Fight Aging!

While its easy to lose perspective amidst the daily grind, we do in fact already live in a science-fiction future, in which researchers are earnestly engaged in engineering the human body and its component parts. For example:

Heart Stem Cells Move Closer to Human Treatments:

In one study, out of Germany, 35 patients who received bone-marrow stem cell transplantation during coronary artery bypass surgery achieved "excellent long-term safety and survival." Ten patients who received similar transplantations after repair of mitral valves also fared well, with improvements in the heart's pumping capacity. Slovenian investigators had similar success, with improvements seen in patients with advanced heart failure who received bone-marrow derived stem cells. There were also advances in gene therapy reported, with Singaporean researchers using nanotechnology to deliver genetically modified cells to help heal heart attack damage in rabbits.

Implanted Neurons Let the Brain Rewire Itself Again:

Transplanting fetal neurons into the brains of young mice opens a new window on neural plasticity, or flexibility in the brain's neural circuits. The research [suggests] that the brain's ability to radically adapt to new situations might not be permanently lost in youth, and helps to pinpoint the factors needed to reintroduce this plasticity. ... If scientists can find a controlled way to trigger plasticity in specific parts of the brain, it would open new avenues for treatment of a variety of ailments. Adults who suffer brain damage from stroke or head trauma have some level of reorganization in the brain - enhancing that plasticity might improve recovery.

That second article goes hand in hand with recent research in mice in which transplant of fetal stem cells extended median life span. There are clearly interesting processes associated with fetal cells. Given the advances in engineering induced pluripotency in recent years, it is not unreasonable to expect that, should studies continue to point towards positive results from fetal stem cell transplants, researchers will find ways to reprogram normal cells into a fetal-cell-like state.

Intriguing research: microvesicles "are several times smaller than a normal cell and contain genetic information such as messenger ribonucleic acid (RNA), other species of RNA and protein. ... During times of cellular injury or stress, or with certain diseases like cancer, infections and cardiovascular disease, these particles are shed and then taken up by other cells in the body. The genetic information and protein in the microvesicles helps to reprogram the accepting cell to behave more like the cell from which the particle was derived. ... Our work suggests that when the lung is injured or diseased and cells within the lung are stressed or dying, they shed microvesicles. Those microvesicles are then consumed by cells within the bone marrow, including stem cells, which are present in small numbers within the circulatory system. Those bone marrow cells then turn into lung cells. ... microvesicles not only supply information to stem cells with lung injury, but this process also occurs in other organs as well, like the heart, liver and brain. ... the change in those stem cells that have consumed microvesicles made by injured lung cells is very stable - the change appears to be permanent. ... This would be relevant to any type of disease - if you want to repair damaged tissue, these microvesicles potentially provide a durable fix, and the hope is that it would be fixed forever."

Link: http://www.eurekalert.org/pub_releases/2010-02/l-ohf022610.php

From the Campaign Against Aging website: "Pictures have just been uploaded of Doug distributing flyers to students at a college campus. ... I had a great time distributing these flyers. I would say 70% or more of the reactions I got were positive. Under 10% of people did not take a flyer, and about 20% responded negatively. I used a few different slogans while distributing the flyers. For the most past I used 'Death sucks. We should stop it.', followed by 'Dying is bad. We shouldn't do it.', and least frequently 'Getting old sucks. We should do something about it.' I got the highest proportion of positive reactions in the same order (which is why I used 'death sucks' most frequently). I distributed about 200-300 flyers total today. ... I talked to several people and groups at length about what is involved in fighting aging. I explained that aging is not a magical process and that we do not have a clock inside our body that makes us get older. Aging is just a building up of damage over time inside our cells, and that damage can be reversed. I explained briefly a few of the different kinds of age related damage, including lipofuscin accumulation and protein cross linking."

Link: http://www.campaignagainstaging.org/campaign/week3and4.php

Rapamycin, as I'm sure you're aware by now, is a drug that has been shown to extend life in mice via a mechanism that may stack with the beneficial effects of calorie restriction on longevity. Unfortunately, its primary effect, and the reason for its commercial development in the first place, is suppression of the immune system. Rapamycin has been used to help prevent rejection of organ transplants for quite a while. It's not the sort of thing you'd really want to take on a regular basis, given the choice.

Nonetheless, now that rapamycin has been shown to influence longevity strongly enough to be worth an entry into the Mprize, interest has been spurred amongst those researchers who aim to slow aging through drug-induced manipulation of metabolic processes. So expect to see a steady flow of papers, as various research communities try it out in their laboratories. For example:

Rapamycin Rescues Learning, Memory in Alzheimer's Mouse Model:

Rapamycin, a drug that keeps the immune system from attacking transplanted organs, may have another exciting use: fighting Alzheimer's disease. Rapamycin rescued learning and memory deficits in a mouse model of Alzheimer's ... Rapamycin also reduced lesions in the brains of the mice, the team found. The lesions are similar to those seen in the brains of people who died with Alzheimer's.

"Our findings may have a profound clinical implication," said Dr. Oddo, who is a member of the university's Barshop Institute for Longevity and Aging Studies. "Because rapamycin is a U.S. Food and Drug Administration-approved drug, a clinical trial using it as an anti-Alzheimer's disease therapy could be started fairly quickly."

I'm of the opinion that the existence of the FDA creates a "looking for the keys under the lamppost" syndrome amongst researchers. The results we actually want - reversal of aging, bold new discoveries in biotechnology, and so forth - lie somewhere out there in the darkness, beyond what has been FDA approved, and in most cases beyond any framework the FDA has set in place to consider medical technologies. But how much easier it is to stick to the small circle of light and commercialize new uses for an already approved drug! The FDA's oppressive regulatory costs create a perverse incentive for researchers to focus their resources upon reuse of existing drugs, work that will never produce anywhere near the benefits that might be realized from completely new developments in medical technology. So we all suffer, and we cannot see the true cost, because that cost is measured in technologies and medicines that might have been brought into being by now, if not for the regulators.

But to return to the theme, I see that Ouroboros posted on the topic of rapamycin today as well:

This isn't exactly news, but it's news to me: Rapamycin has an orally administered derivative, Everolimus, already in use as an anti-cancer and anti-rejection drug. ... But the drug itself might be bad news, especially if it is taken over long periods of time: mTOR, the target of rapamycin, appears to be necessary for reconsolidation of long-term memory in mammals; inhibition of mTOR is efficacious enough at blocking fear memories that it's discussed as a strategy for treating PTSD. ... So, as I've commented before, I have this fear that rapamycin (or a derivative) will turn out to be a bona fide longevity enhancement drug, but one whose chronic use erodes long-term memory, which does defeat the purpose to some extent.

Chinese researchers here demonstrate that some forms of fetal stem cell transplant are unambiguously beneficial in mice - the absence of cancerous development is perhaps surprising. This suggests that if an individual's stem cells could be sampled, altered to look more like fetal stem cells, and returned to the body, then they could achieve the same end: a general improvement in tissue repair, bodily systems, and life expectancy. From the paper: "To determine the role of allogeneil graft of mesenchymal stem cells in mammalian longevity, mesenchymal stem cells were isolated from [mouse fetal tissue] and then were purified and amplified by adherent culture. Identified P1 mesenchymal stem cells were injected [into] the 15-month-old [mother mice] three times. The mice were evaluated ... The results showed that after transplantation, the long-term surviving stem cells were found to be located in many organ tissues ... Median life span was increased in these animals after transplantation. Skin, cardiac, lung, kidney and colon pathology development were delayed. [Amongst other markers of aging, the degeneration] of heart function was attenuated [and markers of oxidative stress] were reduced three months after transplantation. These results support the idea that longevity can be enhanced by transplantation of mesenchymal stem cells."

Link: http://www.ncbi.nlm.nih.gov/pubmed/20179893

Via CryoNet, some advice to follow on from the cautionary tale of a few days ago: "There has been some discussion about relatives causing suspensions to not take place as the cryonics member gets older and how we cryonicists can protect ourselves from this happening. Suspension interference happens more then most cryonicists realize. As a retired member of of Alcor management I have seen a lot of it. ... You think your relatives will continue to honor your wishes as you grow old? A lot of them will tall you to your face that they will, but in reality they believe that cryonics is a waste of your time and your money. So they have no moral reservations about causing you to cancel your membership and have the money go to them if and when they get a chance to take over. How can you protect yourself? Make sure that your life insurance policy says that if you don't get suspended for any reason that the proceeds still go to your cryonics organization and not your relatives. So there is no financial incentive for the relatives to cause you to cancel your arrangements. Put a clause in your will that says that if you don't get suspended that all your estate goes to your cryonics company and not your relatives so that there is a financial incentive for your relatives to see that you do get suspended."

Link: http://www.cryonet.org/cgi-bin/dsp.cgi?msg=32414

Retinitis pigmentosa is an inherited form of slow degenerative blindness, in which essential retinal cells accumulate defects due to one or more mutated genes. Generating replacement, properly formed retinal cells to treat this condition is one of the longer-running initiatives in the stem cell research community; if you look back in the Longevity Meme archives, you'll see it mentioned in 2004, for example. It appears that researchers have now succeeded in restoring sight in mice:

An international research team led by Columbia University Medical Center successfully used mouse embryonic stem cells to replace diseased retinal cells and restore sight in a mouse model of retinitis pigmentosa.

...

In Dr. Tsang's study, sight was restored in one-fourth of the mice that received the stem cells. However, complications of benign tumors and retinal detachments were seen in some of the mice, so Dr. Tsang and colleagues will optimize techniques to decrease the incidence of these complications in human embryonic stem cells before testing in human patients can begin. "Once the complication issues are addressed, we believe this technique could become a new therapeutic approach for not only retinitis pigmentosa, but age-related macular degeneration, Stargardt disease, and other forms of retinal disease that also feature loss of retinal cells," said Dr. Tsang.

As noted, a viable source of replacement retinal cells has much broader application than just retinitis pigmentosa. In the context of the wider picture, it is heartening to see steady progress being made towards the ultimate end goal of a general repair kit for human beings - the biotechnological capabilities and medical community capable of replacing any damaged or diseased tissue safely and at reasonable cost. While the years seem to flicker by for those of us keeping an eye on this field of research, significant progress is taking place.

As a parting note, you might take a look at the actual paper, if you're interested. The website of the publishing journal, Transplantation, is well worth browsing if you'd like to get a sense of what the tissue engineering community is presently working on. It is a very energetic field, and what filters through to the popular science press is a fraction of what's going on in the labs.

Wang, Nan-Kai, Tosi, Joaquin, Kasanuki, Jennifer Mie, Chou, Chai Lin, Kong, Jian, Parmalee, Nancy, Wert, Katherine J., Allikmets, Rando, Lai, Chi-Chun, Chien, Chung-Liang, Nagasaki, Takayuki, Lin, Chyuan-Sheng, & Tsang, Stephen H. (2010). Transplantation of Reprogrammed Embryonic Stem Cells Improves Visual Function in a Mouse Model for Retinitis Pigmentosa Transplantation, 89 (5) : 10.1097/TP.0b013e3181d45a61

Given the vast weight of evidence, it would seem straightforward to say that regular exercise is good for health and longevity. But of course, nothing is ever as simple as we'd like in biology: "We know that exercise is good for us, and increasingly we're understanding how it works at the molecular and cellular level: Physical activity boosts levels of heat shock proteins, which help cells resist stress; it also improves mitochondrial function in a manner reminiscent of calorie restriction (CR). Our knowledge is sophisticated enough that we can identify and develop small-molecule exercise mimetics and drugs that improve exercise tolerance. Overall, then, exercise and its molecular/cellular consequences are consistent with longevity assurance pathways and life extension interventions. However, there are complications emerging. ... In blood flow restriction (BFR) exercise, resistance training is combined with pressure cuffs that significantly decrease blood flow to the exercising muscle; it increases protein synthesis in muscle cells and activates the TOR pathway. Now, Fry et al. have shown that in older men (who don't increase muscle mass in response to ordinary resistance training), BFR activates TOR. Superficially, this would seem to represent a contradiction: a lifespan-extending intervention (exercise) activates a lifespan-shortening biochemical signaling pathway (TOR). How might this seeming paradox be resolved?"

