Google Tech Talk May 29 '07: Aubrey de Grey

Here is de Grey at Google, speaking for an hour about the technology of healthy extension of lifespan.

Hat tip Michael Anissimov and Brian Wang.

Ampakines Back in the News

Brain boosting drugs in the new Ampakine class are back in the news--this time in connection with the problem of respiratory depression from sedative/hypnotic drugs.

Researchers at the University of Alberta (Edmonton, AB) and Cortex Pharmaceuticals (Irvine, CA) believe that AMPAKINE drugs may provide protection from drug-induced respiratory depression, while simultaneously allowing the sedative or analgesic to continue working as it was intended.

The drug tested in this study belongs to a novel class of molecules known as AMPAKINE compounds being developed by Cortex Pharmaceuticals, Inc. located in Irvine, California. AMPAKINE compounds act on the most common excitatory receptor in the brain, the AMPA "Glutamate type receptor," which has been shown in rodent models to boost the brain's own protein for improving age-related deficits in memory mechanisms. In primate models AMPAKINE compounds have replicated the studies in rodents and in adults patients suffering from Attention Deficit Hyperactivity Disorder, significant clinical and statistical improvement in increase attention and decrease hyperactivity have been observed. The U. Alberta research provide evidence that another important AMPAKINE indication is to stimulate primitive areas of the brain called the pre-Botzinger Complex responsible for breathing, without causing side effects. The pre-Botzinger Complex generated respiratory-related oscillations similar to those generated by the whole brainstem in vitro, and neurons with voltage-dependent pacemaker-like properties that have been identified in this brain region.

In a study published in 2006, Dr. John J. Greer of U. Alberta demonstrated that certain AMPAKINE compounds enhance the respiratory drive and breathing rhythm at the brain-stem level containing the pre-Botzinger Complex in laboratory rats whose respiration rates were purposely suppressed by administration of central nervous system depressants.

Dr. Greer found that respiratory depression induced by these agents can be reversed or prevented in test animals with an experimental AMPAKINE drug, without a reduction of pain relief or sedation.

Greer and coworkers treated rats with the opioids analgesic fentanyl or the barbiturate sedative Phenobarbital, both commonly prescribed in the United States. Greer used a technique known as plethysmography, which measures blood flow throughout the body, to determine the level of respiratory distressed caused by the drugs. When drugged rats were treated with the AMPAKINE , the respiratory distress quickly resolved. The drug worked in both newborn and adult rats. Interestingly, the drug on its own did not affect blood flow in animals not treated with the sedative drugs, nor did administration of the drug cause noticeable arousal in the animals.

Greer concluded, in a study published in the September 20, 2006 issue of the American Journal of Respiratory Critical Care Medicine, that CX546, "effectively reverses opioid- and barbiturate-induced respiratory depression without reversing the analgesic response."

"These results open up the real possibility of combining an ampakine compound with commonly prescribed barbiturates or opiates to reduce the likelihood that life-threatening respiratory depression will occur," noted explained Roger G. Stoll, Ph.D., Chairman, President, and CEO of Cortex.

Source

Ampakines hold out a promise for effective palliative treatments for Alzheimer's and other neurodegenerative disease. Currently, the Cortex drug CX717 is being held up by the FDA over toxicity concerns. Consequently the stock price of Cortex is currently quite low--trading below US $3 a share for over a year.

It is easy to see that should Cortex navigate through the labyrinthine bureaucracy of the FDA and reach approval for any of its Ampakines in development, that the stock price could rise rapidly.

Frankly, it is the potential for cognitive enhancement in normal people that fascinates me the most about the Ampakines. But the potential to make a substantial profit on a fairly small investment is also attractive. But do your own research before investing.

The Current Reality of Aging

This New Yorker article describes the current state of the aging process in North America. The reality is particularly stark for those without close family and friends, and with few assets.

By the age of sixty, Americans have lost, on average, a third of their teeth. After eighty-five, almost forty per cent have no teeth at all.

Even as our bones and teeth soften, the rest of our body hardens. Blood vessels, joints, the muscle and valves of the heart, and even the lungs pick up substantial deposits of calcium and turn stiff. Under a microscope, the vessels and soft tissues display the same form of calcium that you find in bone. When you reach inside an elderly patient during surgery, the aorta and other major vessels often feel crunchy under your fingers. A recent study has found that loss of bone density may be an even better predictor of death from atherosclerotic disease than cholesterol levels. As we age, it’s as if the calcium flows out of our skeletons and into our tissues.

To maintain the same volume of blood flow through narrowed and stiffened blood vessels, the heart has to generate increased pressure. As a result, more than half of us develop hypertension by the age of sixty-five. The heart becomes thicker-walled from having to pump against the pressure, and less able to respond to the demands of exertion. The peak output of the heart decreases steadily from the age of thirty. People become gradually less able to run as far or as fast as they used to, or to climb a flight of stairs without becoming short of breath.

Why we age is the subject of vigorous debate. The classical view is that aging happens because of random wear and tear. A newer view holds that aging is more orderly and genetically driven. Proponents of this view point out that animals of similar species and exposure to wear and tear have markedly different life spans. The Canada goose has a longevity of 23.5 years; the emperor goose only 6.3 years. Perhaps animals are like plants, with lives that are, to a large extent, internally governed. Certain species of bamboo, for instance, form a dense stand that grows and flourishes for a hundred years, flowers all at once, and then dies.

The idea that living things shut down and not just wear down has received substantial support in the past decade. Researchers working with the now famous worm C. elegans (two of the last five Nobel Prizes in medicine went to scientists doing work on the little nematode) were able to produce worms that live more than twice as long and age more slowly by altering a single gene. Scientists have since come up with single-gene alterations that increase the life spans of Drosophila fruit flies, mice, and yeast.

The full article is well worth reading, if for no other reason, to understand what gerontologists are trying to fight, and to motivate you to support anti-aging research.

