Fight Aging!

This year's TEDMED conference finished up today. Amongst the speakers were biomedical gerontologist Aubrey de Grey of the SENS Foundation and tissue engineer Anthony Atala of the Wake Forest Institute for Regenerative Medicine. While we'll have to wait to see video of the presentations uploaded to YouTube to match last year's assembled presentations, you'll find coverage of the event at MedGadget:

• TEDMED 2010 - Day 1 - Shaf Keshavjee, Nathan Myhrvoid, Nathan Wolfe, and More
• TEDMED 2010 - DAY 2 - Thomas Goetz, Craig Venter, Alex Berenstein, and More
• TEDMED 2010 - Day 3 - Danny Hillis, Dean Kamen, David Blaine, and More

Next up on stage were aging and life extension scientist Aubrey de Grey and regenerative medicine researcher Anthony Atala. Aubrey is a quirky figure in the world of science, with a long beard and provocative views on aging and immortality. Anthony Atala is, by impression, much more grounded and lives in the world of tissue engineering. The most notable thing about their joint talk was not what they said but rather that their institutions, the SENS Foundation and Wake Forest University, are going to partner together on some projects. They approach the idea of fixing the human body from highly different angles and it will be interesting to see the results from their collaboration.

Atala is one of the luminaries present on the SENS Foundation research advisory board, so collaboration shouldn't be all that surprising. Organ replacement and the concept of reversing aging by repairing biological damage are not incompatible at all: the former could be made to be a method of achieving the latter for specific organs. When clinics are building new organs from a patient's stem cells, it is entirely plausible that accompanying technologies will ensure that those stem cells are free from molecular damage - and thus the organ will have youthful characteristics.

There are still a range of issues relating to the signaling taking place in an aging body - see the work showing the effects of old blood on young muscle stem cells and vice versa for example - but a new, young organ made from your own cells beats a poke in the eye with a sharp stick, issues or no. Functional growth of replacement organs and tissues to order will be a big step forward for medicine and the treatment of the old, which is one of the reasons that the Methuselah Foundation set up the NewOrgan Prize not so long ago.

The TransVision 2010 conference was held in Milan this past weekend, a chance for European transhumanists to meet and make presentations on topics of interest - such as engineering greater human longevity. Some of the conference video is up at the teleXLR8 blog. You might also look at organizer Giulio Prisco's report: "TransVision 2010 is over! I wish to thank all speakers and participants, those who came to Milan and those who participated remotely via Teleplace. ... This was a very interesting event, with great talks by great speakers. I am happy to have seen again many old friends and made many new ones. In the picture above, some speakers and participants at a dinner after the end of the conference. I was not really able to pay attention to any of the talks including my own, and I look forward to watching the video coverage. We recorded everything on video, both in HD with the cameras on site, and from Teleplace. The videos will be available online and on the conference's DVD proceedings. The videos recorded in Teleplace will be available online in a few days, and those recorded on site in a few weeks."

Link: http://telexlr8.wordpress.com/2010/10/25/transvision-2010-october-22-24-2010/

At the SENS Foundation, Michael Rae looks at the NIA Interventions Testing Program examination of resveratrol and rapamycin: "Combined with their positive results with rapamycin, the failure of resveratrol to extend life using resveratrol in normal mice over a very wide range of doses should reasonably be taken to put the resveratrol "story" to test. On the other hand, the ability of rapamycin to extend life in these mice has been confirmed, and expanded to a preliminary extent. Naturally, further studies are underway or proposed to elucidate the full nature of these effects. ... At the same time, whatever these studies may reveal, even the most optimistic reading of these results and an assumption of perfect human translatability is still overshadowed by how limited the results are. Interventions such as rapamycin, which only retard the rate at which aging damage accumulates (or, perhaps, allows the organism to carry on functioning for a longer period of time under its accumulating burden), can only temporarily delay the onset of age-related ill-health, not arrest or reverse it - and in the case of rapamycin, the first pharmacological agent to extend the lives of otherwise-healthy mammals, its ability to do even this has been found to be limited." Drugs that slow aging - slow the rate at which damage occurs - are not a desirable end point for the next twenty years of research, when we could instead be working instead to reverse aging by repairing biochemical damage.

Link: http://www.sens.org/node/1759

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A reminder about the NewOrgan Prize from Sentient Developments: "the Methuselah Foundation recently launched the NewOrgan Prize which will be awarded to the first scientist to produce and successfully transplant an organ using regenerative medicine. The contest is meant to speed up the research process and bring the promise of regenerative medicine to reality. As the US Department of Health & Human Services has stated, 'Regenerative medicine will be the standard of care for replacing organ systems in the body.' The trick is to make it happen. When it comes to reconstructing a new organ, 'new organ engineering' will require the development of all tissues that build the organ including muscle, nerves, arteries and veins. The challenges and limitations of the current system for organ replacement are well documented, including the agony of waiting for a donor to die, lifelong limitations from immunosuppressant drugs, and possible organ rejection. And the sad reality is that many die without receiving a new organ or even qualifying to be considered." As for the Mprize for longevity science, the NewOrgan Prize purse will be formed from philanthropic donations: so if you support the goal, make a donation. Prizes have a multiplying effect: every dollar in the prize purse inspires something like $15 to $50 dollars in research and development funding, based on recent and historical prizes.

Link: http://www.sentientdevelopments.com/2010/10/methuselah-foundations-neworgan-prize.html

The evolved balance between cancer resistance and tissue maintenance is an important determinant of longevity - but it can be fine-tuned so as to have your cake and eat it, as researchers have found in recent years. Here is another example, in flies this time: "Somatic stem cells are critical for regeneration of many tissues, thus ensuring long-term maintenance of tissue function. Proliferation of stem and progenitor cells has to be limited, however, to prevent hyperproliferative diseases and cancer in aging animals. This conflict between the need for stem cell proliferative potential and cancer prevention compromises regeneration in many high-turnover tissues of aging animals, including humans. ... In old flies, intestinal stem cells (ISCs) hyperproliferate, causing an accumulation of mis-differentiated daughter cells (a phenotype termed intestinal dysplasia). We show that the balance between regeneration and dysplasia in this tissue significantly influences lifespan. When ISC proliferation rates are reduced, but not completely inhibited, dysplasia is limited and lifespan is increased. This can be achieved by moderately reducing insulin and stress signaling activities, as well as by expressing protective proteins in somatic stem cell lineages. Our results show that optimizing proliferative homeostasis (i.e. limiting dysplasia, but allowing sufficient regeneration) in high-turnover tissues is an efficient strategy to extend lifespan." The more that is known about the fine details of metabolic and cellular processes, the more that might be done to tinker with them to extend life. But this will never be as efficient a path forward as repair technologies - when we strive to identify and repair damage within our biochemistry, we have no need to fully understand every aspect. We know what a young metabolism and cell look like, and we are trying to revert the clearly identified differences between young and old.

Link: http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1001159

As you all know by now, accumulated mitochondrial DNA (mtDNA) damage is thought to provide an important contribution to degenerative aging. The process by which the small misplaced, changed, or missing segments of DNA known as mutations create the conditions for failing organs - and ultimately death - is complex and has many steps, but it starts with changes in the operation of crucial mitochondrial machinery. You might want to look back into the Fight Aging! archives for an overview of the mitochondrial free radical theory of aging, which walks though the present understanding of this process.

I was interested to note today that there is some evidence for the existence of beneficial mutations to mitochondrial DNA that accumulate with age in at least some populations. On reflection this doesn't seem unreasonable. We know, for example, that some mitochondrial DNA haplotypes are demonstrably better than others - they are associated with people who, on average, benefit from better health and longevity. Some folk have the luck of the draw and inherit good mitochondrial machinery. But our cells are more than just the straight output of their DNA blueprints, both nuclear DNA and mitochondrial DNA, because cellular processes and mechanisms can conceivably influence the way in which those blueprints become damaged over time.

So we have this intriguing open access paper, which suggests that some human populations may have evolved to allow certain specific types of damage to readily occur in their mitochondria, because that damage changes mitochondrial operation in ways that provide benefits to survival. Devious, but then that's biology for you:

It has been recognized for a long time that age-related random damages to mtDNA and the consequent decrease in the respiratory chain capacity are among the major contributors to the aging process. ... However, in the last decade different studies highlighted specific somatic mutations in the mtDNA Control Region (CR) which can reach high levels in aged individuals. These mutations are tissue-specific and occur at mtDNA sites which are critical for replication or transcription.