Link: http://ouroboros.wordpress.com/2010/02/23/a-conflict-between-exercise-and-longevity-control/

From the Technological Citizen: "are Kurzweil's visions of immortality even close to being feasible, given the current state and direction of today's technological advancements? When it comes, realistically, to life extension technologies, where do we really stand today? There's perhaps no group of people to better answer this question than the people of Methuselah Foundation, a non-profit organization founded by David Gobel, which supports Aubrey De Grey's SENS research and is dedicated to enabling humans 'to live longer, better and wiser, by defeating age-related disease and suffering.' I had the privilege of speaking to Roger Holzberg, the Chief Marketing Officer and Creative Director of Methuselah Foundation, about the core philosophies of the foundation and the promising research they are involved with. I asked Mr. Holzberg, what are the areas of life extension available now, and in our short-term future? What fundamentally drives the foundation towards seeking these life extension solutions? ... treating aging as a 'disease' and not a given in life is one of the principle philosophies of Methuselah Foundation. Towards this end, the foundation takes a very methodical, systematic approach to life extension, working to prevent and manage the diseases of aging such as cancer, heart disease, and diabetes, and to encourage research into new ways of prolonging life."

Link: http://thetechnologicalcitizen.com/?p=2460

One of the causes of age-related degeneration and disease is the buildup of amyloid clumps and other forms of aggregated metabolic byproducts. A brief outline:

As we get older, many different types of errant and unwanted proteins, the chemical byproducts of metabolism, build up and accumulate between our cells. Collectively these are known as forms of amyloid, a term that might be familiar to you in connection with Alzheimer's disease, but there are many other types of amyloid beyond that implicated in the destruction that Alzheimer's brings to the brain. For example, the work of the Supercentenarian Research Foundation implicates a different form of amyloid in the deaths of the oldest old. Those people who - though good genes, good lifestyle choices, and good luck - manage to evade heart disease, cancer, and all the other common forms of age-related death are done in by amyloid in the end.

Via the Gerontology Research Group mailing list, my attention was drawn to the recent discovery of a biological process that works to remove aggregates such as amyloid. Evidently our tissues are not doing this well enough, and it is plausible that the mechanism itself declines with aging due to the accumulation of other forms of biochemical damage. But where there is a mechanism, there is the opportunity to manipulate that mechanism - to either restore its operation to youthful levels, or greatly enhance its performance. This may form a useful strategy that could be developed in competion with the SENS approach of training the immune system to attack and destroy amyloid. But here is the paper:

Discovery and characterization of a mammalian amyloid disaggregation activity:

The formation of amyloid, a cross-beta-sheet fibrillar aggregate, is associated with a variety of aging-associated degenerative diseases. Herein, we report the existence of a mammalian amyloid disaggregase activity that is present in all tissues and cell types tested. Homogenates from mammalian tissues and cell lines are able to disaggregate amyloid fibrils ... Amyloid disaggregation and proteolysis activities are remarkably resistant to changes in temperature and pH. Identification and manipulation of the proteins responsible for the amyloid disaggregation/degradation activities offers the possibility of ameliorating aggregation-associated diseases.

There is clearly a lot of work to be done here to validate and expand upon this finding. Immune therapies aimed at training the immune system to destroy specific targets, on the other hand, are much more advanced - trials have taken place in recent years, and a growing and well funded research community exists.

Murray AN, Solomon JP, Balch WE, & Kelly JW (2010). Discovery and characterization of a mammalian amyloid disaggregation activity. Protein science : a publication of the Protein Society PMID: 20162625

Singularity Hub provides a popular science introduction to the FOXO3A gene and its role in human longevity: "The past few decades have seen a growing interest in longevity as medicine continues to advance life expectancy. Groups like the Methuselah Foundation (sponsors of the MPrize) are actively seeking technology to extend lifespans. Yet, understanding aging is not an exact science. We do know that genetics, environmental risks/lifestyle, and strong social bonds are all part of what helps someone live longer. Studies of centenarians, however, have suggested that while genetics don’t seem to make a big difference in the early decades of old age, they have a profound effect determining who makes it into extreme old age. Variants in FOXO3A may be one of the key ingredients that help take a healthy 80 year old, and turn her into a healthy 110 year old. ... everyone has a FOXO3A gene. It is the variation in single sections of that gene (single nucleotide polymorphisms) which are important. ... As we better understand which of these SNPs are key for longevity, you'll be able to test for them with personal DNA tests or whole genome sequencing. ... The FOXO3A gene codes for the FOXO3A protein. If we figure out how longevity variants of FOXO3A change the protein (in its form, frequency, etc) we could then produce drugs that replicate that change and give our bodies long life."

Link: http://singularityhub.com/2010/02/19/want-to-live-forever-better-hope-you-have-the-right-foxo3a-gene/

The two greatest practical hurdles to cryonics are organizational in nature, not technology problems. Firstly to overcome inertia and do the work necessary to sign up as a member of one of the cryonics providers, and secondly to evade all the potential issues and problems that might occur at the time of suspension. This is particularly challenging if death comes unexpectedly, but the cautionary tale I link to here illustrates another common problem. What if your relatives decide to overrule your wishes once you are no longer capable of enforcing your original decision? "In 2006, [Mary Robbins] signed documents giving the Alcor Life Extension Foundation of Scottsdale, Ariz., the right to cryogenically preserve her head and brain. She also agreed to give the nonprofit foundation a $50,000 annuity to cover preservation costs. Her daughter, Darlene Robbins, said her mother changed her mind in her last days because of the procedures that preservation would have required before she died, including tubes in her throat and nose, intravenous lines and medications. Mary Robbins signed new paperwork that would give her family the annuity, the daughter said ... Eric Bentley, an attorney for Alcor, said Mary Robbins didn't sign a written notice rescinding the 2006 agreement. He said Alcor wants to honor the wishes she expressed in that document." From the outside, this looks a lot like the family decided that they wanted that $50,000, and to hell with Mary Robbin's desires - but we will never know for sure. Those folk signed up for cryonics should learn from these events, and adjust their own arrangements accordingly.

Link: http://www.huffingtonpost.com/2010/02/21/mary-robbins-family-battl_n_470718.html

Cancer stem cell theories offers the prospect that various types of cancer spawn from characteristic stem-cell-like initial populations. Cancer exists because random mutations that occur in our cells as a result of damage and age will eventually produce one of these prolific and damaging cell types, possibly by damaging an existing adult stem cell, or possibly by radically mutating a normal somatic cell. Cancer stem cells are hard to eradicate completely through old-style chemotherapy, radiotherapy, or surgery, which is why cancers tend to recur - all it takes is one remaining errant stem cell to rebuild the cancer anew. But the nature of cancer stem cells also means that they are the weak link: destroy them and the cancer cannot survive. Fortunately, identifying and safely destroying specific cell types based on their biochemical differences is a core focus for biotechnology research these days. This is one of the reasons I am confident that my generation will not suffer greatly from cancer in later life: the cancer-killing therapies of three decades from now will be very safe, very effective, and very cheap.

On this topic, I noticed a few recent articles on cancer stem cell research and development today, and thought I would share.

Possible Prostate Cancer Culprit:

"Think about cancer as a disease of stem cells," said study coauthor Owen Witte, a Howard Hughes Medical Institute investigator at the University of California, Los Angeles. Mutations in these cells can cause "normal stem cells to lose their regularized behavior and instead turn into an incipient cancer," he said. Like many other tissues in the body, prostate tissue is made up of several different kinds of cells, including a class called basal stem cells. Normally these cells divide to replenish prostate tissue, but sometimes they become cancerous. Instead of producing normal cells, these stem cells lead to tumors.

$11.5 million NIH Center grant funds novel cancer stem cell research:

"Targeting cancer stem cells, rather than cancer cells, is a completely new strategy for treating cancer," said Dr. Stephen Wong, director of the Center for Bioengineering and Informatics at The Methodist Hospital Research Institute and principal investigator for the grant study. "By attacking the cancer stem cell, we hope to eliminate cancer’s ability to grow, recur or metastasize."

Researchers identify a potential therapeutic target for brain cancer:

Recent studies have increased our understanding of cancer by elucidating some of the differences that exist between tumor cells among patients and even between distinct subsets of tumor cells within the same patient. Evidence suggests there are subgroups of cells - called cancer stem cells or tumor initiating cells - within tumors that are harder to kill with current therapies than other cells within these tumors. Cancer stem cells may in fact be more important to destroy than non-cancer stem cells because they may be responsible for metastasis and for tumor recurrence after therapy. Identifying therapies which specifically target cancer stem cells therefore hold great promise for effective and lasting treatment.

The original paper for that last item makes for interesting reading. You should take a look. But of course things are never as simple as we'd like them to be. Cancer stem cells may not be at the base of all cancers, and there are strong arguments that might lead us to expect this to be the case. This final article from earlier in the month delves into some of these complications.

Dissecting Cancer Stem Cell Theories:

The stochastic, or clonal evolution, model dictates that, "despite the heterogeneity (in cancer), cells of many different phenotypes are capable of proliferating extensively and forming new tumors," Dr. Morrison summarized. The cancer stem cell model, in contrast, says that "cancer stem cells are uniquely capable of proliferating extensively and forming new tumors, and that they go through an aberrant process of differentiation giving rise to phenotypically diverse cancer cells with a limited capacity to divide." Which of these two theories is correct seems to depend upon the type of cancer.

From the Economist: "The great hope of transplant surgeons is that they will, one day, be able to order replacement body parts on demand. At the moment, a patient may wait months, sometimes years, for an organ from a suitable donor. During that time his condition may worsen. He may even die. The ability to make organs as they are needed would not only relieve suffering but also save lives. And that possibility may be closer with the arrival of the first commercial 3D bio-printer for manufacturing human tissue and organs. The new machine, which costs around $200,000, has been developed by Organovo, a company in San Diego that specialises in regenerative medicine, and Invetech, an engineering and automation firm in Melbourne, Australia. ... The first production models will soon be delivered to research groups which [are] studying ways to produce tissue and organs for repair and replacement. At present much of this work is done by hand or by adapting existing instruments and devices. To start with, only simple tissues, such as skin, muscle and short stretches of blood vessels, will be made [and] these will be for research purposes. ... the company expects that within five years, once clinical trials are complete, the printers will produce blood vessels for use as grafts in bypass surgery. With more research it should be possible to produce bigger, more complex body parts. Because the machines have the ability to make branched tubes, the technology could, for example, be used to create the networks of blood vessels needed to sustain larger printed organs, like kidneys, livers and hearts."