Everyone wants to live forever, but no one wants to grow old. It is a conundrum which only very clear and creative thinking can solve.

Edmonton Aging Symposium--Aubrey de Grey Moderates

Here is the first video from the Edmonton Aging Symposium, provided by The Methuselah Foundation.

Biological Flavonoids--Don't Throw them Away Just Yet

A recent study from the Linus Pauling Institute at OSU Corvallis concludes that bioflavonoids have little if any use as antioxidants.

The study, published in Free Radical Biology and Medicine, found flavonoids are highly metabolized, which alters their chemical structure and diminishes their ability to function as an antioxidant. Although the compounds appear to have three to five times more antioxidant capacity than vitamins C or E, the body sees them as foreign compounds and modifies them for rapid excretion in the urine and bile

Source

The authors further stated that biological flavonoids may induce the body to excrete more carcinogens, and possibly reduce the risks of cancer and heart disease through other mechanisms than antioxidant activity.

Another study, from Denmark, purports to show that consumption of anti-oxidant supplements such as Vitamin C, Vitamin A, Vitamin E, and Beta Carotene--among others--are of no use in prolonging life and may actually increase morbidity and mortality.

Both of these studies have been used in an attempt to prove that the consumption of vitamins and phytonutrients are of limited if any benefit in the quest to prolong life and reduce risk of illness.

Unfortunately, the Danish study appears to confuse association with causation--a common error among researchers poorly trained in epistemology--and the Linus Pauling Institute study failed to follow the physiology of ingested flavonoids far enough.

It is abundantly clear that many researchers, in their eagerness to publish, fail to think their subject through clearly enough to present a coherent and valid conclusion to either the public, or to fellow scientists. This is more the fault of the competitive environment of modern science than a sign of intellectual or character deficits in the researchers. It is a publish or perish world for academics and researchers.

Quercetin, Resveratrol, Curcumin, Green Tea, Ginger, proanthocyanidins, and other plant-derived nutrients have demonstrated significant potential for reduction of morbidity of many types.

Many flavonoids have demonstrated clear anti-inflammatory effect in various biological models and syndromes. A serious researcher would look further for the source of the physiologic effects of flavonoids, rather than issuing a blanket statement of "no effect" with respect to the narrow issue of particular ways of measuring anti-oxidant activity in vivo. Much more was left undone and unsaid that is of far more importance, than what was demonstrated.

Particularly disappointing is the response of "science blogs" reporting on these and similar studies. Unfortunately, a false image of the underlying facts has been projected to the lay public, which may have unfortunate long term results for some.

Regenerative Medicine--A New Approach to Embryonic Stem Cell Replacement Tissue

Imagine if you will, being able to grow embryonic stem cells to regenerate your failing cells, tissues, and organs--just from your own sperm or eggs. No need to create a fertilised zygote or mated embryo, so there should be no ethical objections from anti-abortion politicians and their constituents.

In the February 15th issue of G&D, Dr. K. John McLaughlin and colleagues report on their success in using uniparental embryonic stem cells to replace blood stem cells in mice. Uniparental embryonic stem cells are an appealing alternative source of patient-derived embryonic stem cells, as they have several advantages over embryonic stem cell lines generated by somatic cell nuclear transfer (also known as therapeutic cloning).

....This study shows for the first time that parthenogenetic blood cells can replace those of an immunocompromised adult mouse. McLaughlin and colleagues also show that this is also possible using embryonic stem cells where both genomes are solely derived from sperm of one male (androgenetic), adding fertile males to the potential patient pool.

....The researchers took a two-step approach: First they injected uniparental ES cells into wild-type blastocyts to generate chimeric animals; then they harvested these chimeric fetal livers for transplant into lethally irradiated hosts. The scientists found that uniparental ES cells, regardless of parent-of-origin, were able to functionally reconstitute the entire hematopoietic system of adult mice. Furthermore, the scientists were also able to grow progenitor blood cells in culture from uniparental ES cells, and upon transplant into irradiated adult mice, show that these cells contribute, long-term, to the function of their hematopoietic system.

Source.

In other words, using either only eggs for a female or only sperm from a male, researchers were able to grow embryonic stem cells as replacement blood cell progenitors. These replacement cells functioned and kept the mice alive.

There are still issues of "imprinting" to be worked out when attempting to regenerate different body tissues from asexually produced ESC's. But at least the cells from this approach would be immunologically compatible with the donor. Immunological compatibility is something that sexually produced ESC's cannot guarantee, for purposes of organ regeneration.

Either way, it will be several years before humans can take advantage of this new opening in regenerative medicine.Some feminists had hoped that only females would be able to produce viable ESCs by the asexual method. They had hoped to use that leverage to force males in the US Congress to vote for unlimited funding for nuclear transfer and cloning technologies to produce new stem cell lines.

My question is--why not do both? I am constantly disgusted by the leftists who try to minimize the importance of non-embryonal approaches to creating stem cells, just as I am disgusted by the religious rightists who try to make every technology that deals with haploid cells into an abortion issue.

Unfortunately both groups of closed minded individuals have their own areas of power--where they work to limit our choices. Too bad.

Mitochondrial Paradigm for ... Aging and Cancer

In looking at aging, it is not enough to look at the nuclear genome. One must also look at the mitochondrial genome, and how the mitochondria interact with the nuclear genome.

Dr. Wallace looks at the ancient history of mitochondria as a free-living organism, and the subsequent symbiosis of mitochondria living inside eucharyotic cells. Then he looks at the mitochondrial genome and how it might affect a person's prospects for a long healthy life. 58 minutes.

Kombucha and Probiotics--Symbiotic Foods

Scientists have recently theorized that the necessary chemical and hormonal treatments for extending human lifespan, could be produced by "artificial cells" created to be implantable chemical/pharmaceutical factories. By programming the artificial cells to produce just the right bio-modifying agents at just the right time for a particular individual's needs--most people could avoid doctor's offices and hospitals for long periods of time. Particularly if biosensors that could be queried over wireless networks by the the person's physicians, were also implanted.