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Interestingly, it has been found that the CR heteroplasmic point mutations are over-represented in centenarians with respect to younger subjects in the Italian population. Data [on] twin pairs have proposed that the heteroplasmic levels of [point mutations] were genetically controlled. This hypothesis has been bolstered by analyzing centenarians' families, where we demonstrated that CR heteroplasmy in centenarians' descendants (children and nieces/nephews) are significantly higher than in age-matched controls and, moreover, they are significantly correlated in parent-offspring pairs. Thus, it has been proposed that the CR somatic point mutations may represent a remodelling mechanism which would restore the replication machinery, providing a beneficial effect on longevity.

Point mutations, you might recall, are probably not a big deal for the integrity of mitochondrial DNA insofar as aging is concerned. Researchers have demonstrated gene engineered mice packed with an outrageous level of point mutations in mitochondrial DNA, and which suffered no side effects for it. Degenerative aging is most likely advanced by other, more drastic forms of mutational damage that cut out whole sections of DNA or mash up genes in worse ways.

While this is all very fascinating, we shouldn't lose sight of the fact that the inherent quality of our mitochondrial DNA doesn't really matter. All of us lacking very bad luck make it to our thirties in a youthful state regardless of the variations in mitochondrial DNA we carry. The correct big picture view is to be thinking about ways to repair mitochondrial DNA every few decades, so as to return it to its original form before the level of mutational damage starts causing us real harm.

Given funding and motivated researchers, we stand no more than a decade or two away from the ability to replace mitochondrial DNA wholesale in all the cells of a human body. It has been five years since this was demonstrated in a mouse, but there is little work taking place on this path. Similarly, we stand only ten to twenty years from being able to import backup copies of all of the real problem genes in mitochondrial DNA into the nucleus - where they will escape mutational damage and keep the mitochondrial machinery running in tip-top condition. This has been demonstrated for one or two of the thirteen genes needed. Again, there are few research groups engaged in this work, and little funding for it.

Here, as in so many areas of engineered longevity, the science is far, far ahead of public understanding, availability of funding, and the will to get the job done.

An example of early applications of stem cell research forging ahead outside the US: "While stem cells have been making news around the world for their potential, and are even being tried on patients, Dr N K Venkataramana, neurosurgeon, BGS Global Hospital in Bangalore, has successfully used the therapy on patients suffering from Parkinson's disease, Alzheimer's, cerebellar degeneration and cerebral palsy. 'I used adult mesenchymal stem cells derived from the bone marrow. They were transplanted into the brain through keyhole surgery. These stem cells multiply and thereby regenerate the damaged areas of the brain. This leads to reactivation of brain cells, resulting in recovery from the disease.' ... He created a state-of-the-art research facility - Advanced Neuro Science Allies - and began his research into the use of stem cell therapy three years ago. 'I picked out authentic mesenchymal stem cells from bone marrow using a marker. The stem cells were purified and tried on animals for safety. Subsequently, we used the therapy on patients. ... Initially, the findings are that we are on the course to a complete cure. All the patients treated so far have a marked decrease in the need for medication. Their symptoms have reduced drastically. They have an increased feeling of well-being and it is obvious that they are recovering. However, there are still some factors to be addressed and understood.'

Link: http://timesofindia.indiatimes.com/city/bangalore/Viva-Stem-cells-revive-dying-brains/articleshow/6811649.cms

From In the Pipeline: "there's a report out in PNAS that the longtime treatment for leprosy (Hansen's disease), diaminodiphenylsulfone (DDS or dapsone), also prolongs life in the nematode C. elegans. ... The treated animals showed a significantly longer lifespan, faster body movements compared to untreated controls, and a delay in accumulating the 'aging pigment' lipofuscin. Now, DDS kills bacteria by inhibiting folate synthesis, but that doesn't seem to have anything to do with lifespan extension. The authors found that one of its key targets might be pyruvate kinase - and this might be the source for the mild anemia that's sometimes seen as a side effect in human patients. Nematodes have two isoforms of the enzyme, one mostly in muscle, and the other mostly in the digestive tract. Further study (with RNAi, etc.) showed that the lifespan extension seems to be working through the former, but not the latter. But it also showed that this probably can't be responsible for the whole lifespan effect, either: mutant nematodes with that isoform deleted live longer than wild type, but treating them with DDS makes them live longer still."

Link: http://pipeline.corante.com/archives/2010/10/26/dapsone_prolongs_life_well_in_nematodes_it_does_.php

As noted in a recent research paper:

Caloric restriction (CR) causes a reduction in body temperature which is suggested to contribute to changes that increase lifespan. Moreover, low [body temperature] has been shown to improve health and longevity independent of CR. ... Based on current evidence, it is concluded that low [body temperature] plays an integral role in mediating the effects of CR on health and longevity, and that low [body temperature] may exert independent biological changes that increase lifespan. Our understanding of the overlap between CR- and [body temperature]-mediated longevity remains incomplete and should be explored in future research.

Calorie restriction causes increased health and longevity by triggering a set of programmed changes in the complex operation of metabolism. Even though the mechanisms of calorie restriction are far from completely understood, the programmed nature of this metabolic response is demonstrated by the fact that some strategic gene deletions can prevent calorie restricted laboratory animals from gaining health and longevity benefits.

There is reason to believe that enhanced longevity resulting from low body temperature is similarly a programmed response, for all that even less is known about the details of what is taking place under the hood. The hypothalamus is involved in both cases:

Temperature is an important modulator of longevity and aging in both poikilotherms and homeotherm animals. In homeotherms, temperature homeostasis is regulated primarily in the preoptic area (POA) of the hypothalamus. This region receives and integrates peripheral, central and environmental signals and maintains a nearly constant core body temperature (T(core)) by regulating the autonomic and hormonal control of heat production and heat dissipation.

Temperature sensitive neurons found in the POA are considered key elements of the neuronal circuitry modulating these effects. Nutrient homeostasis is also a hypothalamically regulated modulator of aging as well as one of the signals that can influence T(core) in homeotherms.

Nothing in biology is simple, and the effects of temperature and calorie restriction involve overlapping feedback loops and shared mechanisms in our cells. These further overlap with the programmed control of other important processes, such as hormesis and autophagy. A living being is a very, very complex system - less like a line of neat, isolated switches, and more like a bucket of unlabeled dials and levers, all of which are partially wired to the others.

Smoking is just a more subtle way of stabbing yourself - causing damage that will shorten your life. One of the impacts of smoking is degraded blood vessel function, and this has a long-term effect on the brain. It is an example of the way in which the state of general health impacts the rate of neurodegeneration: "Heavy smoking in middle age appears to be associated with more than double the risk for Alzheimer's disease and other forms of dementia two decades later. ... [Researchers] analyzed data from 21,123 members of one health care system who participated in a survey between 1978 and 1985, when they were 50 to 60 years old. Diagnoses of dementia, Alzheimer's disease and vascular dementia were tracked from Jan. 1, 1994 (when participants were an average of 71.6 years old), through July 31, 2008. A total of 5,367 participants (25.4 percent) were diagnosed with dementia during an average of 23 years of follow-up, including 1,136 with Alzheimer's disease and 416 with vascular dementia. Those who smoked more than two packs per day in middle age had an elevated risk of dementia overall and also of each subtype, Alzheimer's disease and vascular dementia, compared with non-smokers. ... Smoking is a well-established risk factor for stroke, and may contribute to the risk of vascular dementia through similar mechanisms." As we non-smokers look at this and shake our heads, it is worth recalling that a sedentary lifestyle can be just as damaging to human life expectancy as smoking. Have you looked at the exercise in your life recently?

Link: http://www.sciencedaily.com/releases/2010/10/101025161034.htm

Developing the means to repair the human brain is essential to engineered longevity - it's the one organ we can't just replace as a last resort. From Sentient Developments: "The human brain degrades quickly with advanced age and, as a result, represents the weakest link in the life extension chain; as far as I'm concerned it's full stop until we can meaningfully fix the cognitive problems associated with aging. Yes, age-associated diseases such as cancer and cardiovascular disease are clearly bad, but the most devastating of these involve the nervous system - diseases like Alzheimer's and Parkinson's. These diseases take a brutal toll on individuals and their families, often virtually killing the person well before they die. That we are facing a looming epidemic of neurological diseases shouldn't really come as a surprise to anyone. But what is surprising is that very few people are actively doing anything about it. And it's not that the writing isn't on the wall - it is. The time to act is now. ... Until we can meaningfully treat age-related cognitive decline, many of these other life extending advances are a moot point; what we're in danger of doing right now is extending lifespan, but not necessarily healthy life span." I disagree with this conclusion on the grounds that I think extending life without extending healthy life would be very hard to accomplish even if we were trying - aging is biological damage, and the outcome flows from the state of damage. Reduce the damage and you extend both life and healthy life. Neurodegeneration is driven in large part by the state of general health, perhaps through the mechanisms of blood vessel health, for example.