Link: http://www.economist.com/science-technology/displaystory.cfm?story_id=15543683

From the Immortality Institute: "Five years ago began one of the most interesting collaborative research projects in the anti-aging field. The concept was bioremediation of indigestible metabolic byproducts in order to improve the health and functioning of human cells. It is well known that these byproducts are prevalent in cases of Alzheimer's (amyloid beta and tau proteins) and heart disease (7 ketocholesterol) among many other age-related diseases. For whatever evolutionary reason, the human body does not produce enzymes to break down this 'junk'. Aubrey de Grey of the SENS Foundation theorized that out in the wilds of nature there must be some bacteria that break down this junk. ... The SENS Foundation put out a call around the world for interested longevity-minded people to send in soil samples. Immortality Institute members responded, enthusiastically sending in hundreds of samples from gardens, forests, deserts, and swamps. The tale of cooperation and outreach is preserved in this Imminst forum. The research was also the subject of an Imminst Sunday Evening Chat in 2007. ... Since the call went out, researcher John Schloendorn and several other Immortality Institute members [have] been testing the soil samples for bacterial enzymes that could break down the plaques and other junk. A multitude of bacteria were tested on the various types of cellular and extra-cellular junk to see which ones would thrive. Several bacteria were up to the job."

Link: http://imminst.org/archive/articles/soil-sens

I have written on the topic of mitochondrial uncoupling in the past, so back into the archives we go for a quick summary:

Mitochondria are the power plants of your cells: they toil to turn food into ATP, used as fuel by the cell. In recent years, the eye of the research community has turned towards the process of mitochondrial uncoupling, whereby the processing of food is uncoupled from the generation of ATP. The result is less ATP and more energy in the form of heat - this is a part of the temperature regulation process in mammals, for example. It also appears to be important in calorie restriction, and therefore possibly important to longevity and aging.

Research is still in full swing, however, and the vision of how mitochondrial uncoupling fits into the big picture of metabolism and aging is present incomplete. A number of natural uncoupling proteins (such as UCP1, UCP2, and UCP3) as well as manufactured uncoupling drugs like DNP have been investigated with contradictory results.

Some groups have demonstrated extension of life span through alteration of mitochondrial uncoupling in laboratory animals, while others have not. Here is a recent paper:

The discovery of novel uncoupling proteins (UCP2 and UCP3) over 10 years ago heralded a new era of research in mitochondrial uncoupling in a diverse range of tissues. Despite the research vigor, debate stills surrounds the exact function of these uncoupling proteins. For example, the level of uncoupling, the mechanism and mode of action are all under-appreciated at this point in time.

Our recent work has used genetic mouse models to focus on the physiological relevance of UCP2. We have used these mouse models to better appreciate the role UCP2 in human health and disease. In this review we focus on new research showing that UCP2 promotes longevity by shifting a given cell towards fatty acid fuel utilization. This metabolic hypothesis underlying UCP2-dependent longevity suggests that UCP2 is critically positioned to maintain fatty acid oxidation and restrict subsequent oxidative damage allowing sustained mitochondrial oxidative capacity and mitochondrial biogenesis. These mechanisms converge within the cell to boost cell function and metabolism and the net result promotes healthy aging and increased lifespan.

Most views of aging and metabolism that involve mitochondrial function boil down to modes of operation for the mitochondria that produce less biochemical damage over time. This is a very common theme, leaning on the mitochondrial free radical theory of aging. It is yet another reason to focus more resources on bringing mitochondrial repair from the laboratory to the clinic. Repair of damaged mitochondria throughout the body should have a far greater effect on longevity than any change to metabolism that merely slows the accumulation of damage - and such repair technologies are comparatively close to fruition.

Andrews ZB (2010). Uncoupling Protein-2 and the Potential Link Between Metabolism and Longevity. Current aging science PMID: 20158496

Via the Alcor News blog, I see that this cryonics provider has openings for a technical coordinator and readiness coordinator: "The Alcor Life Extension Foundation, a 501(c)3 non-profit scientific and research organization, currently has an immediate opening for a Technical Coordinator at our Scottsdale, Arizona, facility. The Technical Coordinator is responsible for maintaining and operating equipment necessary to perform cryopreservation of humans in the field of cryonics. Cryonics is the experimental practice of using ultra-cold temperatures to preserve human life in a state that may be recoverable by future medicine. For four decades Alcor has developed and implemented innovative techniques in the field of cryonics. These techniques involve a combination of experimental interventions and conventional medical skills. ... The Readiness Coordinator will work with Alcor's Transport Coordinator in arranging and performing standbys, postmortem stabilization, and transport of Alcor patients to Alcor's cryopreservation facility in Scottsdale, Arizona. The Readiness Coordinator will also be responsible for purchasing, inventorying, and otherwise maintaining supplies and equipment necessary for cryonics procedures at remote locations and at Alcor's Scottsdale facility. Additionally the Readiness Coordinator will participate in training and outfitting of regional groups in the United States and other countries who assist with stabilization and transport of Alcor patients."

Link: http://www.alcor.org/jobs.html

From Depressed Metabolism: "There are various competing strategies how to achieve meaningful life extension or rejuvenation, including, but not limited to, genetic manipulation, periodical elimination of damage, caloric restriction, molecular nanotechnology and mind uploading. A useful review of these strategies has been published in the book The Scientific Conquest of Death: Essays on Infinite Lifespans (2004) by the Immortality Institute. Most people will recognize that these strategies are not mutually exclusive. Some of them can be practiced right now (e.g., caloric restriction) and others ( e.g., periodical elimination of damage) could serve as a bridge to more comprehensive interventions such as a comprehensive genetic overhaul of human biology. As has often been recognized on this website, cryonics holds a special place among life extension strategies because it enables one to benefit from progress in the biomedical sciences that may not occur during one's lifetime. We would like to think we can escape death by jumping from one successful biomedical innovation to another and that, of course, all the good things will happen in our lifetime, but reality often interferes with such optimism."

Link: http://www.depressedmetabolism.com/2010/02/16/the-science-of-personal-survival/

I notice that the Science Network has published a good selection of video interviews with biogerontologists and other folk involved in aging or longevity research. You'll find them in the Diet, Aging, and Metabolism section of the site.

One of the more interesting interviews is with Paul Glenn, the philanthropist behind both the Glenn Foundation for Medical Research and the ongoing establishment of laboratories for longevity science in a number of different research centers. In comparison to researchers, most high net worth folk who fund aging research tend not to speak to the public all that often - which I think is a pity, and also one of the aspects of the funding environment that has to change as we move further into the biotechnology revolution.

You'll also find interviews with Aubrey de Grey, who you should all know well by now, Andrzej Bartke, current holder of the Longevity Mprize for growth hormone receptor knockout mice, and Cynthia Kenyon, who has produced very long-lived nematode worms in the course of her research. There are a range of other interviewees besides; you should take the time to wander through and see what you learn.

Via the Methuselah Foundation Blog, the latest Foundation newsletter has arrived: "Welcome Doug and Jennifer Bailey, Benjamin Ross Hoffman, Alexey Mitko, Daniel Belov, J.F. Groff, Sigefredo de Carvalho Melo, Alexander Benjamin McLin, Jeremy Keller, Manoj Padki and Manisha Kher, and Capt Herbert Humphreys Jr, to The 300. This exclusive group of donors has responded to the Methuselah Foundation challenge to contribute $85 a month for 25 years. They have made the progress you read about in this newsletter possible. ... Your support continues to make progress in the fight against aging possible. The $3.8 million Mprize Fund is a proof of that. Your donations have made several other advances possible. Dave Gobel, CEO and Founder, is continually on the lookout for other organizations to support as they seek to learn, create and produce products that lead to understanding and increasing longevity. After the jump, read the Methuselah success stories on the Undergraduate Research Initiative, the Supercentenarian Research Foundation, and Halcyon Molecular. ... Methuselah Foundation takes its role as a catalyst very seriously. We will continue to seek out promising work and support worthwhile efforts with your help."

Link: http://blog.methuselahfoundation.org/2010/02/methuselah_foundation_newslett_6.html

Wired notes the challenges inherent in any present study of a potential life-extending therapy in humans: "Longevity is one of the hottest areas of science, but there's a curious hole in the research: Scientifically speaking, nobody knows how to measure aging, much less predict reliably how people will respond to time's ravages. ... Unlike models of drug development for the diseases of aging, which have consensus endpoints to evaluate, we have not reached a consensus in aging. We don't know how to predict how someone will function later in life, and we need to. ... That such a basic gap exists seems counterintuitive. After all, longevity-enhancing research has never been so prominent. ... We need to have a set of thousands of people, representing all groups, that are closely followed on health measures. They'd be tested three or four times a year, for five or 10 years. Then you'd have a good sense of the trajectory of aging ... people enrolled in the proposed study could, after several years, opt to take rapamycin. That would let researchers see whether it works in people as it does in mice. If so, they'd also have a detailed account of resulting gene and protein changes, and insight into whether rapamycin works better in some people than others. ... But take rapamycin out of the equation, and a long-term study of aging biomarkers would be suitable for institutional funding. Of course, it would still be expensive. But even a long-term study of aging in rodents would be useful, and it would also be more affordable. ... If we had a set of biomarkers that at 12 months of age predicted which mice would die younger or older, then we could shorten mouse studies to 12 months."

Link: http://www.wired.com/wiredscience/2010/02/ultimate-aging-study/

One of the nice things about writing online is that if you procrastinate on a topic for long enough, someone else will write that post for you. Often it will be far better than the one you would have turned out, had you been more motivated. The topic for today, and one I've been meaning to discuss for a while, is what happens to science when it passes through the mangler of journalism; in particular, what happens to aging and longevity science. Let me point you to a well-written reminder that professional journalists are known to write spectacularly dumb, inaccurate, and misleading articles on aging research:

Recent work in Newcastle, UK and at the University of Ulm, Germany has been toted as discovering the "secrets to aging" but is really just another small step in understanding why our bodies wear down. The research was published in the journal Molecular Systems Biology, picked up by the Telegraph and then redistributed by the usual lot of copy and paste news feeds. Using human cells, mouse cells and computer simulations, the British-German team explored the mechanism that produces cell senescence - the state in which a cell stops dividing and eventually dies. They found a certain protein pathway was responsible for cells with damaged DNA becoming senescent. That’s a cool bit of science, but it’s not the “secret to aging” and its lightyears from a cure for aging. Unfortunately, journalists can’t sell “scientists take another steady step in large complex problem that may not be solved for decades”, so we’re left with an over-hyped, misunderstood development. Which is a shame, because the Newcastle-Ulm group actually made some interesting discoveries.

Reading mainstream or popular science coverage is a skill, much like reading the scientific journals, though possibly a little easier. You really have to learn how to sift the nonsense from the responsible coverage, and then how to use that responsible coverage to determine what the latest news actually means.

But let us look at the actual paper. You might recall that increasing numbers of senescent cells are one cause of aging; they don't behave well, and secrete biochemicals that cause further disruption in surrounding tissues. The paper's authors suggest that senescence may be largely the result of mitochondrial DNA damage and resulting mitochondrial dysfunction - which would be good, if that is indeed the case. Collapsing two root causes of aging down into one would improve the odds of attaining rejuvenation technologies within our lifetimes, though old people would still no doubt need their existing senescent cell populations cleared out.

The bottom line here is this:

Importantly, our results show that interventions against individual components of the senescent phenotype (e.g. ROS production) are possible in deep senescence. Even if these interventions do not rescue the growth arrest phenotype, they can ameliorate the phenotypic impact of senescent cells onto their microenvironment (the 'bystander effect'). There is a preliminary evidence that ‘anti-senescence’ interventions have potential to delay aging. However, interventions upstream of the cell cycle checkpoint machinery may significantly increase cancer risk.

That last point is important, as senescence is the evolutionary counterbalance to the rising risk of cancer with age. But it will become much less important with time, as cancer therapies become very powerful, safe, and efficient - and very cheap, shortly thereafter.