But that type of thing is at least a decade in the future. Why not take advantage of tiny chemical factories that are already available, and that could be more easily genetically modified? I am referring of course to "pro-biotics". The lactobacilli found in yoghurt, and similar bacteria prevalent in the mammalian gut, have been very helpful to humans over the decamillenia.

Kombucha is a particularly interesting form of probiotic tea.

The tea contains a symbiosis of yeast species and acetic acid bacteria, mostly Bacterium xylinum. Species of yeast found in the tea can vary, and may include: Brettanomyces bruxellensis, Candida stellata, Schizosaccharomyces pombe, Torulaspora delbrueckii and Zygosaccharomyces bailii. The culture itself looks somewhat like a large pancake, and is often mistakenly referred to as a mushroom.

Source.

I was recently introduced to Kombucha by a colleage. Go here for more interesting articles on kombucha.

Bacteria can be made to produce a lot of useful proteins and enzymes, fairly easily. The same is true for yeast. Many of our necessary vitamins are produced in our guts by bacteria. It is time we humans learned to teach our guests how to serve us even better. At this time, the horizons of symbiosis appear to reach a very long way.

Given that these gut bacteria live in the small intestine, beyond gastric acid and gastric proteolytic enzymes, it seems likely that administering peptides via probiotic organisms could be a useful alternative to parenteral administration.

Hormone Replacement: Some People Think It Works

A recent meta-analysis of Human Growth Hormone (HGH) effect on mortality and morbidity painted a pessimistic picture. Certainly a lot of "science" blogs jumped on the story and instantly turned "thumbs down" on HGH replacement. Personally, I say "not so fast." Meta-analysis studies such as this cannot provide a definitive answer to a question. They can only suggest new approaches to experimental study.

While anecdotal evidence is not proof of any scientific principle, some may find it interesting to see examples of "successful" treatment with hormone replacement. These two videos are promotional videos by a hormone replacement clinic in Palm Springs, California. This clinic has been in business for over a decade now.
Total Hormone Therapy Vid. 1
Total Hormone Therapy Vid. 2

The concept of hormone replacement therapy is simple. HGH, DHEA, Thymosin, male and female sex hormones, and often Thyroxin will fall in concentration with age. To better approximate the physical condition of a younger person, you would theoretically want to replace hormones that tend to drop off in concentration dramatically with age. You would also want to see a drop in the pro-inflammatory and other harmful hormone levels that rise with age, at the same time.

It is not proven to work, other than anecdotally. But the idea deserves better experimental analysis than it has received so far, at least in the US.

Michio Kaku: BBC Special Report on Immortality

"This girl may live to be a thousand years old."

So begins Theoretical Physicist Michio Kaku,who is featured in this report on how time perception varies with age, and how that relates to the winding down of the human organism with time.

A fascinating inquiry into long life in nature, and the prospects for human longevity.

Alcor Cryonics Video

This 28 minute video from Alcor looks at the history of life extension technology--specifically the cryonic approach to making "death" reversible indefinitely.

Immortality Institute conference presentation: Brian Wowk

Low temperature suspended animation without freezing is referred to as vitrification. This is a fascinating 26 minute video detailing a method of cryopreservation that prevents cellular damage from expanding ice crystals. This process will be first utilised for preserving organs for long-term storage before transplantation, once early problems are worked out. Eventually animals will be successfully vitrified using this technique. When such animal vitrification and de-vitrification is routinely successful, humans will be next. Related websites: http://www.Mprize.org http://www.ImmInst.org http://www.alcor.org

Exploring Life Extension--A Film by the Immortality Institute

This one hour and 45 minute film explores cryonics (cryogenics), caloric restriction, transhumanism, and other scientific pursuits of extreme life extension. Related websites: http://www.Mprize.org http://www.ImmInst.org http://www.sens.org

TED 2006 Conference Presentation: Aubrey de Grey

Here is a presentation by Aubrey de Grey at the TED 2006 Conference. De Grey's SENS organisation recently received a grant of $3.5 million from Paypal cofounder Peter Thiel. De Grey is certainly not a conventional tie and labcoat type of scientist. But he may be exactly what is needed to shake longevity research out of its doldrums. Presentation by Aubrey de Grey at the Technology Entertainment Design (TED) Conference 2006. http://www.ted.com/conference/flashpage.cfm?conferenceKey=2006 Related websites: http://www.Mprize.org http://www.ImmInst.org http://www.Sens.org

Ray Kurzweil Predicts

Kurzweil predicts human immortality by way of nanomedicine. "Nanobots" in our bloodstreams will repair cellular and tissue damage as fast as it occurs. Affordable computers will be a thousand times more powerful than a human brain . . . Kurzweil clearly believes in "singularity now!"

According to Kurzweil, here's what we can expect in the not-so-distant future:

—Doctors will be doing a backup of our memories by the late 2030s;

—By the late 2020s, doctors will be sending intelligent bots, or nanobots, into our bloodstreams to keep us healthy, and into our brains to keep us young;

—In 15 years, human longevity will be greatly extended. By the 2020s, we'll be adding a year of longevity or more for every year that passes;

—In the same timeframe, we'll routinely be in virtual reality environments. Instead of making a cell call, we could "meet" someone in a virtual world and take a walk on a virtual beach and chat. Business meetings and conference calls will be held in calming or inspiring virtual locations;

—When you're walking down the street and see someone you've met before, background information about that person will pop up on your glasses or in the periphery of your vision;

—Instead of spending hours in front of a desktop machine, computers will be more ingrained in our environment. For instance, computer monitors could be replaced by projections onto our retinas or on a virtual screen hovering in the air;

—Scientists will be able to rejuvenate all of someone's body tissues and organs by transforming their skin cells into youthful versions of other cell types;

—Need a little boost? Kurzweil says scientists will be able to regrow our own cells, tissues, and even whole organs, and then introduce them into our bodies, all without surgery. As part of what he calls the "emerging field of rejuvenation medicine," new tissue and organs will be built out of cells that have been made younger;

—Got heart trouble? No problem, says Kurzweil. "We'll be able to create new heart cells from your skin cells and introduce them into your system through the bloodstream. Over time, your heart cells get replaced with these new cells, and the result is a rejuvenated, young heart with your own DNA";

Source.