Link: http://www.sentientdevelopments.com/2010/10/why-life-extensionists-needs-to-be.html

Why, in a world in which a million people die every week, is cryonics still a fringe activity? Some fairly novel arguments are made in this piece over at Depressed Metabolism: "in the case of cryonics, the idea is so antithetical to the existing order of civilization that it can it only be advanced by insurgent means. This is so because cryonics overturns the Vitalistic view of life, challenges the conventional definition of death, invalidates the core tenets of contemporary medicine, erodes the need for a mystical afterlife, radically redistributes capital (disrupts inheritance, bequests, and mortuary customs), mandates a complete change in reproductive behavior, perturbs generational succession, [requires] profoundly disruptive technologies such as cloning, regenerative medicine, nanotechnology, artificial intelligence ... [thus] the idea that cryonics was just an extension of medicine and is compatible with religion and existing social and political institutions, while superficially satisfying, is both mistaken and bound to fail. ... It is becoming clearer and clearer that demonstrating the technological feasibility of cryonics is not sufficient for the acceptance of cryonics. ... Cryonics advocates often seem to believe that if they refute the common scientific and technical objections to cryonics (which is not that hard to do because the psychological resistance to the idea prevents critics of checking even the most basic facts about the rationale and practice of cryonics) the social and psychological reservations will take care of themselves. This is not just incorrect, such reservations are often the most fundamental."

Link: http://www.depressedmetabolism.com/2010/10/22/cryonics-trans-temporal-communism-and-future-squatters/

If a job needs doing, there's something to be said for stepping up to help out directly. A number of younger folk in the healthy life extension community see that engineered longevity within our lifetimes is possible, and in response direct their studies and career goals towards biotechnology and aging research. A few of the braver older folk have mastered the challenge of switching careers in mid-flow, returning to university in order to become life science researchers, focused on the biology of aging.

Biogerontology is a sub-field of gerontology studying the biological processes of aging. It is composed of the interdisciplinary research on biological aging's causes, effects, and mechanisms in order to better understand human senescence. ... Biomedical gerontology, also known as experimental gerontology and life extension, is a sub discipline of biogerontology that endeavors to slow, prevent, and even reverse aging in both humans and animals. Curing age-related diseases is one approach, and slowing down the underlying processes of aging is another.

So how does a person go about steering studies or a career with the aim of becoming a biogerontologist? I note that academic researcher Joao Pedro Magalhaes maintains a good overview aimed at students in the university system:

By and large, biogerontologists work at research institutions, typically universities or laboratories, though a few also work in the industry and a few companies research aging. The vast majority of biogerontologists have a PhD (or sometimes an MD or both), so if you want to become a biogerontologist you should be prepared to go to graduate and/or medical school. While it is possible to study aging in a private company or as a staff member of a research institution, the majority of well-known biogerontologists have their own research group, like ours, at a research institution. Again, you can certainly contribute to research on aging in a variety of ways and even without making of it your main job, yet if you are serious about becoming a biogerontologist and doing independent research at the highest level then this usually implies developing an academic career.

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One major doubt of students is which topics they should study to prepare themselves for a career in biogerontology. Because aging is a biological process I would suggest that you include biology courses in your education. With the sequencing of the human genome and recent progress in the genetics of aging and longevity, I would also recommend some basic knowledge of genetics. Nevertheless, many different techniques and skills can be employed to study aging. There are physicists, physicians, engineers, biologists, geneticists, computer scientists, mathematicians, and many other different professionals studying aging right now. Therefore, my advice is for you to learn different skills, understand the science of aging, and focus on the area you find more exciting or more adequate to your personal situation.

Where you wind up in life and the degree to which you enjoy success in your goals is all about the connections you make along the way. If you want to make progress in a particular field, you have to establish relationships within that field. For example, the SENS Foundation runs an academic initiative program - whose chief value to the students involved is the opportunity to make connections within the community of researchers interested in repairing the biochemical damage of aging.

Aging is the accumulation of damage, and given that life expectancies have increased over time, we'd expect the aged to presently have less biological damage than was the case in the past. This is challenging to measure, however, given the crude state of medical technology in earlier eras. Here is an unusually clear example: "Today's 70-year-olds do far better in intelligence tests than their predecessors. It has also become more difficult to detect dementia in its early stages, though forgetfulness is still an early symptom ... The H70 study provides data on cognitive symptoms that researchers have used to predict the development of dementia, and also to investigate whether the symptoms have changed in recent generations. The study involves a large proportion of 70-year-olds from Gothenburg, Sweden, who have been extensively examined over the years ... Using the test results, we've tried to identify people who are at risk of developing dementia. While this worked well for the group of 70-year-olds born in 1901-02, the same tests didn't offer any clues about who will develop dementia in the later generation of 70-year-olds born in 1930. ... The improvement can partly be explained by better pre- and neonatal care, better nutrition, higher quality of education, better treatment of high blood pressure and other vascular diseases, and not least the higher intellectual requirements of today's society, where access to advanced technology, television and the Internet has become part of everyday life."

Link: http://www.alphagalileo.org/ViewItem.aspx?ItemId=88238&CultureCode=en

If you wander over to Maria Konovalenko's English-language blog, you'll find a brace of recent posts on research relevant to those of us interested in engineered longevity.

Bioprinting: Laboratory Grown Body Parts Now a Reality

Your liver is failing critically. A transplant would save your life, but there's a long waiting list and the odds are stacked against you. So instead, doctors extract some of your bone marrow, liver and muscle cells, go back to their laboratory and return in a few weeks with … a freshly grown liver! Does this sound like material from a Hollywood sci-fi movie? Well Not anymore. Australian researchers in Melbourne are now hard at work growing spare parts, proving their stuff in animal - and even human trials!

First Clinical Trial of Human Embryonic Stem Cell Therapy in the World Begins

Working in a handful of medical centers around the country, the biotech firm Geron is treating eight to 10 recent paraplegics. The patients will receive an injection of neurons to the site of the damage, followed by a short treatment of anti-rejection drugs. The first patient is reported as a patient in an Atlanta spinal cord and brain injury rehabilitation hospital. To take part in the study, the patient had to have suffered a spinal or brain injury that resulted in paralysis from the chest down. This patient was injected with cells derived from human embryonic stem cells obtained from a fertility clinic. Researchers are optimistic that this human embryonic stem cell therapy will not only help alleviate the symptoms of the injury, but permanently repair the damage that caused the paralysis from the spinal cord injury.

Reverse Aging of Human Muscle Tissue

The study shows that the ability of old human muscle to be maintained and repaired by muscle stem cells can be restored to youthful vigor given the right mix of biochemical signals. Professor Irina Conboy, a faculty member in the graduate bioengineering program that is run jointly by UC Berkeley and UC San Francisco, is the head of the research team that conducted the study. Previous research that Conboy had done in animals, revealed that the ability of adult stem cells to repair and replace damaged tissue is governed by the molecular signals they get from surrounding muscle tissue, and that those signals change with age in ways that preclude productive tissue repair. Those studies also demonstrated that the regenerative function in old stem cells can be revived given the appropriate biochemical signals!

Life Extension Through Nanotechnology

Perhaps the most exciting possibility exists in the potential for repairing our bodies at the cellular level. Techniques in nanorobotics are being developed that should make the repair of our cells possible. For example, as we age, DNA in our cells is damaged by radiation or chemicals in our bodies. Nanorobots would be able to repair the damaged DNA and allow our cells to function correctly. This ability to repair DNA and other defective components in our cells goes beyond keeping us healthy: it has the potential to restore our bodies to a more youthful condition. .