Passos, J., Nelson, G., Wang, C., Richter, T., Simillion, C., Proctor, C., Miwa, S., Olijslagers, S., Hallinan, J., Wipat, A., Saretzki, G., Rudolph, K., Kirkwood, T., & von Zglinicki, T. (2010). Feedback between p21 and reactive oxygen production is necessary for cell senescence Molecular Systems Biology, 6 DOI: 10.1038/msb.2010.5

One of the most common instinctive (and wrong) objections to engineering far longer healthy lives is the belief that we would become bored of life. But even a few moments of thought, as in this post at the IEET blog, will show how ridiculous an idea that is: "What would you do with all of that time? Wouldn't you get bored? What would you do? I asked myself those questions and realized that right now I feel impossibly rushed. There is so much life to experience, in so many ways that I feel compelled to try and do everything at once. Some people spend their teens and twenties partying and living paycheck to paycheck in a visceral, hedonistic, perpetual Bacchanalia of youth. Others cloister themselves away in libraries and academia to emerge in their late twenties/early thirties as The Next Big Thing in their field, granting them a position of influence for decades to come. Others travel, seeing the world, discovering who they want to be and meeting their fellow human beings. Still others start their careers, steadily moving up the ranks and in the process have the financial stability to settle down and have a family. Yet for everyone of these potential ways of living comes at a cost of all the others. The very process of aging forces a choice. But what if I didn’t have to choose because I wasn't aging? What if raising a family didn't take half of my adult life, but barely a tenth of it?"

Link: http://ieet.org/index.php/IEET/more/munkittrick20100216/

The bio page for Aubrey de Grey at the Manhattan Beach Project website includes a ten minute video presentation on the contribution of mitochondrial damage to aging, and how to reverse it. You should take a look: "Aubrey's indepth presentation to a roomful of scientists gathered at the Manhattan Beach Project, [which] includes an update on his mitochondrial free-radical theory of aging and a description of how regenerative medicine may be able to thwart the aging process altogether." You might also want to read up on the MitoSENS research program at the SENS Foundation website: "Mitochondria are very complex; they contain about a thousand different kinds of protein, each encoded by a different gene. But nearly all of those genes are not in the mitochondrial DNA at all - they are in the nucleus! ... Only 13 of the mitochondrion's component proteins are still encoded by its own DNA, and it's therefore only these 13 genes that remain vulnerable to the constant assault from free radicals produced during respiration (the life-giving reaction of oxygen and food by the mitochondria). This gives us a wonderful opportunity: rather than fixing mitochondrial mutations, we can make them harmless to us. By putting 'backup copies' of these few remaining genes into the nucleus, we can prevent the harm caused by any mutations that may occur of the original versions."

Link: http://www.manhattanbeachproject.com/Bio/Aubrey-de-Grey.htm

An article on a human study of alternate day fasting is doing the rounds. Studies of intermittent fasting in animals are divided: on the one hand, the beneficial effects on health and longevity look a lot like those produced by straight calorie restriction; on the other hand, there are differences in gene expression and other line items that might be significant. From the article: "Fasting every other day may be a way to live longer as well as lose weight. It may also lower the risk of conditions such as heart disease and cancer, as well as ease symptoms of chronic ailments. Research suggests that calorie restriction, especially alternate-day fasting, has effects beyond those of simple weight loss, and a trial at the University of California has been investigating the long-term effects of fasting. ... After eight weeks of alternate-day fasting we saw that bad cholesterol was down, along with reductions in triglycerides [fat found in blood], blood pressure and heart rates. And since these are all key risk indicators of heart disease, it may not only help people lose weight but also help them decrease their risk of coronary events. ... One mechanism that has been investigated is that fasting triggers a gene whose job is to promote survival by protecting cells during times when food is scarce. Researchers say it helps repair the damage done by free radicals and prevents cells from dying prematurely, as well as lowering inflammation. The gene can also slow the ageing process by reducing the risk of age-related diseases and health threats."

Link: http://www.dailymail.co.uk/health/article-1250798/How-fasting-help-slow-ageing-process.html

If we miss out on the forthcoming technologies of rejuvenation, then it will be by only a handful of years - and that will be our fault for focusing on other matters and not getting the job done more rapidly. From Psychology Today, an opposing point of view: a skeptic who is doubtful that he will see rapid advances in his lifetime because advances in the past have been slow. "A look at cancer advances over the last 60 years - my current lifespan - is not encouraging. Research on cancer occupies much of the same intellectual terrain as longevity and anti-aging research. Put simply, cancer research primarily looks at why new cell production goes bad, which is also at the center of many of the theories of aging. If we can ensure the continued new production of healthy cells, the reasoning goes, we are on the road to defeating aging. But a recent article in the New York Times, 'As Other Death Rates Fall, Cancer's Scarcely Moves' (April 24, 2009), underlines how little progress there has been against cancer in my lifetime. Although death rates have plummeted for heart disease, stroke, influenza, and pneumonia, for cancer they have barely moved." This might be thought of as the anti-singularity viewpoint - denying that progress is accelerating, and expecting linear change in the future based on a sample of the past. It is almost certainly wrong, but sadly prevalent.

Link: http://www.psychologytoday.com/blog/adventures-in-old-age/201002/immortailty-are-we-the-last-generation-not-live-forever

Ouroboros recently pointed out a fairly new blog on aging and longevity science that I had failed to notice in my wanderings. In my defense, most of the tools for discovering new blog content are so clogged with autospam that it's a wonder anyone can find anything.

I just learned of an excellent new blog - @ging, dedicated to "scientific findings on aging and its underlying mechanisms" ... it’s bilingual in English and Spanish, with almost every article appearing in both languages. Authors Shaday and Layla Michan state their site's mission succinctly as follows: "This space is devoted to analyze and discuss the advances on aging research."

...

The site has been up less than a month; so far, posts have dealt with a wide variety of subject, from demographics to genetics to molecular details of aging. The writing is concise and very readable, in both languages (so far as I can tell; my Spanish is functional but weak). Overall, I’m very favorably impressed. There’s also a great sidebar with links to recent articles in aging-related journals.

You might, for example, take a look at @ging on SIRT3:

SIRT3 is a protein of the sirtuin family that regulates deacetylation of mitochondrial proteins and which has been linked to human longevity. Although the lack of this protein dramatically increases the level of global mitochondrial acetylated proteins, [little] is known about the physiological function of this sirtuin. The first crystal structure of human SIRT3 was reported by the end of last year and during the first two months of the new decade important discoveries have been published regarding the role of SIRT3 in mammals.

Many of the mechanisms associated with the operation of our mitochondria appear to be important to the accumulation of age-related damage and resulting longevity. Mitochondria themselves may be the primary link between metabolism and longevity - the strong correlations between mitochondrial structure and life span between species supports that view, as does the evidence for the mitochondrial free radical theory of aging. The Strategies for Engineered Negligible Senescence (SENS) approach to mitochondria in aging is to engineer away their contribution to degenerative aging. This could be achieved by replacing their DNA every few decades, by replacing just a few crucial genes on the same sort of timeframe, or by shifting some of the mitochondrial DNA into the cell nucleus. This is probably the closest of the SENS programs to some form of meaningful completion, but more work is yet needed.

While we are on the subject of sirtuins and mitochondria, I should also point out today's post from Ouroboros on SIRT3 and what researchers know of its role in mammalian biochemistry.

For those of us of a certain age, the word "bionic" will always be associated with enhanced mechanical limbs. If other organs are bionic, then they had better be devices of chrome and ceramic, electrically powered, and the sort of thing turned out by a high-tech workshop. But the usage of "bionic" or "bionics" in medical technology is much broader than this, and often altered. Consider, for example, that a living, beating, recellularized heart is just as much an artificial, engineered construct as the latest type of electromechanical heart replacements being tested today. Under the dictionary definition of bionic, both of these items are bionic technologies.

On this topic, and via researcher Leonid Gavrilov's blog, I see that one of the folk involved in recellularization work likes the use of the term "bionic" for what he is doing:

"Bionics in medicine of the future" - this is the title of a public lecture by Spanish transplantologist Paolo Macchiarini, which will be held on February 24, 2010 in the conference hall of the rector's building of the Sechenov Moscow Medical Academy. The lecture is organized by Dmitry Zimin foundation "Dynasty", in collaboration with research foundation "Science for life extension", at whose invitation Paolo Macchiarini will visit Russia for the first time.

...

In 2008, Professor Macchiarini led an international team of scientists who performed the transplantation of patient trachea grown out of her own stem cells on donor scaffold in bioreactor. Four days later the trachea has taken root so well, that it was difficult to distinguish it from adjacent sections of the respiratory tract. Just a month later, this trachea brought up its own network of blood supply.

Another unique operation was held in October 2009 - this time the organ was formed inside the patient's body without the use of bioreactor.

Professor Macchiarini is convinced that the regeneration of organs, the formation of an entire organ or a part of it inside the human body can solve almost all problems that modern medicine still can not resolve. In his opinion, this will become possible very soon - within five years. In order to do this, we must create an infrastructure that would integrate scientific research in this area with medical practice. That is he is actively engaged in, promoting achievements and opportunities of regenerative medicine, as a scientist and a surgeon in one person.

If you're of a mind to read scientific papers, you might look up Macchiarini's publications on PubMed and dig in. His proposed timeline is enthusiastic, but for transplants involving recellularization of simpler organs like the heart or trachea, probably on the ball. The roadblocks here are regulatory bodies, as is always the case, and the fact that a donor organ is still required.

Via CryoNet, the announcement of a conference to be held in Florida in April: "Cryonics technology is more advanced than even most signed up cryonicists realize. But most people in the scientific community do not realize the progress that has been made. Indeed, most cryonicists do not realize the protocols and technologies that have been developed in the service of making cryonics a true 'evidence based technology.' ... Details of cryonics process from start to finish. Confirmed presenters include Aaron Drake, Alcor Transport Director, Ben Best, Cryonics Institute President, and Catherine Baldwin, General Manager of Suspended Animation, Inc. ... Suspended Animation, Inc. protocols and technology, now available for members of both CI and Alcor. ... A Refresher course for medical professionals and first responders, including the existing Brevard County Medical Team who will be attending. ... Details of Alcor and CI protocols, procedures, and logistics. ... Who is invited: Cryonicists and potential cryonicists of all types, especially skeptics who have been on the sidelines waiting for the technology to mature, and medical specialists."

Link: http://www.cryonet.org/cgi-bin/dsp.cgi?msg=32381

Numerous research groups around the world are working to build organs from a patient's own cells. Here is one that is illustrative of many: "Researchers at one of the country's leading tissue engineering laboratories are crafting tomorrow's medicine so doctors can replace worn-out body parts with lab-grown organs. Dr. Francois Auger and his team are growing human skin - it's their specialty. They have several other body parts under construction including blood vessels, corneas, ligaments, lungs and bladders. 'This is the medicine of the 21st century,' Auger said in an interview at his brand new laboratory next to the Enfant-Jesus hospital in Quebec City. ... Although this sounds like science fiction, Auger asserts in a few decades, it will be a reality to repair organs or to reconstruct new ones on demand. 'In 50 to 100 years from now, it won't be science fiction. We'll be able to regrow a hand. It's going to be very demanding, very expensive and maybe take a few weeks. But wow, think about it.' In the nearer future, in 20 to 30 years, he believes tissue engineers will be able to regrow a breast for women suffering from breast cancer." Techniques such as recellularization may lead to much more rapid progress than this projected timeline.

Link: http://www.vancouversun.com/health/health/2536736/story.html

Transparency in fundraising and early stage research is the wave of the future. Young biotechnologists - and especially those in the open source biology movement - should be out there blogging their ongoing work, itemizing their costs, and engaging in microscale fundraising.

These days many people could start a company if they wanted to. Direct costs (not opportunity costs, founder labor, etc) for the sort of low capital investment entrepreneurial ventures that catch all the attention are in the $5-20,000 range. That is roughly the amount of money taken to answer the question "is this worth chasing any further?"

