque or pre-cancerous cells) gets stronger. It is this shift in the balance that leads to the symptoms of aging, including susceptibility to disease, which ultimately proves fatal.

Because aging is a natural outcome of the body's internal evolutionary processes, de Grey argues that the standard paradigm for fighting the diseases of aging one by one is flawed. Prevention of one disease, in the form of slowing the processes that cause it, is a doomed strategy.

...Too often, academics use their credentials to spit out biased polemics dressed up as science. Ending Aging is the opposite. It is a crash course in state-of-the-art science dressed up as a polemic. De Grey wears his passion for undertaking a war on aging on his sleeve, yet most of the book consists of scientific analysis that, although simplified to enable a layman to follow, is conscientious in reporting doubts and objections to the author's point of view.

...What de Grey is saying is that today's cautious approach to experimental medical testing significantly slows the rate of progress, which means that many people will suffer and die unnecessarily. However, those people are unseen and unknown, whereas those who suffer and die as a result of medical experiments are identifiable and visible. I think that trying to sell people on the idea of taking more risks in order to advance medical progress is not as straightforward as de Grey makes it sound

...My guess is that de Grey will have better luck if he tries to mobilize wealthy philanthropists. If instead of donating buildings to universities our billionaires would donate money for prizes that reward general-purpose medical technologies, we might not have to wait for government research to adopt a paradigm shift, which is almost surely not going to happen. Wealthy (and not-so-wealthy) philanthropists who are reading this should check out de Grey's organization SENS and look for ways to contribute both to his institute and to a prize fund.

TCS

Future research will make part of de Grey's program moot and unnecessary. Other future research will likely incorporate some of de Grey's ideas. The point is, de Grey's approach is the best one currently operating, so that if someone did have extra money he/she was thinking about donating to science, they could do much worse than to donate to SENS.

I recommend the book to anyone interested in the extension of healthy human lifespan. Getting much of the same information from the SENS website + literature searches is possible, but you wouldn't want to miss Aubrey's unique argumentative style.

SENS3 Conference etc.

SENS3, the third biannual SENS conference was held 6-10 Sept 2007 at Queens College, Cambridge. An excellent summary of the conference is available at Ouroborus. Apparently, progress has been made by several researchers on multiple fronts. To access talks from previous conferences, go to SENS1 here, or SENS2 here.

Aubrey de Grey's SENS is a seven-part approach to engineering increased longevity in humans. SENS research is being funded by the Methuselah Foundation, and other funding agencies and individuals.

Other important recent conferences of note were the Singularity Summit in San Francisco and the Nano-Bio technology Conference in Tucson. Both of those conferences were well covered by Michael Anissimov.

Hat tip Brian Wang

From Al Fin

Virus vs. Cancer: Reolysin Reovirus in Multiple Human Trials

Viruses are hardy pre-lifeforms, that have played a major role in the evolution of humans and other animals and plants. The articles featured in this posting deal with the reovirus labeled Reolysin, by Canadian company Oncolytics.

The novel anti-cancer therapy, REOLYSIN®, is a living virus, not a chemotherapy drug, that is toxic to cancer cells but not harmful to normal cells. This novel therapy, using a living virus, is the first of its kind available at CTRC.

...“This novel therapy has shown success because the reovirus replicates in and destroys the cancer cells within the patient’s body,” said Mita. “Cancer cells have several molecular and genetic abnormalities. In normal, healthy cells, the reovirus is unable to reproduce because of an enzyme named PKR. The enzyme is suppressed in cancer cells, and therefore the reovirus can replicate in the cancer cell and kill it.”

“REOLYSIN® typifies the true targeted therapy approach that seeks to use fundamental differences between cancer and normal cells as the basis for effective anti-cancer approaches and we are thus very excited about the this study,” said Francis Giles, MD, director of the CTRC Institute for Drug Development.

From article discussing human trials of Reolysin for metastatic sarcomas to the lung.

Another trial is ongoing in the UK:

The trial (REO 010) has two components. The first is an open-label, dose-escalating, non-randomized study of REOLYSIN(R) given intravenously with docetaxel every three weeks. A standard dosage of docetaxel will be delivered with escalating dosages of REOLYSIN(R) intravenously. A maximum of three cohorts will be enrolled in the REOLYSIN(R) dose escalation portion. The second component of the trial will immediately follow and will include the enrolment of a further 12 patients at the maximum dosage of REOLYSIN(R) in combination with a standard dosage of docetaxel.

Eligible patients include those who have been diagnosed with advanced or metastatic solid tumours such as bladder, prostate, lung or upper gastro-intestinal cancers that are refractory (have not responded) to standard therapy or for which no curative standard therapy exists. The primary objective of the trial is to determine the Maximum Tolerated Dose (MTD), Dose-Limiting Toxicity (DLT), recommended dose and dosing schedule and safety profile of REOLYSIN(R) when administered in combination with docetaxel. Secondary objectives include the evaluation of immune response to the drug combination, the body's response to the drug combination compared to chemotherapy alone and any evidence of anti-tumour activity. This is the third trial beginning in 2007 that is examining the role of REOLYSIN(R) in combination with standard chemotherapeutics.