Kurzweil as author, is an example of an uber-synthesist. He sifts through mountains of information to find technology trends. He predicts the future, without bothering to have tongue in cheek.

His biological predictions may even be timid, but Kurzweil's predictions of nanotech healers and machine super-cognition may be more than a little optimistic--from his point of view.

Humans are certainly not ready for super-intelligence, and computers have no point of reference. Human intelligence is based on emotions, which are based on biological drives. Computers have nothing similar to build on, other than a need for electricity, more memory, and faster processors. As soon as computers begin to understand the need for speed and power, we may all be in trouble. Computers are not bound by billions of years of kludgy evolution--they can evolve exponentially.

So it comes down to: how soon can engineers/scientists build emotions and drives into computers--computers with actuators and power to act in the physical world? Because that is when Kurzweilian things start happening. Only computers can program massively parallel computers. They simply need a good reason to do so.

Zeroing In on Genetic Mechanisms of Ageing

The genes are largely responsible for how we look, how intelligent we are, and how long we will live. Finding genes that help determine our lifespan is important in the quest to scientifically extend the human lifespan. Now, scientists have zeroed in on one likely gene candidate, p16INK4a, that when over-expressed leads to cellular senescence in pancreatic islet cells, brain, and blood stem cells.

Teams from the medical schools at the University of North Carolina at Chapel Hill, University of Michigan and Harvard University observed similar results in pancreatic islet cells and brain and blood stem cells.

The results show disparate cell types share a common aging mechanism and suggest that aging-related diseases such as diabetes result from a failure of cell growth, said Dr. Norman E. Sharpless, co-author on the three studies and an assistant professor of medicine and genetics at the UNC School of Medicine. "The studies indicate that certain stem cells lose their ability to divide and replace themselves with age as the expression of p16INK4a increases," said Sharpless, a member of the UNC Lineberger Comprehensive Cancer Center.

The trio of reports are published online Sept. 6 in the journal Nature. The three research teams are from the medical schools at UNC, the University of Michigan and Harvard University.

The UNC study focused on p16INK4a effects on the function of pancreatic islet cells. Islet cells are responsible for insulin production and secretion. Because p16INK4a stops cancer cells from dividing and demonstrates increased expression with age, the scientists suspected the gene played a similar role in aging. The researchers developed strains of mice that were either deficient in p16INK4a (the gene was deleted, or 'knocked out") or genetically altered to have an excess of the protein to a degree seen in aging.

According to Sharpless, islet proliferation persisted in p16INK4a -deficient animals as they aged, "almost as if they were younger animals." In mice with an excess of p16INK4a, "islet cells aged prematurely; they stopped dividing early."

"This suggests that if we could attenuate p16INK4a expression in some way in humans, it could lead to enhanced islet re-growth in adults and a possible new treatment for diabetes," Sharpless said.

Similar results were found in the other studies, which focused on brain stem cells and blood stem cells.

The Michigan researchers, led by Dr. Sean Morrison, examined the role played by p16INK4a in neural stem cells, progenitor cells that can form new neurons and other brain cells. The team showed that p16INK4a increases markedly in those cells with aging. Moreover, p16INK4a -deficient neural stem cells work better and don't age to the same extent that wild-type (normal) stem cells do, Sharpless said.

Dr. Janakiraman Krishnamurthy, lead author of the UNC study and a postdoctoral scientist in the Sharpless lab, was a co-author of the Michigan report. The Harvard team, led by Dr. David Scadden, studied the role of p16INK4a in hematopoietic stem cells, which proliferate continuously during the adult lifespan and produce massive amounts of new blood cells on an hourly basis. Their results suggest that p16INK4a is the molecular basis for an old-age "signal" previously observed in blood stem cells. The Harvard study also showed that blood stem cells from old mice lacking p16INK4a functioned better than old cells from wild-type mice, suggesting p16INK4a causes aging of these cells as well.

Sharpless cautions that any promise of a potential new aging treatment based on p16INK4a should include two important caveats. "First, even though old mice lacking p16INK4a show enhanced stem cell function, they do not live longer. This is because p16INK4a is an important cancer-suppressor gene, and mice lacking p16INK4a develop more cancers than old, normal mice," he said.

"Secondly, in all three studies, p16INK4a loss was associated with an improvement in some but not all of the consequences of aging. There are clearly things in addition to p16INK4a that contribute to aging. We don't yet know what they are."

Source.

Now it would be helpful to find a drug or genetic therapy that would block the anti-senescence effect of p16INK4a, but leave the tumour suppressor effect of the gene intact. I suspect that such a treatment would show significant pro-longevity effects.

There are many more pieces of this puzzle to find, but finding this particular piece will lead to the quicker finding of subsequent pieces.

Proteomic Mass Spectrometry--Advanced Tools for Bio-Research

The average cell is flooded with an ever-changing population of proteins. To understand what a cell is doing, it helps to be able to take a "snapshot" of all the proteins, examining them carefully for signs of dangerous mutations.

Brian Druker of the Oregon Health and Science University in Portland and Roberto Polakiewicz, chief scientific officer of Cell Signaling Technology in Danvers, MA, have extended the role of proteomic mass spectrometry in order to detect cell signalling protein mutations that may lead to cancer.

"There are potentially hundreds of mutations in a given patient," says Jeffrey Tyner, a postdoc in Druker's lab. Only some of those mutations actually contribute to the cancer -- and evaluating all of them is time-consuming.