Similarly, many people could fund the answer to an important piece of scientific research if they so desired. Biotechnology is cheap nowadays, and only getting cheaper as time advances. The range of $5-20,000 will buy you a postgrad who knows what he's doing and lab access for long enough to answer an interesting question or produce a proof of principle - roughly the same as "is this worth chasing any further?" Can you use lasers to destroy lipofuscin inside cells, for example, or indeed many of the projects approved for the SENS Foundation undergraduate academic initiative.

The business models for running this sort of low-cost production of results in other fields of endeavor, such as writing or software development, are becoming well established. But scientific research lags, for all that grassroots groups are pointing the way forward:

the longevity science grassroots centered at the Immortality Institute have successfully raised $8,000 to fund research into laser ablation of lipofuscin. Those funds will be matched up to $16,000 at the SENS Foundation and put towards work on a method of eliminating one form of damaging metabolic byproducts that build up with age

Livly is a research collaboration that is taking steps in the right direction. It is a non-profit development of granulocyte cancer therapies set in Silicon Valley, and which comports itself somewhat like a web technology startup. Take a look at their website - you'll see what I mean if you're familiar with the California startup attitude to engagement and information. If the Livly founders can pull that off - openness, transparency, endeavor, and success in a life science field - it will be a promising sign of what is to come.

At some point, the culture of the scientific establishment that sets a wall between the public and fundraising activities has to change. As ever more areas of biotechnology become so cheap that anyone with a will and a goal can pitch in, the priesthood of science must adapt or wither away. Researchers who fail to issue regular updates on what they are doing will be out-evolved by a new breed of folk who keep their funding circle close, engaged, and up to date. Grant writing will fade in importance in comparison to revenue models tried and tested in other field: subscriptions for access, ransoms, support through early commercialization of side-products, and a hundred other widely used methods of fundraising or generating revenue. This is the future of biotechnology and applied life science research - less of the ivory tower and much more from entities that look just like associations, companies, and non-profits.

I believe in supporting those folk who are heading in the right direction. For all that the future I've described above is inevitable, it's late in arriving. Those who are leading the way should be encouraged and helped. So that said, go and take a look at Livly's fundraising and community support page: you'll see that they're itemizing their laboratory wishlist and the costs of equipment. You might read the h+ magazine article on Livly to see how they're keeping costs down and hacking together their own biotech apparatus. Itemizing costs in this way and encouraging supporters to step in is a small step towards what I would regard as meaningful levels of transparency, but it is something I'd like to see more of from all of the research-related organizations I support. Both Methuselah Foundation and SENS Foundation could learn from this, for example.

So I donated $600 to Livly today, and suggested they to use it to hack together a spectrophotometer for their synthetic biology lab. I encourage you pick an item and do the same. As for Livly, I encourage the founders to expand their efforts in generating transparency in both their work and their fundraising.

From the Telegraph: The Gene Therapy Advisory Committee (GTAC) - the ethics body for stem cell clinical trials - has given the research the green light following months of delay. Following the approval, ReNeuron will start the world's first trial of injecting stem cells into patients' brains in the hope they will repair areas damaged by stroke and improve both mental and physical function. ... ReNeuron was first granted permission to conduct the trial by the Medicines and Healthcare Regulatory Agency last January, but needed a recommendation from the GTAC before it could start the Phase 1 clinical trial. A year later, the company has been given the go-ahead and the first of twelve stroke patients is expected to receive treatment in Scotland later this year. Michael Hunt, ReNeuron chief executive, said the approval represented 'the culmination of many months of work'." This is an apt illustration of why it requires so much time and money to bring new medical technology to the clinic - it's the regulators who cause the loss of a year here and a few years there, not the challenges of research and development.

Link: http://www.telegraph.co.uk/finance/newsbysector/pharmaceuticalsandchemicals/7206321/ReNeuron-stem-cell-trial-gets-go-ahead.html

Via Nanowerk: researchers have "developed a fast and cost-efficient method for producing sufficient amounts of bone and cartilage tissue using the body's own cells ... Damage to larger joints such as knees, feet, hips and shoulders is often the beginning of a painful process during which mobility continues to decrease. Because cartilage cannot regenerate after the body has stopped growing, defects caused by injuries and 'wear and tear' cannot be absorbed by producing new cartilage. Genetic engineering and molecular biology have now made it possible to remove healthy cartilage cells and grow these outside the body in special solutions. This cartilage tissue is then applied to the defective cartilage where it attaches and grows. Repairing cartilage and bone damage using the body's own cells is still a difficult process. Cultivating the body's own tissue is still time-consuming and expensive, and much time is needed until the implant has reached its desired functionality. [Researchers now] present a strategy for the 'de novo engineering' of cartilage and bone tissue which requires only three weeks."

Link: http://www.nanowerk.com/news/newsid=14808.php

I think that this news is illustrative of a slow shift that is taking place in the culture of aging research. It now acceptable - and more importantly fundable - for researchers to talk openly about slowing or reversing aspects of aging: "Leading neuroscientists gathered in Dallas last week to discuss recent major findings about the aging brain and to celebrate the launch of the UT Dallas Center for Vital Longevity ... The Center for Vital Longevity is a research center focused on understanding and expanding the capacity of the aging mind. Center researchers use cutting edge brain imaging technologies and advances in cognitive science to understand (a) how the brain changes from young to old adulthood; (b) the consequences of neural aging for everyday function; and (c) what interventions show promise for slowing cognitive aging. ... Denise Park, Ph.D. focuses her research program on understanding how the mind changes and adapts as we age. She is interested not only in the function of the mind and brain, but in determining whether stimulation can maintain the health of the aging brain." The mainstream will slowly catch up to where advocates of the Strategies for Engineered Negligible Senescence have been for a decade: that working to defeat aging is plausible, possible, and what we should be doing.

Link: http://www.utdallas.edu/news/2010/2/11-941_Event-Marks-Launch-of-Center-for-Vital-Longevity_article.html

Researchers continue to offer their thoughts and predictions on how greatly they expect the practice of calorie restriction to extend life in humans. The consensus seems to be "not as much as in mice," but a range of arguments are used to arrive at that position. Here is one of them: "Although it has been known since 1917 that calorie restriction (CR) decelerates aging, the topic remains highly controversial. What might be the reason? Here I discuss that the anti-aging effect of CR rules out accumulation of DNA damage and failure of maintenance as a cause of aging. Instead, it suggests that aging is driven in part by the nutrient-sensing TOR (target of rapamycin) network. CR deactivates the TOR pathway, thus slowing aging and delaying diseases of aging. Humans are not an exception and CR must increase both maximal and healthy lifespan in humans to the same degree as it does in other mammals. Unlike mice, however, humans benefit from medical care, which prolongs lifespan despite accelerated aging in non-restricted individuals. Therefore in humans the effect of CR may be somewhat blunted. Still how much does CR extend human lifespan? And could this extension be surpassed by gerosuppressants such as rapamycin?"

Link: http://www.ncbi.nlm.nih.gov/pubmed/20139716

TIME Magazine is running a collection of articles on the most mainstream of longevity research - such items as centenarian studies, the search for human longevity genes, and efforts to slow aging through calorie restriction or calorie restriction mimetic drugs. On the one hand, I'm always pleased to see more attention given to longevity science or the practice of calorie restriction. On the other hand, and as is usual in the most popular of the popular press, the authors are oblivious to the important distinction between slowing and reversing aging. That state of affairs is something that we advocates need to work on, as the only research strategies likely to produce rejuvenation medicine that will meaningfully help us when we are old are those based on reversing aging, such as the SENS proposals.

It is likely to be easier and less costly to produce rejuvenation therapies than to produce a reliable and significant slowing of aging. A rejuvenation therapy doesn't require a whole new metabolism to be engineered, tested, and understood - it requires that we revert clearly identified changes to return to a metabolic model that we know works, as it's used by a few billion young people already. Those rejuvenation therapies will be far more effective than slowing aging in terms of additional years gained, since you can keep coming back to use them again and again. They will also help the aged, who are not helped at all by a therapy that merely slows aging.

But so far as most people are concerned, longevity science presently means studying old people, finding genes associated with small differences in human life expectancy, or working on drugs that modestly slow down aging - no more than calorie restriction or exercise can already achieve. This work will probably lead to some new knowledge that will help efforts to reverse aging, but I very much doubt it will lead to significant extension of human life spans within the lifetime of people who are middle aged now. That said, here are a couple of quotes from the TIME articles:

How to Live to 100

Most people today fall prey to chronic diseases that strike in mid to late life - conditions such as cancer, heart disease, stroke and dementia - and end up nursing disabilities stemming from these illnesses for the remainder of their lives. Centenarians, on the other hand, appear to be remarkably resilient when it comes to shrugging off such ailments; they seem to draw on some reserve that allows them to bounce back from health problems and remain relatively hale until their final days.

Eat Less, Live Longer

Anytime you go on a diet, after all, you stand a good chance of lowering your blood pressure, cholesterol level and risk of diabetes and other health woes. All that can translate into extra years. With calorie restriction - usually defined as a diet with 25% to 30% fewer calories than normal but still containing essential nutrients - something else appears to be at work to extend longevity. Finding out what that something is - and determining if it works in people - is what [the CALERIE study] is all about. By putting people on a carefully reduced diet for two years, investigators hope to home in on the biological mechanism that links eating less to living longer.

Researcher Chris Patil of Ouroboros recently posted a skeptics' view of modern cryonics:

I’m a cryonics skeptic of the "extraordinary claims require extraordinary evidence" flavor. As I’ve said before, I suspect that long-term preservation of the potential for life by freezing or other means is physically possible, but at present I don’t think we’re making any significant progress in that direction.

It wasn't clear to me from his post whether he was aware of the state of the art in vitrification of tissues at low temperature without ice formation; those who write within the cryonics community are careful to distinguish between vitrification and freezing, which are two quite different things. Suppressing the formation of ice crystals at low temperatures is key to preserving the sort of fine structure in the brain that encodes the data that is the human mind. I said as much in the Longevity Meme news, and Patil later let me know via email that, yes, he is aware of vitrification, but not convinced that the evidence shows it does preserve fine structure sufficiently well at the present state of development. On that we can differ.

However, I do agree that, for all the sterling efforts of the folk at 21st Century Medicine and other groups, progress is slow in this field. It's the standard story of too few dedicated people and too little money. That is something that I believe is best changed through the development of profitable side-lines based on technologies developed for cryonics, such as the use of vitrification for tissue storage, for example. But the state of cryonics as an industry and a community is a whole separate post.

Over at Depressed Metabolism, I see that Aschwin de Wolf has penned a response to Patil's post:

The biology-of-aging blog Ouroboros has posted a skeptical post about cryonics that is highly representative of how most biological scientists respond to questions about cryonics. The discussion of cryonics is largely reduced to a discussion of the technical feasibility of suspended animation and resuscitation requirements. But suspended animation is not cryonics. Cryonics should be discussed in the broader context of decision making under uncertainty. People who have made cryonics arrangements are more than aware that contemporary science is not able to vitrify and resuscitate a complex organism. To them the central question is whether we can reasonably expect that future technologies will be able to repair the injury that is produced by contemporary cryopreservation technologies and rejuvenate the patient.

You should read the full text of both posts.

