Novel Alzheimer's Drugs Coming

• As many as 5.2 million people in the United States are living with Alzheimer’s.

• 10 million baby boomers will develop Alzheimer's in their lifetime.

• Every 71 seconds, someone develops Alzheimer’s.

• Alzheimer's is the sixth-leading cause of death.

• The direct and indirect costs of Alzheimer's and other dementias to Medicare, Medicaid and businesses amount to more than $148 billion each year. _Alz

The older you get, the more likely that you will suffer some form of cognitive impairment -- most likely Alzheimer's. With the aging of North America and the developed world, the need for better ways to diagnose and treat Alzheimer's is critical.

New cognitive tests are being developed to determine whether a person with early cognitive impairment can drive safely. Special MRI techniques can show the early tell-tale signs of Alzheimer brain atrophy.

On the treatment side, "brain games" that develop short term memory appear helpful in reversing early cognitive impairment.

Another hopeful bit of news is that Rember and Dimebon -- two novel drug treatments for Alzheimer's -- are working their way through human drug trials, and show some promise.

A bit further in the future is the promise of Ampakines. Cortex Pharmaceuticals is the foremost developers of Ampakines for a wide range of disorders -- including Alzheimer's in the long run.

Further into the future, an even wider array of drugs are being developed to target several pathological mechanisms that are believed to contribute to Alzheimer's.

The main question at this time appears to involve financing for drug discovery and testing in the midst of an international financial crisis. US governmental policies under the new administration suggest that US pharmaceutical research and research into other vital innovative technologies will be short-changed. New drug development may well move offshore from the US to East and South Asia, where capital is less likely to be diverted to non-productive ends.

It is ironic that just when a relaxation of stem cell research regulations occurs, that draconian economic re-structuring should threaten the future of technological development in the biosciences and most other high tech fields.

Genetically Modified Regenerative Skin Graft Material Designed to Resist Infection

Stratatech’s StrataGraft® tissue is a second-generation human skin substitute that exhibits normal human skin structure and function. It is manufactured using the company’s proprietary NIKS® human keratinocytes, which were discovered at the University of Wisconsin. Keratinocytes are the cells that make up approximately 90 percent of the epidermis, the outer layer of human skin. NIKS® cells are a consistent source of pathogen-free, non-tumor-producing, long-lived adult progenitor cells. These cells faithfully reproduce normal human skin tissue architecture and barrier function when cultured appropriately. _StratatechCorp.

Regenerative medicine company Stratatech Corporation has developed a genetically tweaked living skin substitute for use in skin grafting. The genetic modifications of the living skin replacement makes it far more resistant to infection than currently available skin graft materials -- including autologous skin grafts.

The anti-infective capacity of Stratatech’s genetically-engineered tissue, which is being developed and commercialized by the company as ExpressGraft™ Enhance skin substitute through a worldwide exclusive license from the Wisconsin Alumni Research Foundation, or WARF, is produced by genetically engineering the elevated expression of a naturally-occurring antimicrobial host defense peptide called hCAP-18/LL-37. hCAP-18/LL-37 was selected because of its broad antimicrobial activity against both Gram-positive and Gram-negative bacteria, including methicillin-resistant S. aureus (MRSA), vancomycin-resistant E. faecalis (VRE) and other antibiotic-resistant hospital-acquired infections, as well as some fungi and viruses. The enhanced tissue possesses a full-thickness structure and barrier function similar to that of native human skin. The cell type used to generate the ExpressGraft™ tissue has been demonstrated to be non-tumor-producing and free from detectable pathogens, characteristics critical for cell-based, regenerative medicine therapies for patient use.

“Bacterial infection is a substantial cause of skin graft rejection and additional health care costs,” said Lynn Allen-Hoffmann, Ph.D., Stratatech’s founder, chief scientific officer and chief executive. “The potent anti-infective capability Stratatech has engineered in our living human skin substitute can be an important tool in improving skin-injury patient outcomes, and reducing the incidence and expense of hospital-acquired infections. We look forward to beginning the clinical evaluation of our antimicrobial skin substitute in the near term.