In essence, DNA sequencing reveals only what the cell could do. Protein mass spectrometry, in contrast, provides a clearer picture of what the cell is doing. That's why Cell Signaling Technology believes its approach is more efficient. "Proteomic [mass spectrometry] gives you the true readout of what's going on in the cell," says Mark Cobbold, a clinician scientist at the University of Birmingham, U.K.

Druker's mass spectrometry study focused on acute myeloid leukemia, the most common form of the disease. And, while three common gene mutations are often to blame for it, in 30 to 50 percent of cases, the cause is unknown, says Tyner.

Druker hopes to duplicate his success in previous work on another form of leukemia, which led to the first successful molecularly targeted cancer drug, Gleevec (Imatinib). Approved for clinical use in 2001, the drug works by specifically binding to an abnormal tyrosine kinase protein and inhibiting it. The drug has worked wonders for some patients. "Druker is taking molecular medicine forward. Now he's looking for other [leukemia targets] using a proteomics approach," Cobbold says.

Looking at a cell's actual molecular activity using mass spectrometry lets Druker avoid much of the guesswork in searching for cancer mechanisms. Instead of years, it took his lab just weeks to uncover a mutation in a gene for a kinase called JAK3 that causes the signaling molecule to be abnormally active. They found the mutation in a cell line, then verified the result in patients.

In proteomic mass spectrometry the researchers first break up cancer cells, purify their proteins, and cut them up. They then further purify stretches of protein characteristic of active tyrosine kinases. This mixture is put into the mass spectrometry machine, which sequences the proteins. With this information, researchers know which proteins are abnormally active and why -- because of a mutation, for example -- and can search for a drug that acts against them.

Tyner hopes their work can be translated into clinical tests for determining the molecular cause of a patient's tumor. Protein mass spectrometry profiles of cells from a tumor biopsy could identify which protein is running amok and what drug would work best on it. "It's very attractive, the idea of looking at signaling in tumors and from that uncovering [genetic] profiles," says Cobbold.

Source.


Proteomics research is expanding almost exponentially, as its importance is sinking in. The Wikipedia link above provides several links to proteomics resources. Here is an animation that illustrates the use of mass spectrometry in protein sequencing. Here is a blog that specializes in mass spectrometry, and deals with proteomics occasionally.

This type of technology will become commonplace in the modern anti-aging clinical laboratory. Clients will be scheduled routinely for analysis of cell-signalling networks, both to formulate initial treatments, and to monitor ongoing treatment results. It is likely that many clients will learn initially about their cancers, or other serious diseases, from their anti-aging screening.

Because medical insurance companies are not likely to pay for these procedures for decades yet, early comprehensive anti-aging diagnosis and treatment will be quite expensive.

NF Kappa B and Aging

The Life Extension Magazine has an interesting article on NF Kappa B and its relationship to aging. Previous Al Fin postings on NF Kappa B here, and here, provide more background for understanding this important transcription factor.

From the LEF Magazine article:

The ubiquitous presence of NFkB throughout the inflammation-cancer cycle suggests that the next breakthroughs in cancer treatment will likely center on the inhibition of NFkB and its actions. As scientists learn more about NFkB and the complex systems that regulate it, they also learn more about the wide array of substances that can inhibit its dangerous actions. For example, the anti-inflammatory drug ibuprofen inhibits not only the COX-2 enzyme but also NFkB,12 and has a well-established safety record. This drug, as well as many natural inhibitors of NFkB, will therefore play an important role in controlling the inflammatory components of tumor formation and growth.

Because the NFkB factors are active in both the cancerous cells and inflammatory cells in tumors, nutrients or drugs that can inhibit NFkB show tremendous promise as anti-cancer or cancer-preventive agents.8 Scientists believe that the combination of NFkB inhibition with drugs or cytokines that induce cancer cell death has great promise in fighting cancer.13

Because the NFkB system is also involved in producing healthy immune responses, there are concerns about its long-term inhibition. While NFkB seems to be most profoundly involved in cancer at the stages of promotion and progression,8,14 it may be possible to use inhibitors for relatively short periods. Another potential use for such inhibitors would be in combination with chemotherapy or radiation treatments, as a means of controlling the associated inflammation and enhancing the effects of those treatments.8

....Herbs and spices from around the world have long been sought for their pleasing flavors and healing qualities. Even today, these plant extracts are valued worldwide for promoting health and fighting disease. Scientists are discovering that many of these natural agents act through the universal mechanism of inhibiting the over-expression of NFkB.

Curcumin is a compound found in a number of South Asian spices, most prominently in turmeric, a component of curry seasoning.

Curcumin has well-established antioxidant and anti-inflammatory effects.35,36 The extent to which curcumin exerts these effects by inhibiting NFkB is becoming increasingly clear.37 Curcumin acts directly within the cell’s nucleus and also acts on substances that activate NFkB. For example, it binds iron and copper in brain tissue, reducing the activation of NFkB that is associated with the production of amyloid beta proteins in Alzheimer’s disease.35

Strong evidence suggests that curcumin may fight the following inflammatory diseases:

* Colitis. Dietary curcumin supplements strongly suppressed NFkB activation in a rat model of colitis,38 resulting in both decreased tissue wasting and colonic inflammation. When curcumin was given to experimental animals before the induction of colitis, there was reduced NFkB activation and less visible damage to the colon.39 This effect was accompanied by reduced activity of several enzymes involved in inflammation in the gut.
* Liver disease. The development of alcoholic liver disease, resulting in chemical hepatitis and eventually cirrhosis, has recently been associated with NFkB-mediated gene expression. When laboratory rats were fed sufficient alcohol to produce alcoholic fatty liver with liver cell inflammation and necrosis, dietary curcumin inhibited NFkB activation, preventing both the microscopic and biochemical changes associated with alcoholic liver disease.40 In an experimental model of non-alcoholic fatty liver degeneration (which induces substantial oxidative stress), investigators found that dietary curcumin significantly reduced inflammation and the release of inflammatory modulators through NFkB inhibition.41
* Chronic neurodegenerative diseases. NFkB-induced inflammation involving brain glial cells is thought to be one mechanism contributing to the formation of amyloid beta proteins, which are characteristic of Alzheimer’s and other degenerative brain diseases.42 In several recent studies, curcumin has been shown to reduce the glial cell expression of inflammatory mediators.43,44 Curcumin likewise has been shown to reduce amyloid beta formation in animal models by inhibiting NFkB.45,46
* Arthritis. Curcumin’s inhibition of NFkB reduces the degenerative changes to arthritic joints.47,48 Just this year, curcumin was shown to enhance the anti-inflammatory effects of the COX-2 inhibitor drug celecoxib.49 This is an important finding, since COX-2 inhibitors have adverse effects on the cardiovascular system. This caused scientists to propose that co-treatment with curcumin could reduce the dose of selective COX-2 inhibitors required to achieve significant relief from inflammation.
* Cancer. Curcumin has been found to suppress, retard, and even reverse cancer development at each stage of the disease.50 By inhibiting NFkB, curcumin reduced expression of proteins needed by cancer cells for proliferation (the promotion stage) and for invasion and metastasis (the progression stage).51 Curcumin also reduces cancer progression by increasing cell death in cancer cells, thereby depriving them of the “immortality” they need to survive and invade other tissues.52,53 This has allowed curcumin to be effective in highly chemotherapy-resistant cancers;54 it has also been shown to increase the effect of chemotherapy in animal models of advanced human cancer.51

....Capsaicin, the main ingredient in red pepper, has both anti-inflammatory and anti-cancer effects.81-83 Red pepper compounds have long been used to manage inflammatory joint conditions.37 Capsaicin inhibits the induction of two inflammation-provoking enzymes in stimulated macrophage immune cells.82 This effect is attributable to its inhibition of NFkB activation.83 Capsaicin also induces cell death in many cancers by modulating NFkB.81 Like curcumin, capsaicin inhibits the growth of adult T-cell leukemia cells by impairing NFkB activation.84 Capsaicin further impairs cancer progression by reducing levels of vascular endothelial growth factor, thus depriving growing cancers of nutrients.85

Clove extract (eugenol) inhibits NFkB-mediated expression of inflammatory cytokines.86,87 Like capsaicin, eugenol inhibits NFkB activation in stimulated macro-phage immune cells,87 reducing their synthesis of COX-2 and inflammatory cytokines.86 Oil of cloves has been used in dental care for centuries, and eugenol is now widely used to promote healing and prevent excessive inflammation after root canal surgery.88,89

Ginger extracts exert anti-inflammatory activity and stimulate cancer cell death by inhibiting NFkB.90-92 Ginger reduces expression of the key inflammatory enzymes COX-1 and COX-2.93 Topical application of ginger extract inhibits skin inflammation in a mouse model92 by inhibiting NFkB.91 A ginger extract was shown to enhance tumor cell death and down-regulate production of tumor invasion factors by preventing activation of NFkB.90

Basil and rosemary extracts, which contain ursolic acid, reduce cancer cell proliferation and tumor progression through NFkB inhibition.94-96 By inactivating NFkB, ursolic acid prevents initiated cells from reproducing and also triggers tumor cell death.95 This compound further down-regulates molecules that are required for tumor invasion and metastasis.96 Ursolic acid works through its effects on NFkB to induce resting macrophage immune cells, and thus to participate in tumor cell destruction in the early stages of cancer.97 Ursolic acid derivatives that inhibit NFkB have been shown to suppress pro-inflammatory enzyme expression in mouse models of inflammation.98 This effect has been associated with reduced cardiac fibrosis (scar tissue) in the heart tissue of diabetic mice.94

Garlic has now been shown to exert its anti-inflammatory and immunomodulatory effects by inhibiting NFkB.37,99 Garlic extracts lowered NFkB activity by up to 41% in human blood and kidney cells that had been exposed to an inflammation-provoking challenge, thus reducing the expression of certain cytokines.100 These effects may be linked to the observation that a garlic compound inhibits damage to endothelial cells lining blood vessels and reduces atherosclerotic changes.101 Garlic’s inhibition of NFkB leads to reduced production of chemicals that cause lipid peroxidation, and this could provide further protection from atherosclerosis.102 NFkB inhibition is credited for garlic’s ability to protect liver cells from auto-immune damage in an animal model,103 as well as induce cell death in leukemia.104

Pomegranate fruit extract protects cells against the effects of ultraviolet B radiation by inhibiting ultraviolet light-stimulated NFkB activation.105 Pomegranate fruit extract also prevented chemically induced skin cancers in mice through NFkB-mediated effects on both cancer initiation and promotion.106 Blockade of NFkB by pomegranate fruit extract has shown promise in osteoarthritis by inhibiting the production of protein-digesting enzymes and inflammatory cytokines.107 Pomegranate wine reduced the activation of NFkB in vascular endothelial cells by inflammatory mediators or biomechanical stresses,108 thus protecting against atherosclerosis.109
Summary

Scientists have discovered that by controlling our DNA, nuclear factor-kappa beta (NFkB) plays a central role in determining our health and longevity. By integrating signals of inflammation, NFkB appears to be the common link between such diverse conditions as heart disease, cancer, and arthritis.

Agents that control NFkB’s influence within the human body—such as omega-3 fatty acids, phytoestrogens, curcumin, garlic, licorice, ginger, rosemary, and pomegranate—hold great promise in fighting many diverse diseases and in promoting long and healthy lives.

More at Source.

While the LEF article over-simplifies the role of NF Kappa B, it is a helpful first look for non-scientists, at a very important transcription factor involved in cancer, inflammation, and ultimately life extension.

Curcumin, garlic, and ginger are all quite safe and proven to be helpful in several degenerative conditions of middle age and senescence. It is currently not known how much of their beneficial effects come from their effect on NFKB.