The evolution of aging might be traced all the way back to how dividing cells split up their load of damage and unwanted byproducts. From Ouroboros: "One approach is to distribute everything equally amongst your two offspring. ... A second approach is to give all the crap to one of the two new cells and keep the other one pristine. Lets call these two cells the crap cell and the pristine cell. ... The crap cell (I love this nomenclature) will become inviable sooner under this strategy, but the alternative would be a symmetric division strategy in which all descendants accumulate garbage, ultimately causing the extinction of the entire lineage. ... Both single-celled yeast and mammalian stem cells employ this asymmetric strategy in order to preserve the viability of an indefinitely dividing lineage. ... One of our initial premises was that aggregates are biochemically hard to handle, which is why they accumulate rather than being degraded. But now we know that cells can bundle aggregates onto actin cables and move them around - why not sort the aggregates into vesicles or membrane blebs and dispose of them? Granted, in order to export an aggregate out of the cell, it would have to cross a membrane, but this would be no more difficult topologically than mitophagy. The obvious (and trivial) answer to this question is 'because it didn't evolve that way,' but I'm curious to know whether there's some compelling reason why it couldn't have evolved that way."

Link: http://ouroboros.wordpress.com/2010/02/09/ill-never-be-like-you-daughter-cells-send-toxic-aggregates-back-to-mom/

Published at PLoS Genetics, an unexpected longevity gene: "Expansion of a stretch of glutamines near the amino-terminus of huntingtin (htt), the protein product of the IT15 gene, is a deleterious mutation that causes Huntington's disease (HD). Here we show, in contrast, that deletion of htt's normal polyglutamine stretch (deltaQ-htt) is a potentially beneficial mutation that can ameliorate HD mouse model phenotypes when deltaQ-htt is expressed together with a version of htt with the HD mutation. In addition, deltaQ-htt expression can enhance longevity when expressed in either an HD mouse model or in non–HD mice. deltaQ-htt's effects on both lifespan and HD model phenotypes are likely due to an increase in autophagy, a major recycling pathway in cells that is involved in the turnover of cellular components, and aggregated protein. Based on our results, we suggest that development of therapeutic agents that can stimulate autophagy may help both in treating neurodegenerative disorders like HD and also in increasing longevity."

Link: http://dx.doi.org/10.1371/journal.pgen.1000838

Whilst living in comfort and security amidst plenty unimaginable to their ancestors, Malthusians of the developed world look at the poverty and suffering caused by kleptocratic governances elsewhere, and cry that this is the result of too many people:

[Malthusianism] is, fundamentally, a failure of understanding. It is to look at the undeniably bad situations and unpleasant regions of the world and say "this is because too many people are using too many resources," rather than to see that in fact it's all due to misallocation of existing resources and the failure to develop new resources - a grand procession of waste, corruption, and the inhumanity with which human beings treat one another. These situations are problems that can be solved through development and tearing down corrupt systems of rulership - they are not immutable facts of life that must lead to the deaths of millions.

Despite the occurrence of localized pits of suffering and poverty that last for decades or lifetimes, our broader human culture has benefited from centuries of sustained, accelerating economic and technological growth. This growth is thanks to the incentives put upon people to profit, compete, build better devices, and access new resources. As early as the 18th century, increased longevity went hand in hand with increased population and increased standards of living. Despite this big picture, each new generation spawns devotees of Malthus, each crying out that the sky is falling, that resources will soon run out, that there are too many people. All past Malthusians were wrong, and the present generation is just as wrong; these are people who do not understand how the world works, how development and growth happens, or how people respond to foreseen shortages. In short, economic development and competition ensures that people work to create new resources and makes old ones far more productive in response to demand.

In the early 1800s, there were approximately 980 million human beings on the planet Earth. One of them was the population scaremonger Thomas Malthus, who argued that if too many more people were born then 'premature death would visit mankind' - there would be food shortages, 'epidemics, pestilence and plagues', which would ‘sweep off tens of thousands [of people]’.

...

In 1971 there were approximately 3.6billion human beings on the planet Earth. And at that time Paul Ehrlich, a patron of the Optimum Population Trust and author of a book called The Population Bomb ... He said India couldn’t possibly feed all its people and would experience some kind of collapse around 1980.

Over at Reason Magazine, Ronald Bailey recently examined the work of John Davis and Russell Blackford on Malthusian fears and engineered longevity:

"How dare you do this research? The earth is already being raped by too many people, there is so much garbage, so much pollution."

Ten years ago, an anti-aging researcher described this hostile reaction to her work in the pages of The New York Times. Not much has changed since then. The first objection one hears when one advocates radical life extension is that it will produce a Malthusian Hell of overpopulation and resource depletion. Objectors clearly believe it would be immoral to make it possible for lots of people to live to be, say, 150 years old. But is that so? Two newish papers from two controversial philosophers take on that reasoning, and tear it apart - with the help of their pocket calculators.

You should read the article. Sadly, as Bailey notes, Malthusian opposition to engineering greater human longevity thrives in our cultures. It reveals something unpleasant about human nature that so many of us are willing and ready to call for longevity science to be abandoned, and thus force billions of people to suffer and die as a consequence:

And yet, alongside the ethos of human rights and the development of heroic medicine, contemporary society appears estranged from its own humanity. To put it bluntly: it is difficult to celebrate human life in any meaningful way when people - or at least the growth of the number of people - are regarded as the source of the world’s problems. Alongside today’s respect for human life there is the increasingly popular idea that there is too much human life around, and that it is killing the planet. ... today’s Malthusians share all the old prejudices and in addition they harbour a powerful sense of loathing against the human species itself. Is it any surprise, then, that some of them actually celebrate non-existence? The obsession with natural limits distracts society from the far more creative search for solutions to hunger or poverty or lack of resources.

On that topic, and as a footnote, you might consider looking at some of Blackford's past work on the moral imperative to engineer away suffering and death caused by aging.

An unexpected potential use for embryonic stem (ES) cells: "One of the most auspicious, yet challenging, avenues for combating malignancies is to enlist the immune system to come to the defense of the patient. However, myriad components of the immune system interact in extraordinarily complex ways with active or dormant neoplastic cells, an interaction matrix that is incompletely understood at best. ... [Researchers] reason that exposure of the immune system to novel tumor-associated antigens might boost an otherwise inadequate immune response into an effective antitumor action. What distinguishes the study is the source of these tumor-associated antigens: human ES and iPS cells. Specifically, the study investigated whether vaccination of mice with human ES or iPS cell lines would trigger an enhanced immunological response against shared antigens expressed by the primitive normal cells and the colon carcinoma cell line CT26 ... vaccination of mice with the human ES cell line H9 induced both strong cellular and humoral immune responses against CT26 colon carcinoma. ... There is a certain irony in the fact that human ES cells, which themselves possess many features of neoplastic cells - including sustained telomerase activity, formation of tumors after injection into mice, and infinite growth - would be exploited against cancer. By analogy, it is like fighting fire with fire."

Link: http://www.nature.com/mt/journal/v18/n1/full/mt2009287a.html

Chris Patil of Ouroboros is a cryonics skeptic: "I'm a cryonics skeptic of the 'extraordinary claims require extraordinary evidence' flavor. As I've said before, I suspect that long-term preservation of the potential for life by freezing or other means is physically possible, but at present I don't think we’re making any significant progress in that direction. Part of the problem is that there's very little serious initiative within the mainstream of academia or industry to build the many, many necessary precursor technologies. Another part is that the problem is really, really hard - harder than the comparatively simple but still unsolved problem of maintaining cellular viability within tissues at low temperatures." From reading what he's written, I think he's either out of the loop on the technology of vitrification, or not convinced that present day vitrification methods as used by Alcor are actually going to preserve fine structure in brain cells (i.e. preserve the data that is the mind). I disagree with him on that last point, if that is his view - the evidence clearly points to the viability of vitrification on that count.

Link: http://ouroboros.wordpress.com/2010/02/05/corpsicles-in-the-new-yorker/

Investors Business Daily is running a profile of entrepreneur turned longevity science advocate Dave Kekich, who you might recall was one of the first wave of donors to support the Methuselah Foundation back when it was getting starting. If you'd like to know more about the driving force behind the Maximum Life Foundation and the recent Manhattan Beach Project activities, then take a look.

Dave Kekich Seeks The Fountain Of Youth:

Told that he would never walk again, Kekich sank into hopelessness. "I felt my life had pretty much ended because I was much into the physical aspect of life," he told IBD.

...

Having regained a great deal of lost confidence, Kekich started a venture capital firm in his bedroom. He raised money for entrepreneurs from angel investors and took a few companies public. Over 10 years, he closed about $22 million in venture capital deals. He pocketed millions in income but declines to say exactly how much.

After raising $300,000 for paralysis research over 12 years, Kekich realized that even if he could walk again, he'd "still be faced with all the horrible (side effects) of aging - cancer, heart disease, Alzheimer's," he wrote in his 2009 book, "Life Extension Express."

He figures that 150,000 people in America suffer from spinal cord injuries, but they're dwarfed by the 6.5 billion people who will one day have to contend with old age. So with a few hundred thousand dollars of his own money, he founded the Maximum Life Foundation and moved back to California.

His nonprofit is dedicated to raising money for biotechnology research that will lead to medicine and therapies to reverse aging.

It is an illustrative lesson for those folk who wonder what it is they can contribute to the future of human longevity. Never let it be said that you can't succeed, or can't contribute, or can't find a way to do what you want to do in life. It won't be easy - nothing worthwhile ever is - but what you achieve is almost entirely up to you.

A novel approach to the treatment of age-related bone loss is demonstrated: "An investigational drug that inhibits serotonin synthesis in the gut, administered orally once daily, effectively cured osteoporosis in mice and rats ... Serotonin in the gut has been shown in recent research to stall bone formation. The finding could lead to new therapies that build new bone; most current drugs for osteoporosis can only prevent the breakdown of old bone. ... Prior to this discovery, serotonin was primarily known as a neurotransmitter acting in the brain. Yet, 95 percent of the body's serotonin is found in the gut, where its major function is to inhibit bone formation (the remaining five percent is in the brain, where it regulates mood, among other critical functions). By turning off the intestine's release of serotonin, the team was able, in this new study, to cure osteoporosis in mice that had undergone menopause. ... [Researchers] administered the compound orally, once daily, at a small dose, for up to six weeks to rodents experiencing post-menopausal osteoporosis. Results demonstrated that osteoporosis was prevented from developing, or when already present, could be fully cured. Of critical importance, levels of serotonin were normal in the brain, which indicated that the compound did not enter the general circulation and was unable to cross the blood-brain barrier, thereby avoiding many potential side effects."

Link: http://www.eurekalert.org/pub_releases/2010-02/cumc-isi020110.php

The title of this EurekAlert! release is misleading - this isn't the first identified genetic variant associated with human longevity. But is is nonetheless interesting: scientists "have identified for the first time definitive variants associated with biological ageing in humans. The team analyzed more than 500,000 genetic variations across the entire human genome to identify the variants which are located near a gene called TERC. ... two forms of ageing - chronological ageing i.e. how old you are in years and biological ageing whereby the cells of some individuals are older (or younger) than suggested by their actual age. ... There is accumulating evidence that the risk of age-associated diseases including heart disease and some types of cancers are more closely related to biological rather than chronological age. What we studied are structures called telomeres which are parts of one's chromosomes. Individuals are born with telomeres of certain length and in many cells telomeres shorten as the cells divide and age. Telomere length is therefore considered a marker of biological ageing. In this study what we found was that those individuals carrying a particular genetic variant had shorter telomeres i.e. looked biologically older. ... The effect was quite considerable in those with the variant, equivalent to between 3-4 years of 'biological aging' as measured by telomere length loss."

Link: http://www.eurekalert.org/pub_releases/2010-02/uol-sif020410.php

I notice some thoughts from Colin Farrelly, who came to support as much progress as possible in longevity science from a very different original position to my own:

As a political theorist interested in aging and longevity science, I am in a minority among researchers in the field. The literature on distributive justice, multiculturalism, equality, liberty, deliberative democracy etc. is voluminous and detailed. Little has been written on science and justice, let alone a marginal field of scientific inquiry like biogerontology.