...Stratatech’s genetically-engineered skin substitute was generated using a non-viral vector, or carrier. The company believes it is the first time a virus-free approach has been used to genetically modify a living, cell-based tissue substitute. The data published in Molecular Therapy demonstrate that the modified tissue contained 139-fold more anti-infective proteins called host defense peptides than unmodified tissue in vitro. _BusinessWire

This is only the beginning of genetically improved, artificially grown bio-replacement materials. This skin replacement product from Stratatech should do well in the marketplace if it lives up to its promotion. But expect competing products that improve on the ExpressGraft's performance to emerge before long. This graft material does not perfectly reproduce the full, intricate layered structure of natural skin. But it is a good start.

Other more intricately structured grown replacement parts should follow on rather quickly. We are entering the age of regenerative medicine, when body parts and tissues will be grown in labs, rather than being donated by accident and crime victims. If these replacements can be designed to be tougher than the original parts being replaced, all the better.

Not Over the Hill Yet, Baby!

From the journal Stem Cells: UCLA researchers have managed to program human induced pluripotent stem cells into the precursors of human reproductive cells -- eggs and sperm. As quoted in Biosingularity:

Theoretically, an infertile patient’s skin cells, for example, could be taken and reprogrammed into iPS cells, which, like embryonic stem cells, have the ability to become every cell type in the human body. Those cells could then be transformed into germ line precursor cells that would eventually become eggs and sperm. Clark cautioned, however, that scientists are still many years from using these cells in patients to treat infertility. There is still much to be learned about the process of making high quality germ cells in the lab.

In another important finding, Clark’s team discovered that the germ line cells generated from human iPS cells were not the same as the germ line cells derived from human embryonic stem cells. Certain vital regulatory processes were not performed correctly in the human iPS derived germ cells, said Clark, an assistant professor of molecular, cell and developmental biology.

So it’s crucial, Clark contends, that work continue on the more controversial human embryonic stem cells that come from donated, excess material from in vitro fertilization that would otherwise be destroyed.

When germ cells are formed, they need to undergo a specific series of biological processes, an essential one being the regulation of imprinted genes. This is required for the germ cells to function correctly. If these processes are not performed the resulting eggs or sperm, are at high risk for not working as they should. This has significant consequences, given that the desired outcome is a healthy child. _Biosingularity

In other words, women past menopause or who have had their ovaries removed and men without testicles or with very low sperm counts will soon be able to produce viable sperm and eggs with the best of the twenty-somethings! Yes, I know that most people of a certain age do not want to have more children. But modern women often pursue their careers through the ages of optimal reproduction, and find that it's too late to have children by the time they feel they are ready. There are many other situations where persons might want to have their own children but can no longer produce the germ cells to do the job.

Eventually we will have artificial wombs that will take early embryos and support healthy gestation all the way to birth. By then, most of us will probably be living in good condition to 150 or beyond. Some may live long enough to raise three generations of offspring to adulthood. Why not, if you enjoy it and you can do it well?

Because by then, the question will not be "where will we put all these people?" The question will be, " where will we ever get enough people to do all the things that need to be done in this big universe?"

New Drug Class Promises a Medical Revolution

Image Source

Research into the effects of melanocortins has a huge potential to revolutionise medicine. Here are a few of the effects of melanocortin peptides on the brain:

Increase of motivation
Increase of attention
Improvement of short-term memory
Increase of visual retention
Lowering of auditory, gustatory and olfactory detection thresholds
Functional antagonism of opiate effects
Inhibition of feeding (satiety-inducing effect)
Antiinflammatory effect (sites of action: brain and immunocytes)
Antipyretic effect
Reversal of hypovolemic hypotension
Reversal of shock
Resuscitation after prolonged asphyxia
Improvement of recovery after traumatic brain lesions and spinal cord injuries
Delay of the aging-linked behavioural deficits
Beneficial influences in neurodegenerative disorders
Increase of regenerative capacity of peripheral nerves in postlesion repair
Improvement of diabetic and toxic neuropathies
Induction of spontaneous penile erections
Increase of [sexual] proceptivity and receptivity (in females)

_Pharmacological Research

Like I say, those are a few of the effects that have been discovered so far for the melanocortins (melanocyte stimulating hormones [MSH], ACTH). New drugs which can either block or stimulate these hormone receptors will likely revolutionise treatment for:

1. Alzheimer's and other neurodegenerative disease
2. Stroke
   
3. Diabetic Neuropathy
4. Hemorrhagic Shock
5. Sexual Dysfunction for males and females
   
6. Obesity
7. Anorexia and Cachexia
8. Depression
9. Anxiety
10. Various learning disorders

...and quite a few things more. It is only in the past decades that scientists have been able to distinguish different receptor types for the many peptides and neurotransmitters affecting the brain and nerves. Now, it looks like nothing can stop the steamroller of biomedical and biotech research -- except perhaps bad government that wastes precious resources on policies that have failed for many generations.