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Aging is fundamentally no different from any other physical disorder; it is no magical effect of calendar dates on a mysterious life-force. Brittle bones, wrinkled skin, low enzyme activities, slow wound healing, poor memory, and the rest all result from damaged molecular machinery, chemical imbalances, and mis-arranged structures. By restoring all the cells and tissues of the body to a youthful structure, repair machines will restore youthful health.

When it comes right down to it, all medicine is nanomedicine - every therapy involves attempts to change specific nanoscale structures in our bodies, replacing or repairing damaged biological machinery. The advance of medicine is exactly a case of producing ever more sophisticated, capable, and controlled ways of accomplishing these goals.

We know that wealth correlates with greater life expectancy. Aging and late-life disease are the consequences of ongoing biological damage, and we might theorize that wealthier people on average have greater means and knowledge to reduce the rate at which that damage occurs - though I believe that knowledge and the will to use it are more important than means. No present day medical technology can do as much for a healthy person as exercise and calorie restriction, available to rich and poor alike. But all in all, we shouldn't be surprised to find statistically significant biological differences between the metabolisms of the wealthy and the poor, reflecting the differences in lifestyle and levels of biological damage: researchers "found evidence that biological ageing is slower among people with better socio-economic circumstances. ... It found that the wealthier people were, the higher their levels of DHEAS. The discovery raises the possibility that the hormone could be artificially produced and used to make people live longer. The scientists also found that those with higher levels of it tended to do greater amounts of exercise, lead a more active life with lots of pastimes, and have more friends and family. ... The research also found higher levels of a second hormone - growth factor I (IGF-I) - in those who are wealthier."

Link: http://www.telegraph.co.uk/health/healthnews/8077779/Hormone-research-suggests-rich-live-longer.html

The p53 protein is a pivot point between aging and cancer: suppressing cancer at the cost of faster aging. p21 has a similar role, and is also a regulator of regeneration: p21-deficient mice are capable of regenerating injuries that normally don't heal in mammals. mTOR is a calorie restriction associated protein that when manipulated can extend life in mammals. These proteins influence many aspects of cell growth and other important metabolic processes, and are all tied together in the mechanisms of the cell: "The mechanism(s) by which p53 chooses between outcomes of senescence or quiescence has remained elusive. ... Recent studies [have] shown that [gene expression] of p21, a key p53 downstream target that is required for both senescence and quiescence, drives [cancer cells] into senescence ... Notably, rapamycin, a classical inhibitor of the mTOR pathway, can also suppress p21-mediated senescence suggesting the possibility that p53 might supress senescence by inhibiting mTOR signalling. Several key components of the mTOR pathway are, in fact, down-regulated by p53. ... Collectively, these analyses pinpoint p53-mediated inhibition of the mTOR pathway as a major effector in suppressing senescence, depending on whether p53 levels are above or below a critical threshold." This isn't all abstract low-level research: sophisticated manipulation of p53 can extend life in mice by 50%, and better understanding should mean better results.

Link: http://www.impactaging.com/papers/v2/n10/full/100212.html

Gregory Benford is a man of many hats: prolific science fiction writer, professor of astrophysics, and chairman of the board at Genescient, for example. Lightspeed Magazine recently published a short article by Benford on the topic of cryonics, an item that should be on the mind of everyone past a certain age.

As cryonics' determined subculture - clustered around a few companies such as Alcor - labors to make the theoretical into a reality, how close are we to actually making cryonics a real path to immortality? Well, in large measure, cryonics is real right here and now. Today, about a hundred people - including baseball legend Ted Williams who was frozen in 2003 - lie in liquid nitrogen baths awaiting resurrection and the cure for what ailed them.

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Exciting, yes. The bad news? It will take approximately fifty years, if not a century, to develop nanotech to the point that it is able to repair the damage freezing and thawing does to human cells. Good thing about being frozen, though: you aren’t going anywhere. What's another hundred years or so?

Benford doesn't mention the replacement of freezing with vitrification in the cryonics industry, but a commenter does. Vitrification doesn't cause the same damage the freezing does, and preserves the fine structure of cells very well. It's a great improvement in terms of reducing the technology barrier to restoring the cryopreserved to active life once more.

An ugly truth we have to face is that the technologies of rejuvenation, ways to repair the biochemical damage of aging in living bodies, will not arrive in time for everyone alive today. A billion, or two billion, or more people will die and decay to nothing simply because they were born too soon, or were on the cusp and didn't take good enough care of their health. For everyone who might paint a plausible picture of their lives on the wrong side of the line, cryonics is the best way forward - the only shot at a far longer and better life in a future age.

As Michael Anissimov notes, we're all left wondering why so few people step up to grasp this brass ring. Arranging your own cryopreservation requires time and effort - a lot of things can go wrong if you assume you don't need preparation and organization. But that isn't enough to explain why people don't go through with it. From the article:

Ray Bradbury once told me he was interested in any chance of seeing the future, but when he thought over cryonics, he realized that he would be torn away from everything he loved. What would the future be worth, he asked, without his wife, his children, his friends? No, he told me, wouldn’t take the option at any price.

This is an example of the "neighborhood" argument, which says that mature people are so entwined with their surroundings, people and habits of mind, that to yank them out is a trauma worse than death. One is fond of one's own era, certainly. But it seems to me that ordinary immigrants from every era have faced similar challenges and managed to adjust and make freer, better lives in their new homes. Just ask your grandparents.

People's appetite for risk and change diminishes with age, it seems. The acceptance of personal oblivion seems to increase: it's the younger folk who are truly fiery on the topic of defeating death. One might argue on how much of that is physiological versus cultural - if you had the body and neurology of a 20 year old at 80, would you still have the same level of psychological inertia? It seems unlikely that we'll know the answer to that before there are 80 year olds with youthful physiques taking on the world.

And people are still dying. Another two thousand in the time it took me to write this post - lost and gone forever, cut short within sight of the ageless societies that will emerge from advances in biotechnology. Matters could be different, but they are not, as we don't live in a particularly sane world.

Advanced glycation endproducts (AGEs) build up with age and cause all sorts of issues. As this paper notes, some of these problematic effects stem from RAGE, the cellular receptor for AGEs - which you might think of as one key upon the control keyboard for a cell. If that key is being constantly hammered by too many AGEs in the system, then that is a problem. "The formation of advanced glycation endproducts (AGEs) occurs in diverse settings such as diabetes, aging, renal failure, inflammation and hypoxia. The chief cellular receptor for AGEs, RAGE, transduces the effects of AGEs via signal transduction ... Data suggest that RAGE perpetuates the inflammatory signals initiated by AGEs via multiple mechanisms. AGE-RAGE interaction stimulates generation of reactive oxygen species and inflammation-mechanisms which enhance AGE formation. ... Taken together, these considerations place RAGE in the center of biochemical and molecular stresses that characterize the complications of diabetes and chronic disease. Stopping RAGE-dependent signaling may hold the key to interrupting cycles of cellular perturbation and tissue damage in these disorders." I'm still in favor of breaking down AGEs as the primary strategy: interfering in RAGE doesn't stop the build up of AGEs that causes it to be a problem in the first place.

Link: http://www.ncbi.nlm.nih.gov/pubmed/20957395

Species with large differences in longevity between the genders - sometimes tenfold or more - might teach us something about the comparative importance of different mechanisms in aging. In bees, it appears to have much to do with resisting oxidative stress, and this looks to be the case for tarantulas as well: "Reactive oxygen species (ROS), i.e., the by-products of oxidative metabolism, have emerged as the main proximate cause of ageing. Because ROS are mainly produced by the mitochondria, their production is linked to metabolic rate, and this may explain the differences in longevity between large and small species. ... Mitochondrial superoxide production of hemolymph immune cells and antioxidant and oxidative damages plasma levels were measured in adult male and female [tarantulas] at different ages. We found that female spiders are producing less mitochondrial superoxide, are better protected against oxidative attack and are then suffering less oxidative damages than males at adulthood. ... once reaching sexual maturity, males have a life expectancy reduced to 1 to 2 years, while females can still live for 20 years, in spite of the fact that females continue to grow and moult. This study evidences an increased exposure of males to oxidative stress due to an increase in mitochondrial superoxide production and a decrease in hemolymph antioxidant defences. Such a phenomenon is likely to be part of the explanation for the sharp reduction of longevity accompanying male tarantula maturity."