Source

An animal model study using childhood sarcoma cell lines demonstrated significant activity of Reolysin against childhood sarcomas.

Particular viruses can be very useful for treating human disease, and eventually for augmenting normal human function and lifespan. That is because viruses have evolved to be excellent gene therapy vectors, and clever cell sneaks. Viruses can slip into cells and into cell nuclei, and have their way with the cell and its transcriptional apparatus--before the cell is even aware that anything has changed.

Viral therapies have the potential to be misused or misdirected, just like any other revolutionary approach to medicine and life extension. But it is important to understand that the tools that viruses bring to the table are significant, and are the result of billions of years of viral/cellular co-evolution.

More on Resveratrol

Scientists at Harvard and MIT have added to the "Resveratrol mystique." Their research adds weight to the Resveratrol::Sirt1 connection, and suggests that Resveratrol may be useful in preventing neurodegenerative diseases such as Alzheimer's.

The scientists have shown that a gene called SIRT1 and a plant compound found in red wine called resveratrol can protect against neuron degeneration in a mouse model of Alzheimer's disease and amyotrophic lateral sclerosis. The researchers demonstrated that activating SIRT1 and injecting resveratrol, which have both been previously associated with life-span extension in lower organisms, can also prevent cognitive problems in the mice.

The mice used in the study develop an approximation of human neurodegenerative disease over a period of weeks. As neurons in their brains die and lose connections, their spatial learning is impaired, and the mice develop difficulty associating cause and effect. Treatment with resveratrol reduced the death and degeneration of neurons in these mice and also restored their learning abilities to a level comparable to that of normal mice not suffering neurodegeneration. "Thus, resveratrol is not only neuroprotective, it also improves cognitive function after severe neurodegeneration," says Li-Huei Tsai, the professor of neuroscience at MIT who led the research with David Sinclair, a professor of pathology at Harvard. Tsai says this improvement in function suggests that resveratrol has potential for treating human neurodegenerative diseases.

....The study is the first to suggest that resveratrol could actually improve cognitive function in patients with neurodegenerative diseases. "Generally, SIRT1 has been observed to be neuroprotective," says Leonard Guarente, the professor of biology at MIT who uncovered the connection between life span and the yeast equivalent to SIRT1 about 10 years ago. What's new about Tsai and Sinclair's work, he says, is its demonstration that activating SIRT1 prevents cognitive decline in mice with neurodegenerative disease. The study shows that "resveratrol can protect against memory loss and learning decline," says Guarente, who was not involved with the research.

Guarente says the study suggests that compounds that can activate SIRT1 could be used to treat neurodegenerative disease in humans as long as they can pass through the blood-brain barrier. This membrane surrounding and protecting the brain from chemicals in the blood presents a major challenge to any researcher developing drugs that target the brain. Mice in the study received injections of resveratrol directly into blood vessels in their brains, which would not be practical in human patients.

Source

This type of regenerative gene control via phyto-nutrients is particularly encouraging, given the most famous source of the nutrient is red wine.

Resveratrol and other phyto-nutrients have significant potential to benefit an aging population in the developed world--far beyond whatever in vivo anti-oxidant activity they may possess. The particular mechanisms of their beneficial potential is yet to be worked out.

Care for a Brand New Thymus?

Japanese scientists have built an artificial "lymph node" from thymus tissue, and transplanted it into immunodeficient mice.

The researchers, from RIKEN's Research Center for Allergy and Immunology in Yokohama, constructed their mouse aLNs by impregnating a two- to three-millimeter-diameter scaffold of the fibrous structural protein collagen with connective tissue extracted from the thymus of newborn mice and dendritic cells. Earlier work suggests that it is the connective tissue stromal cells which organize the structure of lymph nodes.

The aLNs were initially implanted into mice with a normal, healthy immune system, which had previously been injected with a harmless antigen compound to trigger an immune response. So the aLNs became populated with immune system T-cells and B-cells which specifically recognize and counter germs or cancer cells expressing the injected antigen.

These primed aLNs were then transplanted into two sets of mice--a group with a normal immune system which had never been exposed to the antigen, and a group in which the immune system did not function. When then exposed to the antigen both groups responded immediately by making appropriate protective antibodies--and the response to the antigen lasted for longer than four weeks, which means immune cells which retained 'memory' of the antigen had been generated.

Further investigation of the immunodeficient mice showed that T- and B-cells from the aLNs migrated to their spleens and bone marrows and were there generating large numbers of antigen-specific antibody-forming cells. The results also revealed some of the compounds involved in directing this migration process.

Source
This research has implications for the study of treatments for immune diseases, cancer, aging, and infectious disease such as AIDS. Thymosin is one of the several hormone levels that falls abruptly in the aging human. Growing an artificial thymus to boost thymosin levels appears within reach, if proven to be beneficial.

Also, here is a free collection of articles on Nanotechnology in Cancer.

And, here is more on an improved method for cervical cancer screening.

Better screening and better treatments. The two need to go hand in hand. Add better prevention to the mix and you are getting somewhere.