If you have an interest in any of the listed diseases or hormonal effects above, visit the linked article and skip down to the section that interests you particularly. It is a long review article that covers a wide range of effects and potential therapies. I strongly recommend learning to read scientific articles -- despite their dryness -- because any person who can draw meaning from the early stages of research can often see into the future, and profit from that vision. If you wait until "science journalists" spell it out and dumb it down for you, it may be too late.

When the baby revolutions of nanotechnology, biotechnology, information sciences, and cognitive sciences begin to grow up and converge, you will begin to understand how quickly things can change.

From al fin

Constructing New Infrastructure for Regeneration

Tissue scaffolds are the next big thing for implants of the future. Like the scaffolding we see on construction sites, the nano scaffolds are being created by Ko to reconstruct damaged tissue within the human body. Burn victims would benefit from scaffolds used to regenerate new skin. Those with failing heart valves or damaged nerves could count on scaffolds to regenerate these parts from within the patient’s own body. As healing progresses, the scaffold, being constructed from a biodegradable material, is absorbed and metabolized by the body while slowly releasing drugs to aid in the healing process. _CyborgAge

Almost every part of the body presents opportunities for scaffold bio-engineers to experiment. From the heart to the spine to the skin, all parts of the body eventually wear out and need to be replaced or regenerated. Scientists at UC Berkeley are taking an entirely new approach to bio-scaffold development. They are using viruses (bacteriophages) to build a proteinaceous infrastructure that promotes regeneration of nerve tissue.

Some biological engineers are using scaffolds made of polymers to try to mimic the supportive matrix of real tissue. Seung-Wuk Lee, a bioengineer at the University of California, Berkeley, has turned to viruses instead. "Viruses are smart materials," he says. "Once you construct the genome, you can make billions of phages, and they're self-replicating materials." The phage that Lee is working with, called M13, is long and thin like the protein fibers that make up the cellular matrices inside the body.

First, Lee and his colleague Anna Merzlyak genetically engineered M13 to display nerve-friendly proteins on their outer coats. These proteins are known to help nerve cells proliferate, adhere, and extend into long fiberlike shapes. Next, the researchers grew large numbers of the viruses in bacterial-cell hosts and dropped them into a solution containing neural-progenitor cells. These cells are more fully developed than stem cells but are still young and need coaxing to form new tissues. In the solution, the viruses align themselves like a liquid crystal, says Lee. He and Merzlyak used pipettes to inject the solution into agar, a Jell-O-like cell-culture medium, creating long, nerve-like fibers of the virus interspersed with cells. The progenitor cells then multiplied and grew the long branches characteristic of neurons. Lee says that the phage are well suited to making long, fiberlike structures such as nerve tissue but can also be made into more complex structures by varying their concentration or manipulating their position with a magnetic field. _TechnologyReview

Lee is planning to move to research inside live animals next. He is interested to discover how the immune systems of animals will react to viral construction workers hammering, drilling, and welding new infrastructure deep inside the organism.

For regenerative medicine to take that next big step forward, it will need the ability to grow specific infrastructure for every tissue and organ type that will be replaced or regenerated. Then, scientists will need to integrate growth factors and stem cells into the new matrix, and provide optimal nutrient solution. The prognosis for significant progress in this area is extremely favourable.

Nerve Regeneration Gene Pathway Discovered

Image Source

Research at the University of Utah has pinpointed specific genes in worms that appear to trigger nerve re-generation, and make old worms behave like younger friskier worms when the genes are over-expressed.

"One of the coolest things is we can improve regeneration," Nix says. "We originally looked at loss of this gene, dlk-1. The loss blocks regeneration. We can cut the nerve in these mutants and they don't regenerate. So we see worms with nerve stumps that don't do anything. But when we overproduce dlk-1 make an excess amount of it then we see an improvement in regeneration."