Link: http://www.plosone.org/article/info:doi/10.1371/journal.pone.0013104

A large existing market primed to accept a new medical technology is a powerful thing: it can help to drive commercial application of that new technology far more rapidly than would otherwise happen. I've noted in the past that the hair restoration industry is a good example of this process in action. It's a large enough industry to support its own research community, and the concept of applying tissue engineering to hair regrowth is not a great leap for a customer already thinking about hair loss.

Some years ago it was discovered that when [dermal papilla] cells are relocated, an entirely new hair will grow. That observation is only useful, though, if you can multiply dermal papilla cells - and do so in a way that allows them to keep their ability to induce hair growth. For, in normal culture, dermal papilla cells quickly lose this sought-after ability. ... The long and short of it is that being able to multiply these cells while preserving their efficacy opens the way for unlimited supplies of head hair.

An article in Wired on the work of Cytori Therapeutics makes the case for the industry of breast reconstruction and augmentation to be in a similar position to help advance tissue engineering technologies:

There: a chest as flat as a floor mat from a double mastectomy. There: one so misshapen after a partial mastectomy, it's possible to determine what it actually is only because of its healthy companion. "We realized that for these women there was a huge unmet need for a disruptive change in technology," Calhoun says of the work that has consumed his team of researchers and surgeons for the past eight years. "It's the first practical cell therapy." He pauses. "And it’s breasts." Which means cancer victims with breasts mutilated by surgery - as well as women who are simply unhappy with their natural assets - can now grow a new and improved pair, with raw materials harvested from their own body fat.

..

But breast augmentation is just one development (so to speak) in the company’s more ambitious plan: to introduce stem cell medicine to the mass market ... It makes sense to apply Cytori's technology to enhance breasts instead of, say, repair urinary sphincters as a strategic way to move the patented technology out of rats and into people as soon as possible. Hearts, kidneys, and even sphincters have to work in order for us to survive. But we can live just fine without breast tissue, and, outside of feeding offspring, breasts don’t have to do much. The fact is, the scientific and regulatory hurdles to getting Cytori's cells into clinical use will be easier to clear for breasts than for other tissue: Breasts simply aren’t as necessary as other organs, so the bar for proving to regulators that the technology works will be lower.

You'll notice there one of the more subtle damaging effects of risk-averse regulation of medical research and development, or, more accurately, bad-press-for-otherwise-unaccountable-bureaucrats-averse regulation. It drives efforts towards less meaningful therapies, discouraging investment in the most important solutions and goals by making it harder to bring the fruits of research to market.

An interesting study: "In human populations, variation in mate availability has been linked to various biological and social outcomes, but the possible effect of mate availability on health or survival has not been studied. Unbalanced sex ratios are a concern in many parts of the world, and their implications for the health and survival of the constituent individuals warrant careful investigation. We indexed mate availability with contextual sex ratios and investigated the hypothesis that the sex ratio at sexual maturity might be associated with long-term survival for men. Using two unique data sets of 7,683,462 and 4,183 men who were followed for more than 50 years, we found that men who reached their sexual maturity in an environment with higher sex ratios (i.e., higher proportions of reproductively ready men) appeared to suffer higher long-term mortality risks than those in an environment with lower sex ratios. Mate availability at sexual maturity may be linked via several biological and social mechanisms to long-term survival in men."

Link: http://www.ncbi.nlm.nih.gov/pubmed/20879678

A defining characteristic of Malthusianism is that no matter how often it is proved wrong, you'll still find many who people fervently believe it. Overpopulation is a baseless fear, caused by a fundamental misunderstanding of the way in which people respond to potential scarcity. New resources are developed and old ones made more efficient - demand spurs progress in free societies. From a recent Reason Magazine article: "According to research published by the Royal Society, it looks as though the world will be able to feed 9 billion people by 2050, perhaps even allowing some farmland to revert to nature. Water is a problem, but economic and technological solutions show promise in ameliorating it. But more importantly, [overpopulationists] get the causality backwards. Poverty is the cause and high fertility is the symptom. Poverty traps and failed states which result in high maternal death rates, starvation, pollution, and deforestation are not created by population, but by bad policies. Working to spread economic freedom and political liberty is a lot harder than self-righteously blaming poor people for breeding too much. But it's the only real option."

Link: http://reason.com/archives/2010/10/19/the-eternal-return-of-overpopu

Researchers are well underway in the quest to control human cells: transforming cells from one type into another, for example, with an eye to creating low cost methods of producing cells for transplant on demand. Today's stem cell therapies and technology demonstrations of controlled cellular differentiation are the foundations of tomorrow's regenerative medicine, organ regrowth, and repair of age-worn tissues.

Here are a couple of recent articles that are illustrative of the state of cell research today - a lot of technology demonstrations, many potential therapies a step away from early development, and many scientists hard at work.

Scientists turn stem cells into cells for cartilage repair

The researchers [took] human embryonic stem cells - the pluripotent stem cells that can turn into any of the cells that make up the different tissues in our body - and developed a culture procedure involving a precise sequential programme of conditions to specifically produce chondrocytes, the cells that go on to form cartilage. ... The big challenge with embryonic stem cells is getting all the cells in a culture to do the same thing together, in order to make specific cells types. This work is a big step towards that. Using the same principles we could adapt the procedure to produce not just chondrocytes, but other types of cells, for different clinical applications. To do this so efficiently for directing embryonic stem cells towards chondrocytes was a great result.

Functional nerve cells from adult skin cells generated by UConn scientists

Scientists at the University of Connecticut Health Center have successfully converted stem cells derived from the adult skin cells of four humans into region-specific forebrain, midbrain, and spinal cord neurons (nerve cells) with functions. ... The UConn team [used] cell reprogramming protocols to first transform the adult tissue into "induced pluripotent stem cells" that are all but identical to embryonic stem cells. ... The researchers then exposed these reprogrammed human cells [to] a series of chemical mixtures to drive them into becoming specialized neuronal cells.

If you read the rest of the articles, you'll see that fine control - quality control, in effect - is a present challenge. Cells are complex, adaptive machines, and a cell culture is not the environment they evolved to perform in. Pluripotent cells have the capacity to become many different cell types, and restricting a whole bunch of them to one desired end point is presently hard and expensive. Like many other infrastructural procedures in biotechnology, however, we should expect to see it become easy and cheap within a short span of years. This is, after all, an age of revolutionary progress.

From Accelerating Future: "Yesterday I had the pleasure of meeting John Furber, an anti-aging scientist known as the founder of Legendary Pharmaceuticals. The company's homepage has an excellent introduction to the biology of aging and senescence, and a giant chart with over a hundred nodes and links describing the process of aging. (I got to see a large poster version, which really had an impressive visual effect.) Furber's analysis of the mechanisms of aging are interesting because it strongly parallels Aubrey de Grey's but with a slightly different emphasis and other things to say. Furber has an article out in the hot-off-the-press Springer compilation The Future of Aging 'Repairing Extracellular Aging and Glycation'." Furber is one of the few researchers presently interested in developing a way to break down glucosepane, the most common advanced glycation end-product that builds up with age in human tissue, damaging biochemistry and causing some fraction of the process of degenerative aging.

Link: http://www.acceleratingfuture.com/michael/blog/2010/10/john-d-furbers-comprehensive-aging-graph/

An interview with the SENS Foundation founder: "I've always found that basic scientists who are interested in testing hypotheses think very differently from technologists who are interested in, you know, changing the world in some way. A large part of the difficulties I've had in getting my colleagues in gerontology to really understand what I'm saying is that they're all scientists and not really technologists. In this case what I'm saying is if we implement SENS properly, comprehensively, then it will actually postpone age-related ill health substantially. And we certainly don't have any data plus or minus on that because, of course, we haven't implemented it yet, right? ... 'theoreticians' or generalists are almost non-existent in biology. Unlike physics, where you've got whole departments of theoreticians trying to bring ideas together from disparate areas ... And to the extent it is known, it's given very little respect ... But the thing is, a small coterie of theoreticians in biology who do take care have a rather high hit rate. If you look at winners of the Nobel Prize in biology, you'll find a fair smattering of people who don't know how to work a pipette."

Link: http://www.wired.com/wiredscience/2010/10/aubrey-de-grey/

A recent open access paper from Japan on the effect of one product of electrolyzed water on nematode life span makes a good point, buried down near the end. The study of antioxidants and metabolism in lower organisms is a challenge:

There are many contradictory reports that [reactive oxygen species (ROS) are or are not] responsible for the regulation of the lifespan of nematodes. It has been reported that many antioxidants cannot extend the lifespan of C. elegans, or can extend the nematode lifespan, but not because of their intracellular ROS-scavenging activities. Because the regulatory mechanisms for lifespan are extremely complication, it is possible that [any given newly evaluated antioxidant] extends the lifespan of C. elegans not only be alleviating ROS accumulation, but also by other mechanisms.