SENS Challenge: Debating Aubrey de Grey

There is ongoing and lively debate at Technology Review concerning the "SENS Challenge", with a prize of US $20,000 at stake. The challenge was issued a year ago, with the $20,000 prize offered to anyone who could prove that SENS was "unworthy of learned debate."

Technology Review has provided links to the entire debate (scroll down). Most of the entries failed to approach the level of serious consideration by the challenge judges, however one entry by Preston Estep was considered well enough argued to be awarded a $10,000 grant, which had nothing to do with the prize money for the challenge.

Links from other challengers are also provided on the TR SENS Challenge page, along with Aubrey de Grey's rebuttals, and the counter-rebuttals by the challengers. Finally, Preston Estep posted a strong protest to the judges' decision.

At the MPrize website, the editors correctly proclaim that SENS has withstood the challenges so far, and the $20,000 prize remains unclaimed. The $10,000 award to Estep is briefly discussed there as well.

The real debate is taking place as you read this, on the discussion forum of Technology Review, and other websites. A quick blog search query brought up a large number of news and blog reports on the decision of the judges. Start at the TR SENS Challenge page, and follow the links.

No one is staking his life that SENS is correct in every detail. That level of perfection is not necessary for SENS to have a profound positive impact on anti-aging research. It is only necessary that the SENS theories help lead to positive results, either directly or indirectly, for the theories to have been worthwhile in the long run.

There are backwaters of science that need to be shaken up from time to time. Gerontology had certainly become one of those backwaters. The entry of SENS into the arena has been like a splash of cold water to the face, and like a breath of fresh air, simultaneously.

Technology Review is to be congratulated for helping to stimulate this lively debate, and for furthering interest in this incredibly important field of study.

Glimpses Into the Near Future

The master control program for development and repair of the human organism is being de-encrypted. Using tools from genetic programming, stem cell research, and nanotechnology, it will be possible to assist the body in maintaining health and youth. Here is a brief progress report for a few interesting tools and technologies:

Creating embryonic stem cell (ESC) lines is controversial. Destroying embryos to create a single ESC line strikes some as wasteful of human life. But what if you could take an embryo and create millions of distinct ESC lines from it?

This Nature abstract discusses the protein Nanog, which may allow the creation of any number of "hybrid" ESC lines-- reprogramming adult stem cells to pluripotency. Eventually it should even be possible to reprogram adult stem cells without having to use an ESC. Here is a bit more detail in this Bio.com newsrelease:

The Edinburgh scientists fused mouse embryonic stem cells with brain stem cells, a type of adult stem cell. They found that the addition of Nanog resulted in a massive increase in the numbers of hybrid cells, all of which behaved like embryonic stem cells. Most importantly the hybrid cells showed the capacity to make many different cell types, such as heart and gut. "This means that the genetic programme of the brain cells has been erased and replaced by the unspecialised programme of an early embryo cell" says Dr Jose Silva, first author of this study.

Dr Silva adds "The effect of Nanog is remarkable. All of the hybrid cells become fully converted to embryonic stem cells. If we can figure out how Nanog does this, it may become possible to switch cell types without fusion or cloning." However, the Edinburgh team must also identify at least one other key gene. "Nanog has great power" says Professor Smith, "but it does not work in isolation, only in partnership with other genes present in embryonic stem cells".

As an organism ages, it loses the ability to replace lost cells. At some point, cells lose the ability to replicate, but even before that point they show signs of incompetence in gene expression. This Nature abstract discusses research that reveals this increased variation in gene expression of aging myocytes:

One possible mechanism by which increased DNA damage could lead to cellular degeneration and death is by stochastic deregulation of gene expression. Here we directly test for increased transcriptional noise in aged tissue by dissociating single cardiomyocytes from fresh heart samples of both young and old mice, followed by global mRNA amplification and quantification of mRNA levels in a panel of housekeeping and heart-specific genes. Although gene expression levels already varied among cardiomyocytes from young heart, this heterogeneity was significantly elevated at old age. We had demonstrated previously an increased load of genome rearrangements and other mutations in the heart of aged mice3, 4.

This means that in order to perform DNA repair on senescent cells, it will be necessary to have templates of relatively young cells of that type. At some point it would be necessary to replace the old cells with new cells--much like replacing the rotten planking of an old wooden boat with new planking. It is still the same boat, but the new planking gives it a new life. Stem cells--tissue specific programmed ASC's from preserved ESC's--would provide the replacement cells.

That is why drugs such as the recent Korean discovery CGK-733 will not work as life extenders. They only extend the replication lifetime of cells--they do not keep the ageing cells young. The senescent incompetence of gene expression is still present, along with increasing risks of cancerous transformation.

Next, what good is a body made of young vibrant cells, if the mind is asleep or deranged? This Eurekalert newsrelease discusses the discovery of Neuropeptide-S, a new brain protein that promises to help wake the walking sleepers.

Neuropeptide S (NPS), so named by Rainer K. Reinscheid, Ph.D., assistant professor, Program in Pharmaceutical Sciences, University of California, Irvine, is produced by a small cluster of cells in the brainstem, yet its specialized receptors are found in several areas of the brain, including those that are associated with the regulation of arousal, sleep and wakefulness, anxiety, appetite, learning and memory. Dr. Reinscheid and his colleagues reported finding the new neuropeptide just last year and described animal studies showing how binding of NPS to its receptors on the surfaces of neurons promotes strong arousal, suppresses all phases of sleep and lessens anxiety in stressful or unfamiliar situations.

Now, at ICN 2006, Dr. Reinscheid's group reports how NPS also can reduce the biochemical and behavioral symptoms of schizophrenia in an established animal model for this mental illness that affects some 2 million Americans. Animals pretreated with NPS before receiving a drug that normally induces psychotic-like behaviors did not develop the signature behavioral symptoms and neurochemical features of schizophrenia, reported Naoe Okamura, M.D., Ph.D., who is a co-worker of Dr. Reinscheid at the University of California, Irvine.