Jorgensen an investigator with the Howard Hughes Medical Institute says that "normally, young worms regenerate really well; old worms don't regenerate at all. What we can do by overexpressing dlk-1 is make old worms regenerate like young worms."

The chain of events the researchers identified as playing an essential role in nerve regeneration is known as a "MAP kinase pathway." Various MAP kinases play roles in cell division, response to stress, and cell specialization, Jorgensen says.

The pathway discovered in the new study "is unique in that it is not used by the nervous system during normal embryo development, yet it is absolutely required for regeneration," Bastiani says. "Most of us believed that virtually everything we found in regeneration also would be involved in development. So it is surprising."

He says while the dlk-1 gene is the most obvious target for new drugs to stimulate nerve regeneration, other genes in the pathway also could be potential targets. _GEN

Humans possess the same sets of genes that were studied in worms. It remains to be proven whether the genes have the same effect in humans for nerve regeneration, as in worms.

We are finding that older cells become leaky and let more damaging substances into their nuclear compartments, where DNA becomes damaged. Better means of preventing nerve damage and reversing that damage are beginning to come within the grasp of science.

Optical Coherence Tomography Provides an Active Window on the Brain

Optical Coherence Tomography (OCT) is a powerful new tool for monitoring both degenerative and malignant activities occurring deep within the brain -- by looking into the eyes. The OCT scanner uses two light beams (diodes or pulse lasers) to generate a 3d image of the depth of the retinas. This information tells medical specialists many different things about what is happening inside the skull.

One beam of light is fired at the tissue and another at a reference mirror. When the reflected beams have travelled an identical distance, interference will make their combined beam brighter than if the distances are different. So by reflecting one beam off of different layers of tissue, and moving the reference mirror until the combined reflected beam is brightest, the technique can measure the depths of each section of tissue and build up a detailed image of its structure. It has proved particularly useful in ophthalmology because the semi-transparent nature of retinal tissue makes it possible for OCT to penetrate to greater depths - up to several millimetres. When applied to the OND it can give information about both the shape and thickness of retinal nerve fibres, allowing even subtle changes to be tracked.

Such changes can be used to monitor the progression of diseases non-invasively and relatively cheaply. Unlike MRI, which is expensive and can require patients to remain still for an hour or more, OCT is increasingly available in clinics and can be carried out in a few minutes. "It's extremely inexpensive compared to other tests," says Valenti.

One possibility is to use OCT to monitor the effectiveness of treatments for neurodegenerative diseases, says Danesh-Meyer: "These drugs can have a lot of side effects, so if they are not having a benefit then you won't want to continue with them." _NS

The progress of brain tumours, multiple sclerosis, Alzheimer's, Parkinson's, and other brain diseases can be tracked over time using this non-invasive technique.

As the technology improves and allows for faster, less uncomfortable scans, it is likely that a routine baseline scan will be done on all adolescents as part of their permanent medical records. Should any new symptoms warrant it, later OCT scans can be compared with the baseline study to look for signs of brain pathology.

Longer lives mean more chances for new pathology. Pathology in the brain has been historically very hard and expensive to track over time. Newer technologies such as the OCT should allow medical scientists and practitioners to determine which persons need treatment, and which treatments provide the best result. The time saved by such new procedures should translate into a more functional lifespan.

SIRT 6 May Have Important Aging Role

SIRT1 has been the most studied of the SIRT family of proteins, but mice studies suggest that SIRT6 may also plan an important role in aging:

A formerly underappreciated member of the sirtuin family of proteins may hold the key to youthfulness and is the first sirtuin shown to specifically govern the activity of genes, scientists report.

Researchers from Stanford University report in the Jan. 9 Cell that SIRT6, a sibling of the aging-related protein SIRT1, is an important regulator of gene activity in mice.

“This is a big, big discovery,” says Raul Mostoslavsky, a chromatin biologist at the Massachusetts General Hospital Cancer Center and Harvard University Medical School in Boston. And one, he adds, that could shift some of the limelight away from SIRT1, a molecule implicated in the aging process.

“I’d say 95 percent of the literature is on SIRT1. I think that is going to change,” Mostoslavsky says. “People will start realizing that other sirtuins are probably important for regulating many biological functions.”