And thus I suspect many theorists think my interest in aging is odd, if not frivolous. When there are so many pressing problems in the world today the idea of fixating on aging has little, if any, intuitive appeal. A fews ago I use to think this same way. But after pondering these questions, learning some biology and following the pace of scientific discovery in the field of aging research, I have come to now hold the view that the stakes at risk in these debates are very important indeed. I would go so far as to suggest that tackling global aging is one of this century's most important challenges. And because very few people see aging as a problem the challenge of tackling aging is an even bigger problem than it would otherwise be if we all saw it for the problem it really is.

We live in a world in which most people don't give much thought to degenerative aging until it happens to them, and once in that unfortunate position, they don't give much thought to what might be done to stop this from happening to everyone. Consider how easy it is for a state-level politician in the US to raise a million dollars from the public at large (done in under a week in some cases that spring to mind) versus how hard it is for even a noted researcher in the field of aging research to do the same. Yet that politician doesn't matter in the grand scheme of things; he cannot create new technology, he will be fat on bribes and gone in a few years, and all his actions will be unimportant in comparison to the daily toll of death and suffering caused by aging:

While you were reading this sentence, a dozen people just died, worldwide.

But people have their hobbies, their sports teams, their politicians. The hundred pressing distractions from grander matters. Beyond the more valid daily concerns relating to putting bread on the table, so very many motivated folk throw themselves into things that will never change the world - which is their choice, and a free society is founded upon the right to choose as you will. But persuade even a fraction of these people to see the scope of age-related death and suffering, and the great potential of medical technology to alleviate these harms within a few decades ... well, then we'd be off to the races. No barrier or limitation can long withstand the attentions of a large and motivated group of humans.

Researchers have been killing cancer cells in the lab through a combination of targeted nanoparticles and laser heating for a couple of years now, but here is an interesting advance on that method: scientists "have discovered a new technique for singling out individual diseased cells and destroying them with tiny explosions. The scientists used lasers to make 'nanobubbles' by zapping gold nanoparticles inside cells. In tests on cancer cells, they found they could tune the lasers to create either small, bright bubbles that were visible but harmless or large bubbles that burst the cells. ... Single-cell targeting is one of the most touted advantages of nanomedicine, and our approach delivers on that promise with a localized effect inside an individual cell. The idea is to spot and treat unhealthy cells early, before a disease progresses to the point of making people extremely ill. ... In laboratory studies published last year [researchers also] applied nanobubbles to arterial plaque. They found that they could blast right through the deposits that block arteries. ...The bubbles work like a jackhammer. ... nanobubble technology could be used for 'theranostics,' a single process that combines diagnosis and therapy. In addition, because the cell-bursting nanobubbles also show up on microscopes in real time, [the] technique can be use for post-therapeutic assessment, or what physicians often refer to as 'guidance.'"

Link: http://www.eurekalert.org/pub_releases/2010-02/ru-rpk020410.php

From the Maximum Life Foundation blog, a video from the Manhattan Beach Project meeting on the projected cost and time taken to develop various aging-slowdown or actual rejuvenation therapies: "How much will it cost and how long will it take to develop an effective caloric restriction mimetic - one that will add many years if not decades to the human lifespan? What will it take to come up with a drug that turns on telomerase and thus lengthens telomeres? How about immune system restoration, tissue/organ storage, mitochondrial medicine, and other medical technologies?" For another perspective on time and cost, you might look at the SENS Foundation information on pushing to completion therapies for the seven contributing aspects of aging. We could expect working rejuvenation in mice with ten years of work and a billion dollars, for example - the challenge has always been convincing people that this is in fact the case, and raising those funds. Predicting how long it will take to move from mice to people is much harder, as this depends far more on regulation and politics than anything else. Two decades doesn't seem unreasonable in the present environment.

Link: http://maxlifefoundation.typepad.com/maximum-life-foundation/2010/02/david-kekich-how-long-will-it-take-and-how-much-will-it-cost-to-cure-aging.html

Fight Aging! was inaugurated at the end of January 2004, a dark age of the distant past that we shining folk of this new era barely recall. Tempus fugit. For all this great passage of time, the Fight Aging! mission remains as I have described it in past years. Constancy is still regarded as a virtue in some quarters, I am told.

A conversation is presently taking place on the topic of healthy life extension, although it may not always look like a conversation in the traditional sense. It wends its way throughout human interactions and publications; articles, magazines, websites, blogs, actual physical conversations, letters public and private. It is a single pathway in the great marketplace of ideas and culture.

Sometimes our conversation is hard to find, however. ... someone has to be talking on topic to keep the conversation growing, to avoid lapses in which newcomers might miss the party - hence the existence of Fight Aging!

Somewhere along the way, I started to use Fight Aging! as a part of my own efforts to better educate myself on the biochemistry of aging, the state of modern biotechnology, and work taking place on longevity science. If the earlier posts contained more advocacy than science, the last couple of years have been fairly evenly divided between those two topics. But the archives have grown large indeed - somewhere in the vicinity of 1800 posts - and almost every topic related to engineered longevity that I consider useful or interesting has been touched on in some way. Indeed, six years of writing has generated more than enough material to surprise me on a regular basis by what turns up in the Fight Aging! archives. Memory is the first thing to go, or so they say.

So is all this effort getting us anywhere? That is an interesting question, and one that is a challenge to answer. My visibility into the reach of Fight Aging! is limited to what I hear and the statistics on traffic I gather, neither of which are particularly reliable in and of themselves. From what I know, however, I am reasonably certain that readership has remained constant over the past couple of years. On the one hand, talking in detail about fairly complex scientific research is an excellent way to drive people away. On the other hand it seems as though there should be an increasing level of interest in engineered longevity - even if only from those folk who are looking for age-slowing pills and drugs as a result of increased publicity for the search for calorie restriction mimetics.

My analysis is that Fight Aging! has ossified a little as a pillar (one of many modest pillars) of a forward-looking longevity science community that is not growing very fast. I'm starting to lean towards the present Methuselah Foundation view that working to greatly expand the community of supporters is presently as important as fundraising initiatives.

Via ScienceDaily: "Stem cell researchers exploring a new approach for the care of respiratory diseases report that an experimental treatment involving transplantable lung cells was associated with improved outcomes in tests on mice with acute lung injury. ... Respiratory diseases are a major cause of mortality and morbidity worldwide. Current treatments offer no prospect of cure or disease reversal. Transplantation of pulmonary progenitor cells derived from human embryonic stem cells may provide a novel approach to regenerate endogenous lung cells destroyed by injury and disease. ... [Researchers] used a genetic selection procedure they created to generate a type of lung cell known as alveolar epithelial type II, which secretes surfactant, a substance that keeps the lung inflated, and can turn into another important lung cell that regulates the transfer of oxygen into the blood and the removal of carbon dioxide. ... the experimental stem cell treatment [not only] prevented or reversed visual hallmarks of pulmonary injury, but also restored near normal lung function to mice. ... additional tests in other animal models and eventually humans will be needed before these cell transplants can be used to treat respiratory diseases."

Link: http://www.sciencedaily.com/releases/2010/02/100203091221.htm

From the Huffington Post, an article on the science and practice of calorie restriction that focuses on extended longevity, and so manages to omit mention of the demonstrated health benefits in human studies: "The science of aging is among the most dynamic and provocative in modern biology. Over the past two decades we have seen a virtual explosion in research investigating the molecular and behavioral systems that control the aging process. But the more researchers uncover about the science of aging, the more questions emerge. Dietary restriction has long been considered the most potent regulator of aging. Restricting food intake by any means induces a series of metabolic changes in organisms from yeast to primates that serve to extend life. Studies are currently underway to investigate the ability of dietary restriction to extend life in humans. ... The genes linking diet and aging are highly conserved through evolution, indicating that there is a great chance human aging is sensitive to diet. Indeed, insulin-related genes have been found to be important in long-lived human populations. This suggests that the pathways discovered in worms and other organisms have similar functions in humans. What is not clear is how much influence diet has on lifespan and to what extent we are able to manipulate it."

Link: http://www.huffingtonpost.com/darya-pino/can-you-live-longer-by-cu_b_447907.html

If you wend your way back through the Fight Aging! archives, you'll find a lot of material on mitochondria, mitochondrial DNA, and how accumulated damage to mitochondrial DNA contributes greatly to aging. The short version is this:

Mitochondria are the cell's power plants, important in the operation of metabolism, central to the mechanisms by which metabolism determines life span, and implicated as the culprit in many age-related diseases. As described in the mitochondrial free radical theory of aging, a small number of mitochondrial genes are known to be crucial to its operation as the cell's power plant. Damage to those genes is unfortunately a natural consequence of the operation of a mitochondrion, and leads to a Rube Goldberg sequence of events in which is a healthy cell is turned into a damaged cell that spews forth damaging biochemicals into your body. As these errant cells accumulate, their actions collectively give rise to many of the unwelcome forms of change and damage that come with age: systems failing, organs shutting down, and important biochemical processes running awry because their component molecules are corrupted.

But you should certainly read one of the longer versions, as that will provide a better introduction to the mitochondrial free radical theory of aging. You should also look into some of the early stage work presently taking place to either replace damaged mitochondrial DNA throughout the body, replace just the few relevant damaged genes, or make all such damage irrelevant and harmless. We can hope that these lines of research will gain the funding and support needed to produce therapies capable of reversing mitochondrial damage and its contribution to degenerative aging. Knowledge is power.

I noticed a paper today that might be taken as evidence that working to repair mitochondrial DNA is an idea slowly gaining popularity in the scientific community. These researchers note that a range of natural repair mechanism exist (but are clearly overwhelmed by damage over a human life span), and that improving upon these mechanisms is only a matter of time:

Mitochondrial DNA (mtDNA) directs key metabolic functions in eukaryotic cells. While a number of mtDNA mutations are known causes of human diseases and age-related dysfunctions, some mtDNA haplotypes are associated with extreme longevity. Despite the mutagenic mitochondrial environment naturally enhancing somatic mtDNA mutation rates, mtDNA remains grossly stable along generations of plant and animal species including man. This relative stability can be accounted for by the purging of deleterious mutations by natural selection operating on growing cells, tissues, organisms and populations

...

In the adult multicellular organism, however, mtDNA mutations accumulate in slowly dividing cells, and, to a much higher degree, in postmitotic cells and tissues. [The following processes:]

1) Dynamic mitochondrial fusion and fission, by redistributing polymorphic mtDNA molecules;

2) mitophagy, by clearing defective mitochondria and mutated mtDNA;

3) compensatory mutations and mtDNA repair

can compensate for the accumulation of mtDNA mutations only to a certain extent, thereby creating a dysfunctional threshold. Here we hypothesize that this threshold is naturally up-regulated by both vertical and horizontal transfers of mtDNA from stem cells or cell types which retain the capacity of purging deleterious mtDNA through cell division and natural selection in the adult organism. When these natural cell and tissue mtDNA reserves are exhausted, artificial mtDNA therapy may provide for additional threshold up-regulation.

Replacement of mtDNA has been already successfully accomplished in early stage embryos and stem cells in a number of species including primates. It is thus simply a matter of refinement of technique that somatic mtDNA therapy, i.e., therapy of pathological conditions based on the transfer of mtDNA to somatic eukaryotic cells and tissues, becomes a medical reality.