It is comparatively easy to alter the life span of smaller, short-lived animals - and thus hard to separate out meaningful effects that are worth testing in mammals. Things become somewhat more clear once you move up to mice, as in general it seems to be the case that the larger the beast, the less plastic its maximum life span becomes. Researchers can make nematodes live many times longer than normal, mice 50-70% longer, and no-one seems to expect the calorie restriction based techniques that extend mouse life span by up to 40% to do more for humans than provide an extra couple of years. Insofar as antioxidants go, the only things worth talking about in mouse studies are those that target mitochondria - as everything else does nothing.

But back to the electrolyzed reduced water, which may or may not have anything to do with mitochondria, and even if it did, may or may not do anything for life span in mammals. As it is, the researchers had to tilt the playing field to make anything happen in worms. Alterations in the chemistry of the local fluid medium are very different ball game when considering the differences between a nematode and a mouse:

Electrolysis of water typically produces two forms of water: electroyzed reduced water (ERW) or alkaline ionized water, produced at the cathode site, and electrolyzed anode water (EAW), produced at the anode site. ... Recently, ERW has attracted much attention because of its antioxidative potential. ERW scavenged reactive oxygen species in vitro and protected DNA from oxidative damage.

...

In the present study, a new culture medium, which we designated Water medium, was developed to elucidate the effects of ERW on the lifespan of Caenorhabditis elegans. Wild-type C. elegans had a significantly shorter lifespan in Water medium than in conventional S medium. However, worms cultured in ERW-Water medium exhibited a significantly extended lifespan (from 11% to 41%) compared with worms cultured in ultrapure water-Water medium. There was no difference between the lifespans of worms cultured in ERW-S medium and ultrapure water-S medium. Nematodes cultured in ultrapure water-Water medium showed significantly higher levels of reactive oxygen species than those cultured in ultrapure water-S medium.

If you parse out exactly what the researchers did there, you'll see that they established a growth medium that caused the worms to suffer greater oxidative damage, and then demonstrated that using electrolyzed reduced water prevented a modest fraction of that damage. But on its own, for worms in a normal growth medium, electrolyzed reduced water didn't do much of anything to life span.

This is actually a very representative example of the study of antioxidants and longevity. You can often show some benefit by increasing the levels of ongoing damage and oxidative stress - but under normal conditions, the antioxidant is a wash. I'm usually wary of studies that show that a given approach rescues animals from some form of abnormal engineered deficiency - unless that deficiency occurs in a specific disease, there may be no real application for what is learned. The electrolyzed reduced water research quoted above shows why it is wise to bear this mind.

Politicians in the developed nations long ago set themselves upon the course to financial disaster. Matters are accelerating now, but all along it has been about the growth of entitlements, and especially forced transfers to wealth from the (largely poor) young to the (largely wealthy) old. As longevity increases, the system becomes ever more bankrupt - and the sooner it breaks down the better. Nothing more is needed to fix these problems than for the hand of government to be removed. "First the good news: We're living longer, healthier lives than ever before. ... Now for the bad news: At this rate, we can't afford to live so long. And by 'we,' I don't just mean you, me and our often insufficient long-term-care insurance policies. I mean 'we the people.' I mean the bureaucratic 'we.' ... For the first time in human history, people aged 65 and over are about to outnumber children under 5. In many countries, older people entitled to government-funded pensions, health services and long-term care will soon outnumber the work force whose taxes help finance those benefits. ... How are the most developed countries handling preparations for the boom in the elderly population - and for the budget-busting expenditures that are sure to follow? For a majority, not very well."

Link: http://www.nytimes.com/2010/10/17/business/17stream.html

A longer article on branched chain amino acids (BCAA) and mouse longevity from Singularity Hub: "First and foremost, the work is in mice. Yes, mice are one of the most common test animals for longevity, and yes, the same BCAA cocktail also worked with yeast cells (another common test organism), but none of that means that humans are guaranteed to benefit. Second, the mice used were all males, and as we've seen with previous work in longevity, some techniques simply do not translate from one sex to another. Third, only 30 mice were used in the BCAA test group (30 in the control as well). That's simply not a very big sample. ... Finally, we should point out that while the Italian experiment showed a 12% increase in median lifespan, the range of lifespans didn't improve nearly as much. Maximum longevity for the BCAA mice was 1043 days compared to 979 days in the control group - a more modest 6.5% increase. If we look at the top 10% of mice in each group, the BCAA mice only improved 4.5% (981 compared to 938). In other words, while the amino acid treatments helped the mice live longer as a group, they didn't produce any super old mice."

Link: http://singularityhub.com/2010/10/15/amino-acids-extend-mice-life-by-12-humans-might-easily-benefit-from-same/

In the course of noticing the shiny new design recently applied to the Alcor News blog, it occurred to me that I've never mentioned the archive of Cryonics Magazine issues that is maintained at the Alcor Life Extension Foundation website. There is a lot of material there, with quarterly or monthly issues dating all the way back to 1981.

The present day interest communities whose members advocate transhumanism, engineered longevity, cryonics, strong artificial intelligence, and advanced nanotechnology (in the sense of molecular manufacturing) didn't spring forth from nothing. They are an ongoing evolution that started with much smaller groups in the 70s and 80s, their growth and changing form spurred by the advent of the internet, web, and other advances in communication and distributed organization.

Anyone with an interest in the formative history of our community would do well to browse the Cryonics Magazine archive. After all, many of the more interesting and pivotal folk involved in advocacy or research and development for transhumanist technologies - such as greatly extending the healthy human life span - have in some way touched upon the cryonics community.

From Spectroscopy Now: "Eat less and you could live longer. That's the view held by an increasing number of people around the world, with the Calorie Restriction Society one of the main standard bearers. ... Following this diet brings about a reduction in the white adipose tissue mass and this has been proposed as a principal factor in longevity. Aging itself tends to have the opposite effect, increasing adipose tissue stores and insulin resistance and this is where clarification is needed. What are the effects of CR and how do they relate to those of aging? ... [researchers] studied the protein profiles of white adipose tissue of rats. One set was maintained on a 40% CR diet from age 12-24 months, with a second age-matched set fed ad libitum (AD). Proteins were extracted from the white adipose tissue ... a total of 133 proteins were found to be differentially expressed between the CR and AD animals. Many of the CR-induced changes were unaffected by age, implying that CR does not simply arrest or reverse age-associated changes. The influences of the two processes appear to operate under different mechanisms. ... [some] protein expression changes induced by CR gave improved protection against oxidative stress by halting the age-associated reduction in the levels of several antioxidant enzymes and decreasing the levels of stress-induced proteins. ... Both CR and aging also changed the expression of proteins involved in the cytoskeleton, iron storage and energy metabolism ... In the long term, the results could also lead to the identification of novel biomarkers of aging and possible targets for mimetics of CR that could provide the same outcome, an extended lifespan, without having to follow a rigorous and controlled diet."

Link: http://www.spectroscopynow.com/coi/cda/detail.cda?id=24357&type=Feature&chId=10&page=1

Maria Konovalenko looks at the work of researcher Ana Cuervo: "the current challenges in the field of aging are two-fold: To continue and complete the molecular dissection of the factors that contribute to aging and to promote the translation of these novel findings into interventions to improve the health-span of the aging human population. ... Dr. Cuervo identified certain defects that lead to decreased activity of chaperone-mediated autophagy (CMA) with age and how to correct and improve cellular function. Dr. Cuervo theorized that the decrease of autophagy could be a determining factor in why some older organisms are unable to fight off cell abnormalities. Her research looked at the breakdown of the various autophagic pathways as the body ages and if restoring these pathways would jumpstart normal cellular activity. ... CMA is involved in at least 30% of the body's cell degradation processes and upon studying this pathway, Cuervo determined that the LAMP-2A protein acts as a vital receptor in the pathway. In recent experiments, livers in genetically modified mice 22 to 26 months old (the equivalent of octogenarians in human years), that were injected with the LAMP-2A protein, cleaned blood as efficiently as those in animals a quarter their age! By contrast, the livers of normal mice in a control group began to fail."