Mostoslavsky was not involved with the current study, led by Katrin Chua and Howard Chang of Stanford University, but he is familiar with all seven of the sirtuins found in mammals. He was the first to genetically engineer mice to lack each individual member of the sirtuin family. Mice missing SIRT6 develop normally for the first weeks of life, but then rapidly decline as if they are prematurely aging. The mice die by one month of age, ultimately of low blood sugar.

Last year, Chua’s group showed that SIRT6 is an enzyme that specifically removes a chemical called an acetyl group from a specific spot on a histone protein. Histones wrap DNA into a package that can fit inside the cell and are also important for controlling which genes turn on and off. Removing acetyl groups from histones generally shuts genes off.

Chua’s group has also previously shown that SIRT6 helps keep genomes stable and protects the ends of chromosomes, known as telomeres, from damage.

Now Chua’s and Chang’s groups together show that SIRT6 works with a master regulatory complex called NFkappa-B to govern activity of genes associated with aging, inflammation, immunity and metabolism. When SIRT6 is missing, NFkappa-B becomes hyperactive and turns up activity of aging-linked genes.

Reducing the amount of NFkappa-B in SIRT6-deficient mice restores normal life span and corrects many of the premature aging symptoms. But the mice still have low blood sugar, and many other genes not regulated by NFkappa-B show abnormal activity when SIRT6 is absent. _ScienceNews

Whether these findings are applicable to normal aging in mice or humans remains to be proven. Nevertheless, continued explication of the mechanisms of gene expression across the normal lifespan of mammals will eventually provide avenues to modifying the aging process.

Brain - Cooling Techniques

Scientists and physicians are developing new brain - cooling techniques to reduce morbidity after heart attacks (and presumably strokes) and to aid successful resuscitation after heart attacks. One device, like a reverse hair drying hood, cools the scalp and its blood vessels, achieving about 1 degree C cooling of the brain per hour. Another device sprays a refrigerant deep into the nose to indirectly cool arteries passing nearby, heading for the brain. The nasal device cools the brain by 2.4 degrees C per hour. A third device uses an icy slurry lavage into lung airways, to cool blood passing into the carotid arteries to the brain.

For some time, doctors have observed that cooling patients following a heart attack can reduce brain damage. Although they are not yet sure of the mechanism behind this effect, researchers suspect that cooling the brain by 4 °C, to around 33 °C, reduces the metabolism of brain cells, reducing their hunger for oxygen for the crucial moments during which blood is in short supply. Damage seems to be reduced even if the brain is only cooled once the heart has been restarted, suggesting that cooling may also slow the release of toxic chemicals from neurons and glial cells - a process called the ischaemic cascade, which triggers further brain-cell death up to 24 hours after a cardiac arrest or stroke.

Previously, doctors have induced "therapeutic hypothermia" by applying ice packs or cooling blankets to the whole body, or injecting cold saline solution into the veins. However, cooling the whole body can increase the risk of infection and pneumonia, so researchers are now building targeted devices that chill the brain directly.

...The ice slurry can cool the brain by 4 °C - the safe limit before damage is risked - in less than 15 minutes, says Kasza, who has so far tested the technique on pigs. His team is investigating whether their icy slurry could also be applied to the kidneys (see picture) and the heart during invasive surgery, to prevent damage to the organs when blood flow is suspended for the operation.

One of the main advantages of all the new techniques is that they are simple enough to apply before or immediately after resuscitation following a heart attack - minimising the delay between the heart malfunction and cooling the brain. "A paramedic could deliver the slurry," says Kasza.

What's more, a recent study in pigs suggests that immediate cooling with the RhinoChill device, besides reducing brain damage, could also improve the chances of success of the resuscitation itself, although it is not yet certain why this is. Sixteen pigs were given a heart attack, and then left for 15 minutes before CPR was applied to start their hearts again. Of the eight pigs cooled using the RhinoChill system during CPR, six survived, compared with just two of the eight who were left unchilled (Resuscitation, DOI: 10.1016/j.resuscitation.2008.03.087).

Rapid application of such techniques could be particularly good news for stroke victims. "Clot-busting drugs can only be administered after diagnosis and brain scans in the hospital," says Andrews. "But applying therapeutic cooling at the scene of the stroke could lengthen the time window in which the drugs are effective - before too much damage has occurred," he says. _NewScientist

These techniques are a far cry from the advanced cryonics and vitrification methods needed for long - term organismic storage or hibernation. But experiments with them, and experience using them should add to the knowledge needed to develop the longer - term methods.