"Although preliminary, our animal studies indicate the NPS receptor should be explored as a target for the development of novel antipsychotic drugs. Whether molecules activating the NPS system will prove to be better drugs than others used to treat the symptoms of schizophrenia remains to be seen. We still have a very long way to go before proving it can alleviate symptoms in humans as we've seen it do in rodents," said Dr. Reinscheid.

A peptide that wakes people up, and makes them less anxious and perhaps less psychotic too? Quite the improvement over amphetamine. Perhaps exactly what is needed in the coming age of tumultuous transition to a next level world.

Some nanotechnologists and singularitarians believe that tiny nanobots will be able to store and carry the early genome to all cells, and busily repair any errors that may occur in replication--even in ageing cells. Such nanobots could conceivably detect early cancerous transformation, and act to trigger apoptosis in cells with such changes.

Research in biotechnology is now at such a profound level, that breakthroughs in one are can quickly lead to breakthroughs in several other areas. It is obvious that ageing is related to malignancy as well as autoimmune and other inflammatory diseases. In addition, improvements in the tools of biotechnology research almost immediately suggest newer and more profound areas of research and discovery. It is becoming easier to believe Ray Kurzweil's analysis of exponential knowledge growth.

Now, two more postings on aging: the first deals with mitigating the effects of aging in those already old. The second posting will deal with new theories of cryopreservation that may finally provide a workable way forward to safely place people into "stasis" for later "re-animation".

A compound that stimulates the secretion of growth hormone can help older adults improve their physical function and lower their body fat percentage, according to study results that will be presented Wednesday, June 21, at the International Congress of Neuroendocrinology in Pittsburgh. The results will be presented by Dr. George Merriam, professor of medicine at the University of Washington and a physician with the VA Puget Sound Health Care System. Merriam helped coordinate endocrine aspects of this multi-site study, along with Dr. Heidi White of Duke University and researchers at Pfizer, Inc. Nearly 400 adults from 65 to 84 years old were enrolled in the study, and were divided into groups receiving a placebo or one of four different levels of an oral growth hormone secretagogue (GHS), which stimulates the secretion of human growth hormone. Researchers measured the participants' fat and lean body (muscle) mass, as well as their performance in physical tests like stair climbing and a heel-to-toe walk. The participants also received blood tests for levels of growth hormone and a compound called IGF-1, a hormone which responds to growth hormone and mediates some of its effects. Participants receiving the GHS treatment saw a significant increase in lean body mass – about 1.5 kilograms, or 3.3 pounds. The GHS treatment led to improved physical function over the six- to 12-month study period. Participants also had higher levels of growth hormone and IGF-1 in their bloodstreams. Patients receiving the GHS treatment had minor side effects, including increased fatigue, insomnia, and fasting glucose levels. Growth hormone is vital in childhood growth, and production of the hormone peaks during puberty. However, it continues to affect physical function throughout our lives, and it regulates metabolism and body composition. As adults move into middle age, growth hormone production begins to taper off. Many of the effects of aging – increased abdominal fat, reduced muscle mass, and decreased physical function – look very similar to the symptoms of growth hormone deficiency in younger people. As those aging effects set in, many older adults find it difficult to care for themselves, and they lose quality of life and often turn to long-term care. Source.

Last, new ideas on cryopreservation:

In medicine, cryopreservation involves preserving organs and tissues for transplantation or other uses. Only certain kinds of cells and tissues, including sperm and embryos, currently can be frozen and successfully rewarmed. A major problem hindering wider use of cyropreservation is formation of ice crystals, which damage cell structures. Cyropreservation may be most familiar, however, as the controversial idea that humans, stricken with incurable diseases, might be frozen and then revived years or decades later when cures are available. Bogdan's experiments involved a form of water termed "glassy water," or low-density amorphous ice (LDA), which is produced by slowly supercooling diluted aqueous droplets. LDA melts into highly viscous water (HVW). Bogdan reports that HVW is not a new form of water, as some scientists believed. ...."It may seem fantastic, but the fact that in aqueous solution, [the] water component can be slowly supercooled to the glassy state and warmed back without the crystallization implies that, in principle, if the suitable cyroprotectant is created, cells in plants and living matter could withstand a large supercooling and survive," Bogdan explained. In present cryopreservation, the cells being preserved are often damaged due to freezing of water either on cooling or subsequent warming to room temperature. "Damage of the cells occurs due to the extra-cellular and intra-cellular ice formation which leads to dehydration and separation into the ice and concentrated unfrozen solution. If we could, by slow cooling/warming, supercool and then warm the cells without the crystallization of water then the cells would be undamaged." Source: American Chemical Society More at source.

In the future, several approaches to aging will be available. Those who choose to age "normally" will have the option of "optimising their years" without adding to them appreciably. HGH promoters, pumps, and depo injections will be useful for them. Others will want to add a few decades of high functioning years to their lives. For those, drugs that aid in DNA repair, protein crosslink repair, calorie restriction mimetics, and anti-oxidant/anti-inflammatory supplements will probably do the trick. For those who want more radical extension to their lives, SENS-like approaches to rejuvenation engineering may eventually pay off. Stem cell repair and organ re-growth will definitely be available in the next few decades. More cyborg replacement parts will also be available in the next half century. The grand strategy is genetic engineering of a longer living body that rejuvenates itself constantly, and heals rapidly when injured.

Should safe and reliable cryogenics become available before the more radical lifespan extension strategies, it is conceivable that some might opt to be placed in "suspended animation" until the technologies for longer life are perfected. That might be particularly true for those dying prematurely of terminal illnesses.

Research into these technologies is being funded, sometimes under other descriptions. It is very likely that the goal of doubling the human lifespan will be achieved before the end of the century. Perhaps before the midpoint of the century.