Link: http://mariakonovalenko.wordpress.com/2010/10/15/expert-on-cellular-and-organ-aging-%E2%80%9Cthe-bodys-ability-to-dispose-of-cell-debris-could-extend-life-%E2%80%9D/

With advancing age, muscles weaken and lose mass. This makes it harder for older people to gain the benefits of exercise, and eventually it leads to frailty. This process of degeneration was given the name sarcopenia some twenty years ago, and efforts have been underway for some years to have the FDA recognize it as a disease rather than "a normal part of aging." Until the FDA does so, there is no way to raise significant funds for research and development, or make the results of what research has taken place commercially available. It's a sad and sick society we live in, wherein the people at the cutting edge of research - those who know best what needs to be done - must bow and scrape for years so that unelected, unaccountable, ignorant bureaucrats will deign to permit work to proceed.

In any case, here is an open access review paper that serves as a useful introduction to the present state of research into sarcopenia.

The term sarcopenia first coined by Irwin Rosenberg in 1989 is now widely accepted to describe the steady and involuntary loss of skeletal muscle mass during aging. Although the word sarcopenia is used in the field of gerontology to describe this phenomenon of aging, the complex multifactorial changes in muscle fiber quantity and quality, protein synthesis rates, alpha-motor neurons of spinal cord, anabolic and sex hormone production are poorly understood. These changes combine and result in a smaller, slower contracting muscle with impaired capacity to generate sufficient strength and power for activities of daily living.

...

In 2004, Janssen et al estimated that the annual healthcare cost attributable to sarcopenia was approximately $18 billion in the United States. In the current environment of global aging, the future health burden of sarcopenia is self-evident, and interventions are needed to slow or reverse the loss of muscle mass and function in our aging populations.

...

The published data on sarcopenia are vast, and this review is not intended to be exhaustive. The aim of this review is to provide an update on the current knowledge of the definition, etiology, consequences, and current clinical trials that may help address this pressing public health problem for our aging populations.

As a researcher noted a while ago:

[When] I was heading aging at Glaxo Smith Kline, the issues that I faced were that I was very interested in developing medications for frailty and weakness in muscle for when people get old because when people get weak they usually stop eating and then they fall and break a hip and end up in the hospital and die potentially, but the regulatory apparatus isn’t there yet. Sarcopenia isn’t recognized as an official disease by the FDA, so the pathway to get drugs approved for frailty and to get more people mobile and into society is just not there.

There's something very wrong with the picture of medical research in this day and age, and that has everything to do with the unchecked growth of government.

Researchers continue to catalog the parts of our cellular machinery that are affected by longevity-enhancing changes in metabolism, such as the practice of calorie restriction: "Metallothionein (MT) is a low molecular weight protein with anti-apoptotic properties that has been demonstrated to scavenge free radicals in vitro. MT has not been extensively investigated within the context of aging biology. The purpose of this review, therefore, is to discuss findings on MT that are relevant to basic aging mechanisms and to draw attention to the possible role of MT in pro-longevity interventions. MT is one of just a handful of proteins that, when overexpressed, has been demonstrated to increase mouse lifespan. MT also protects against development of obesity in mice provided a high fat diet as well as diet-induced oxidative stress damage. Abundance of MT is responsive to caloric restriction (CR) and inhibition of the insulin/insulin-like signaling (IIS) pathway, and elevated MT gene expression has been observed in tissues from fasted and CR-fed mice, long-lived dwarf mice, worms maintained under CR conditions, and long-lived daf-2 mutant worms. The dysregulation of MT in these systems is likely to have tissue-specific effects on aging outcomes. Further investigation will therefore be needed to understand how MT contributes to the response of invertebrates and mice to CR and the endocrine mutations studied by aging researchers."

Link: http://www.ncbi.nlm.nih.gov/pubmed/20933613

This is a novel formulation of aging, though I don't think it has any great impact on the justification for repair strategies such as SENS: "In the past, it has been assumed that all the biological and medical changes that occur in old age are deleterious. It has therefore been concluded that treatment and prevention of such changes in old age should increase healthspan and delay death. However, accruing epidemiological and clinical trial evidence in older humans suggests that this is not the case. Some studies have shown that antioxidants and hormone supplements increase mortality, whereas high blood pressure, obesity, and metabolic syndrome are often associated with improved outcomes in very elderly people. Perhaps, some of these supposedly detrimental changes accompanying old age are in fact evolutionary adaptations to prolong life after reproduction in humans. Indeed, a form of reverse antagonistic pleiotropy or adaptive senectitude might be occurring. Some common biological and medical changes in old age might actually enhance longevity and represent novel targets for improving health in older people."

Link: http://www.ncbi.nlm.nih.gov/pubmed/20937675

Over at the Scientist, you'll find an interesting researcher's perspective on a topic that's come up here a couple of times: the relationship between the mechanics of cell division, garbage management, and aging. In essence we might look back at the origins of cellular life and decide that aging was in some way an inevitable adaptation in bacteria and other single celled life, stemming from the need to manage their garbage load. A cell, after all, accumulates garbage in the form of malformed proteins and gunk that cannot be broken down. If allowed to build up indefinitely, that garbage will destroy the cell. In order to preserve a lineage, cells therefore practice garbage management when they divide: one daughter cell is given all the garbage, allowing the other to continue pristine.

This works out well for single celled organisms - after all, they can just write off the occasional daughter lineage turned into a garbage disposal mechanism. It isn't so helpful for the multi-cellular organisms that later evolved. Now the garbage-cluttered cells can't just be written off: they're still present in the organism, being broken, inefficient, and gradually messing up the cellular environment. The ugly realities of cellular garbage gives rise to the garbage catastrophe in aging, and related issues, such as the age-related failure of garbage recycling mechanisms that have evolved to deal with multi-cellular existence.

The bigger picture is far more complex and less certain than the simple outline I provide, of course, so you might look back into the Fight Aging! archives for a longer introduction.

• The Relevance of Bacterial Aging
• Aubrey de Grey on Bacterial Aging
• The Deep Roots of Aging

And here's that article from the Scientist, which ranges from personal account to speculation on information theory applied to cell biology to outline of aging research:

Unicellular organisms were thought to be capable of dividing forever, as long as conditions allowed: one generation begetting the next down through time - a sort of immortality. If unicellular organisms were like somatic cells, then they would age as they divide, reach the Hayflick limit, and die. It wasn't until the 1950s that researchers who thought about aging began to change their minds. It became clear that the daughter cells of some unicellular organisms seemed to rejuvenate, to start from scratch, while the mother cells accumulated the cellular aberrations that signaled aging. This pattern of aging was seen in such evolutionarily distant organisms like Saccharomyces cerevisiae, known as budding or baker’s yeast, and bacteria such as Caulobacter crescentus and Escherichia coli.

...

For me, that realization begged a more fundamental question, one that as biologists, we are scarcely allowed to ponder: Why do cells allow some mistakes to accumulate? If evolution is such a powerful process - one that finds solutions to all manner of problems - how could there be processes or problems that can’t be fixed? As I continued my research into aging and cell division, I couldn't help but think about how to categorize these "unfixable" problems like aging. Could there be a mathematical description that might capture and explain biology's fallibility?

Read the whole thing; it's an interesting line of thought.

Via EurekAlert!: scientists "report a new experimental compound that can improve memory and cognitive function in ageing mice. The compound is being investigated with a view to developing a drug that could slow the natural decline in memory associated with ageing. ... the team has identified a preclinical candidate that they hope to take into human trials within a year. ... memory loss has been linked with high levels of 'stress' steroid hormones known as glucocorticoids which have a deleterious effect on the part of the brain that helps us to remember. An enzyme called 11beta-HSD1 is involved in making these hormones and has been shown to be more active in the brain during ageing. ... the team reports the effects of a new synthetic compound that selectively blocks 11beta-HSD1 ... Normal old mice often have marked deficits in learning and memory just like some elderly people. We found that life-long partial deficiency of 11beta-HSD1 prevented memory decline with ageing. But we were very surprised to find that the blocking compound works quickly over a few days to improve memory in old mice suggesting it might be a good treatment for the already elderly. ... The effects were seen after only 10 days of treatment."