Universal Aging Mechanism?

As an organism changes, its pattern of gene activation/deactivation and repair changes from a vibrant youthful pattern to a less efficient and effective senescent pattern. Harvard scientists are learning more about some of the underlying mechanisms behind this "genetic control shift of aging."

The researchers found in studies of mammalian stem cells that the protein SIRT1 controls the packaging of DNA into chromatin, thereby setting the youthful pattern of gene activity by keeping select genes switched off. In response to DNA damage, those SIRT1 proteins leave their posts to go off and assist in the necessary repairs. That change in SIRT1's job description leads to shifts in gene activity that parallel those seen in the aging mouse brain, they show. They suspect similar changes would also be found in other body tissues as well.

" The critical protein controls both which genes are off and on as well as DNA repair; it's used for both processes, and that's the catch," said David Sinclair of Harvard Medical School. "As cells accumulate DNA damage, the protein can't do both jobs sufficiently." Once SIRT1 loses control, gene activity goes haywire, a state of affairs that leads to symptoms associated with aging.

Sinclair's team also found what they consider to be good evidence that the aging process can be slowed. Mice with an excess of SIRT1 had an improved ability to repair DNA and prevent those unwanted changes in gene expression. The hope is that those improvements could be reproduced with a drug that stimulates SIRT1, they said. _Eurekalert

Permanent gene therapy to boost SIRT1 for both gene repair and maintaining a youthful gene activity pattern seems preferable to a daily pill or injection. In fact, genetic therapy will likely replace most pharmaceuticals as we learn more about the underlying physiology and pathology of our organisms. SIRT1 will be but a small part of the overall story of aging. But for now, it appears to be an important early step in our understanding.

MK-677, Oral Ghrelin Mimetic, Stimulates Youthful Pulsatile HGH Secretion in Elderly

Via NextBigFuture, this Annals of Internal Medicine article looks at the effect of an oral ghrelin mimetic on secretion of HGH, and various physical measurements such as muscle mass, visceral fat, etc.

Conclusion: Over 12 months, the ghrelin mimetic MK-677 enhanced pulsatile growth hormone secretion, significantly increased fat-free mass, and was generally well tolerated. Long-term functional and, ultimately, pharmacoeconomic, studies in elderly persons are indicated.

Previous trials in which growth hormone was administered to elderly persons were small, poorly controlled, or too short (8); in addition, growth hormone replacement does not restore pulsatile growth hormone secretion. MK-677, the first orally active ghrelin mimetic (a growth hormone secretagogue and growth hormone secretagogue–receptor agonist), increases pulsatile growth hormone secretion in older adults to levels observed in young adults (9, 10). Our primary objectives were to determine whether 25 mg of oral MK-677 daily would increase growth hormone and insulin-like growth factor I (IGF-I) levels in healthy older adults, prevent the decline in fat-free mass, and decrease abdominal visceral fat, with acceptable tolerability.

...Frailty is one of the scourges of elderly persons, and as researchers are beginning to learn about its causes, they are asking whether growth hormone deficiency is one of them. A systematic review (8) concluded that the risks of exogenous growth hormone outweigh the benefits and that it is not the long-sought solution to frailty. The promise of MK-677 is that it seems to restore endogenous growth hormone levels in a physiologic secretory pattern, unlike the single high-amplitude pulse observed after exogenous growth hormone administration. We believe that our study sets the stage for an adequately powered clinical trial of sufficient duration in a population vulnerable to frailty. _AnnalsIntMed

The effects of the more physiologic pattern of HGH secretion seen in MK-677 recipients vs. standard HGH replacement protocols, suggests that more indirect route of using an oral ghrelin mimetic may provide better long-term results.

The most significant adverse effect was an increase in appetite, which in many elderly might be seen as more of a positive miracle than an adverse effect. I encourage anyone interested to go to the article itself and read it in full. The complexity of homeostasis in the human organism should discourage simplistic and cavalier interventions for purposes of senescence mitigation. The study quoted above is a good example of a thoughtful and fairly comprehensive look at a measured intervention. The findings should be confirmed and integrated into the leading theories of senescence mitigation and reversal.

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.

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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.