You'll notice the reference to mitophagy there. This is one aspect of autophagy, or recycling of cellular components - here the interest is in that recycling process when it operates to tear down damaged mitochondria before they can cause harm. Recall that it is plausible that much of the benefit to health and longevity derived from increased autophagy, such as occurs in calorie restriction, administration of calorie restriction mimetic drugs, and in most of the life-extending genetic manipulations examined to date, is due to cells more aggressively clearing out mitochondrial damage.

Dani MA, & Dani SU (2010). Improving upon nature's somatic mitochondrial DNA therapies. Medical hypotheses PMID: 20116178

From Ouroboros: "One of [the] most significant breakthroughs [in biogerontology] last year was the announcement that the macrolide drug rapamycin can extend longevity in mice. More specifically, rapamycin can accomplish this when administered to adult, wildtype mice. In other words, no genetic modification or early-life intervention is necessary, making rapamycin one of the first compounds that meets the criteria for an anti-aging drug that could be used for people who are already alive and well down the road toward aging themselves. The lifespan extension achieved is modest (~10%), but this is more impressive in light of the fact that the mice were quite old at the time treatment began, and the study used only a single dose rate. Future studies will undoubtedly seek to optimize the dose and regimen with the goal of achieving greater enhancement of lifespan. How does it work? As the saying goes, further study is required, and at multiple levels. ... There's a good deal left to discover about the rapamycin’s effects on aging in general - and regarding the specific mechanistic relationship between translational control, senescence, and organismal aging - but I have it on good authority that there's a great deal of effort being exerted in that direction. Watch this space for future developments."

Link: http://ouroboros.wordpress.com/2010/02/02/rapamycin-reviewed/

From EconLog: "Ron Bailey's Liberation Biology quoted Frank Fukuyama: 'Life extension seems to me a perfect example of something that is a negative externality, meaning that it is individually rational and desirable for any given individual, but it has costs for society that can be negative.' I couldn't believe my eyes. Did Frank Fukuyama actually mean that when a person has another year of healthy life, the net effect on other people is negative? If so, why do people cry at funerals, instead of celebrating? Fukuyama's statement was so hateful and twisted that I wondered if he was being quoted out of context. So I dug up the full paragraph ... The extra words definitely make Fukuyama's position more confusing, but they take away none of the horror. The extra words definitely make Fukuyama's position more confusing, but they take away none of the horror. You'd think that a 'perfect example' of a negative externality would be easy to explain and hard to dispute - like air pollution. But to make his case, Fukuyama has to appeal to the controversial notion of group selection: Human beings evolved to die because it's adaptive for society. His specific mechanism - death stops elders from impeding progress - would be controversial even for believers in group selection. After all, during our evolutionary history, there was almost no progress to impede! ... On purely pragmatic grounds, then, Fukuyama's argument is about as feeble as 'Life extension is bad for morticians.'"

Link: http://econlog.econlib.org/archives/2010/02/fukuyamas.html

For many years, up until fairly recently, life science researchers who talked in public about altering or reversing the course of aging found that this was a quick and effective way to destroy fundraising prospects. The mainstream institutions involved in grants are conservative indeed. So next to nobody said anything - in public at least. But times are changing. It has to be said that scientists involved in aging research are now becoming noticeably more comfortable about talking in public on the topic of extending life span. Perhaps a little too comfortable here in the choice of title, but the science is sound:

Spermidine: A novel autophagy inducer and longevity elixir:

Spermidine is a ubiquitous polycation that is synthesized from putrescine and serves as a precursor of spermine. Putrescine, spermidine and spermine all are polyamines that participate in multiple known and unknown biological processes. Exogenous supply of spermidine prolongs the life span of several model organisms including [yeast, nematodes, and flies] and significantly reduces agerelated oxidative protein damage in mice, indicating that this agent may act as a universal anti-aging drug.

Spermidine induces autophagy in cultured yeast and mammalian cells, as well as in nematodes and flies. Genetic inactivation of genes essential for autophagy abolishes the life span-prolonging effect of spermidine in yeast, nematodes and flies. These findings complement expanding evidence that autophagy mediates cytoprotection against a variety of noxious agents and can confer longevity when induced at the whole-organism level.

We hypothesize that increased autophagic turnover of cytoplasmic organelles or long-lived proteins is involved in most if not all life span-prolonging therapies.

I've mentioned spermadine in the context of longevity and autophagy in the past, and the authors of the paper quoted above are far from the only folk who think that all roads lead to autophagy when it comes to altering metabolism to increase life span.

The better known life extension mechanisms in lesser animals are all driven by changes in autophagy - or so say the autophagy specialists. It's true that the various hyperspecialized communities of modern biology are overly cloistered and ignorant of one another's research, but the autophagy researchers are assembling compelling evidence for this position.

You might notice the similarity between the longevity-enhancing effects of calorie restriction and those of spermadine: both stop working if researchers eliminate autophagy in lower animals.

Madeo F, Eisenberg T, Büttner S, Ruckenstuhl C, & Kroemer G (2010). Spermidine: A novel autophagy inducer and longevity elixir. Autophagy, 6 (1) PMID: 20110777

A new film on aging and longevity science, "To Age or Not to Age," will be premiered in New York on February 11th, with a discussion panel of biogerontologists to follow: "The New York City screening will be followed by a live panel discussion. The panel discussion will be simulcast to venues screening the film nationwide and will stream live online. Panelists include: Dr. Robert Butler, Gerontologist, Psychiatrist & Pulitzer-Prize Winner; President and CEO of the International Longevity Center. ... Dr. Aubrey de Grey, Biomedical Gerontologist; Chief Science Officer, SENS Foundation. ... Dr. Leonard P. Guarente, Novartis Professor of Biology, MIT; Director, Paul F. Glenn Lab for Science of Aging. ... Dr. Gordon Lithgow, Biomolecular Geneticist; Head of the Lithgow Lab, Buck Institute on Aging. Moderated by Robert Kane Pappas, director of To Age or Not to Age. The scientists featured in To Age or Not to Age have found the means to postpone and possibly mitigate diseases tied to aging, such as cancer, cardiovascular disease, neurodegenerative diseases, and diabetes."

Link: http://www.toageornottoage.com/

From h+ Magazine: "For now, the best way to supplement the body's own defenses is through vaccines, but vaccines are far from a panacea. Each vaccine must be prepared in advance, few vaccines provide full protection to everybody, and despite popular misconception, even fewer last a lifetime. For example, smallpox vaccinations were lifelong, but tetanus vaccines generally last 5-10 years. There is still no vaccine for HIV infection. And when it comes to bacteria like tuberculosis, current vaccines are almost entirely ineffective. What's more, the whole process is achingly indirect. Vaccines work by first stimulating B cells and T cells in order to induce production of antibodies. They don't directly produce the needed antibodies. Rather, they try (not always successfully) to get the body to generate its own antibodies. In turn, stimulation of T cells requires yet another set of cells - called dendritic cells - and the presence of a diverse set of molecules called the major histocompatibility complex, creating still further complexity in generating an immune response. Our best hope may be to cut out the middleman. Rather than merely hoping that the vaccine will indirectly lead to the antibody an individual needs, imagine if we could genetically engineer these antibodies and make them available as needed. Call it immunity-on-demand. At first blush, the idea might seem farfetched. But there's a good chance this system, or something like it, will actually be in place within decades."

Link: http://www.hplusmagazine.com/articles/bio/re-engineering-human-immune-system

The aging science group blog Ouroboros has been defunct for some months now, which is more the pity. Working your way through the archives will show you that it was a quality effort whilst it lived - and those archives continue to provide value for those interested in learning more about evidence, debates, and directions in aging research. But that is not dead which can eternal lie. Glancing in the direction of Ouroboros today, I notice signs of renewed life from organizer Chris Patil, one of the Buck Institute for Age Research folk:

I’m trying to claw my way back from a long period of inactivity. In late 2009, experiments and other work prevented me from devoting time to this project, and even after some of those obligations lightened, I was finding it difficult to get back in the saddle. My last moment of inspiration turned out to be a false alarm, and rumors of my resurrection had been greatly exaggerated. Most of the posts in the final quarter of last year were made by one of our other writers (turritopsis’ excellent coverage of the SENS4 conference).

...

But I’ve decided that this is important to me, for a variety of reasons, both selfish and other-centered. I like the way that Ouroboros helps me keep on top of the literature - even if I’m deciding not to write about an article, I’m thinking about it - and I’ve been missing that. I also liked the small but growing sense that I was doing something that other people enjoyed, and that benefited the field as a whole. On the careerist side: Knowing the field helps me choose the best experiments to do in my own work. Beyond that, as my generation gradually takes over the reigns of academic science, more and more people will appreciate the value of activities like blogging - so hopefully there will be no ultimate career tradeoff between time spent blogging and time spent on research activities.

So as of tomorrow, I’ll be back, in some form.

Profit, either monetary or in the form of other personal benefits and growth, is the incentive that enables longer-term initiatives. If there is no profit, no personal benefit, then sooner or later even the most starry-eyed altruist will burn out. All too few authors write regularly on the topic of aging and longevity science, especially when it comes to addressing laypeople in the wider audience beyond the research community. Progress in the big picture of fundraising for aging research is as much a matter of educating people of the potential inherent in present longevity science as anything else, and more voices are the way to achieve that goal. So if you found Ouroboros valuable whilst posting was regular, then drop by and offer a few words of encouragement.

First generation stem cell therapies are offered in many locations around the world, and medical tourism is booming, but what sort of due diligence should you perform before trying to take advantage of a particular therapy? Here are some good suggestions: "The International Cellular Medicine Society (ICMS) has promulgated laboratory, practice standards and maintains a non-profit stem cell treatment registry. The easiest way to determine if the cell therapy is credible is to see if the clinic is ICMS certified. ... The development of treatment protocols for stem cells is difficult and disease as well as tissue specific. This means that valid treatment isn't as easy as sprinkling magic stem cells on the patient. For example, the treatment protocol for knee osteoarthritis has a completely different approach than cardiac disease. Some stem cell clinics are operating at a high level focus on a small collection of diseases and perfect their protocols for those diseases. This may take years for each application. So if the clinic advertises that it treats everything from ALS to Parkinson's to knee arthritis, this usually indicates that it's not operating at a high level of credibility.... Where are the stem cells obtained? Are they from the same patient (autologous) or from an allogeneic source? Many experts agree that autologous cells are more likely to have a much more robust safety profile than cells obtained from a donor. In particular, genes of the donor remain active in the host (which could have either a potentially positive or negative impact)."

Link: http://www.faim.org/guestwriters/christophercentenovettingstemcelltherapies.html

Promising news for sufferers of autoimmune conditions: "A researcher [has] invented a novel way to halt and even reverse rheumatoid arthritis. He developed an imitation of a suicide molecule that floats undetected into overactive immune cells responsible for the disease. ... This new therapy stopped the disease cold in 75 percent of the mice. The best part was we didn't see any toxicity. ... Healthy immune cells are supposed to die after they attack an invading virus or bacteria. But in rheumatoid arthritis, the immune cells called macrophages live and go rogue. They proliferate in the blood, build up in the joints and invade cartilage and bone. Currently, there is no effective, nontoxic way to stop them. ... immune cells in rheumatoid arthritis are low in a critical molecule called Bim, whose job is to order the cells to self-destruct. To correct that shortage, [researchers] developed an imitation of the molecule, called BH3 mimetic. When [injected into] mice with rheumatoid arthritis, it floated ghostlike into their macrophages and bam!, the misbehaving immune cells self destructed. ... the molecule could prevent the development of rheumatoid arthritis as well as trigger a remission of existing disease. ... the next step is to develop nanotechnology for a more precise method of delivering the drug."

Link: http://www.northwestern.edu/newscenter/stories/2010/01/arthritis.html