Link: http://www.eurekalert.org/pub_releases/2010-10/wt-pdc101110.php

Ben Goertzel reports on the recent Personalized Life Extension conference at h+ Magazine: "It was a pretty sophisticated crowd with an attitude both radical and down-to-Earth - the general feeling was something like 'We all pretty much believe that "longevity escape velocity" is likely to happen sometime this century, due to a combination of scientific and technological advances, so if we can just live long enough into the century, we may be able to live centuries or millennia or longer. So now the question is: What can we do, in practice, and so increase the odds that we do live long enough to see the really radical life extension technologies emerge?' Or to put it in Ray Kurzweil's terms: how can we live long enough to live forever? If Kurzweil is right, then in 2045 or so, technology will have advanced far enough that involuntary death will be an unlikely tragedy. In that case, what really matters is to keep our meat-bags chugging till that wonderful date. Whether the precise date is really 2045 or not, the concept still has value. Aubrey de Grey has called it 'the Methuselarity' - the date at which, if you live that long (by hook or by crook), cascading improvements in life extension technology will likely keep extending your lifespan forever."

Link: http://hplusmagazine.com/editors-blog/two-days-among-immortals

The Immortality Institute 2010 conference was held in Brussels this past weekend: a mix of life science researchers and advocates for greater research into engineered human longevity attended and gave presentations. From what I hear, the conference went well, with congratulations being due to the volunteers who organized it.

That was absolutely a great event, with some of the most cutting-edge scientists in the field, presenting new facts, some of them not published yet, that will certainly change the face of the world in the next years or decades. I felt that scientists were really touched by this young dynamic generation that understands their work and supports them, and we could feel that this bridge between generations as well as between researchers and amateurs is bringing a lot of cohesion into this movement for life extension.

...

It was a great event - a masterful achievement by the organizers. Thank you! I was happy to be part of it. Indeed, most inspiring was the young dynamic generation, devoted just as we are to making greatly extended lifespan a reality and enjoying superb health.

For those who couldn't make it, some video from the conference is online already:

Paul McGlothin on Calorie Restriction in Humans at ImmInst 2010 via Teleplace

Paul McGlothin is Vice President for Research and Director of the Calorie Restriction Society and co-author of "The CR Way".

Michael Rose on A New Immortalist Strategy at ImmInst 2010 via Teleplace

Prof. Dr. Michael Rose is one of the most eminent evolutionary biologists specialized in aging. He has written several books including "The long tomorrow". Prof. Rose is Chief Scientist at Genescient.

You'll also find some of the live video archived at Ustream.tv, but the quality is poor, as is usually the case with archived live feeds. There you'd most likely be better off waiting for the Institute volunteers to process and post higher quality conference video.

The quality of automated translation for Norwegian is apparently lagging behind that of more widely used languages, but here is an earthy men's magazine piece on biomedical gerontologist Aubrey de Grey: "There are trees that can live for 5,000 years, and there is evidence that some bacteria have survived for 25 million years. And a small freshwater creature, [called] hydra, does not seem to age at all. They can die [through accident or violence] but [if left alone] will most likely live forever. Old age - which [de Grey believes] is the worst humanitarian crisis of all time - will never kill it. Then it's different with us humans. 100,000 of us die of old [age] every day. ... We are experiencing something that is equivalent to 30 World Trade Centers [each] day, and nobody does a damn thing about it, says de Grey. ... de Grey's great a-ha experience came at four in the morning in June 2000. De Grey had twisted his head back and forth over the old age problem, and now he was jet-lagged in a hotel in Manhattan Beach in California and let the mind drift. Then it hit him: Instead of trying to understand the problem [of aging], it's easier just to fix it. ... de Grey took out pen and paper and wrote down everything in the body that need to be fixed to prevent physical and mental [degeneration]. Surprisingly enough, this list only on nine points, and today it is down to seven. And since then he has worked with a step-by-step treatment for old age, called Strategies for Engineered Negligible Senescence or SENS shortened. He has a dedicated laboratory with researchers who are under the supervising eyes of de Grey, and if it was not [for lack of funding] they believe [that] we will have eternal life [in a laboratory mouse] in a decade."

Link: http://translate.google.com/translate?hl=en&sl=auto&tl=en&u=http://www.nettavisen.no/side3/article3000673.ece

A report by Ben Best can be found at Depressed Metabolism: "On the first weekend of October, 2010 I was an invited speaker at 'Applied Cryobiology – Scientific Symposium on Cryonics held in Goslar, Germany ... The meeting was the first effort by the German Society for Applied Biostasis (DGAB) to create a milieu for scientific discussion of cryonics-related issues as well as to elevate the scientific status of cryonics and bring more scientists into the field. DGAB hopes to have another such symposium in two years. ... The symposium was originally to be held mainly in German, but there were twice as many attending (about 50) as had been anticipated - and so many were from outside Germany that the organizers decided to have all sessions in English. Although many of the participants had impressive scientific backgrounds, they were overwhelmingly people with a personal interest in cryonics. The organizers struggled to get speakers with scientific credentials, but many of those who would have been otherwise interested and qualified did not want to risk their careers by participation." As is the case for other facets of longevity-related research and development, such as the Strategies for Engineered Negligible Senescence, cryonics has a good scientific foundation, but much of the scientific community - especially in cryobiology - reject and shun it for reasons that have nothing to do with science.

Link: http://www.depressedmetabolism.com/2010/10/11/october-2010-cryonics-symposium-in-germany/

Research suggests that changes in messenger RNA (mRNA) translation - a step in the complex process by which proteins are built from the blueprint of a gene - are important in the metabolic determination of longevity. This appears to be one of the ways in which the TOR gene, and thus rapamycin, influences longevity: "Appropriate regulation of mRNA translation is essential for growth and survival and the pathways that regulate mRNA translation have been highly conserved throughout eukaryotic evolution. Translation is controlled by a complex set of mechanisms acting at multiple levels, ranging from global protein synthesis to individual mRNAs. Recently, several mutations that perturb regulation of mRNA translation have also been found to increase longevity in three model organisms: the budding yeast Saccharomyces cerevisiae, the nematode Caenorhabditis elegans and the fruit fly Drosophila melanogaster. Many of these translation control factors can be mapped to a single pathway downstream of the nutrient responsive target of rapamycin (TOR) kinase. [This suggests] that mRNA translation is an evolutionarily conserved modifier of longevity and [could] influence aging and age-associated disease in different species."

Link: http://www.ncbi.nlm.nih.gov/pubmed/20886753

This open access PDF editorial is illustrative of the mainstream scientific examination of human longevity. Demographic studies lead to genetic studies - to identify long-lived populations and then the genetic roots that make them different: "It is now evident from various socio-demographic studies that a greater portion of the population survives into old age, above the seventh decade of life. Projections for Europe estimate that in 1995 13.3% of the population was over the age of 65, whereas by 2015 this figure is expected to rise to 16.3%. However, the factors that promote living after the seventh or eighth decade of life remain unknown. Therefore, a question may arise: what is the 'formula' that allows some elders to avoid chronic diseases, such as cancer and cardiovascular disease? ... Clearly, longevity is a complex attribute determined by factors, such as exposure to disease, variability in sleeping patterns, smoking habits, physical activity and diet, that have a direct effect on longevity, in addition to their indirect emotional and cognitive influence on physiological pathways." This sort of work will continue for many decades, with little sense of urgency and equally little effect upon our lives. It is a world removed from the engineering approach to extending life span advocated by the SENS Foundation, amongst others.

Link: http://www.hellenicjcardiol.org/archive/full_text/2010/5/2010_5_479.pdf

Today I'll point you towards a translated blog post from Alexey Moskalev, a biogerontologist in Russia. He offers some views on the history of mankind's adversarial relationship with death, and how this informs what should be our modern view of gerontology and aging research. As always, you'll have to excuse the quality of automated translation: it is improving rapidly, and is good enough for comprehension, but still, I think, stumbles on structural differences in the way in which different cultures use language to express themselves.

Unconscious fear of death occurs in a child already at birth. There he and the animals [are the same]. Fear of death plays an important biological role: along with the pain he wakes survival instinct that forces to avoid danger or flee from it. However, in humans, as a rational being, there is awareness of their own mortality. The child begins to recognize their mortality at the end of preschool age, and even earlier. Understanding of powerlessness in the face of death is inconsistent with fear of death and the unconscious desire to save his life. This contradiction [gives rise to two distinct psychological reactions] - adaptation or confrontation.

[No-one can prosper in a wasteland]. Similarly, we can formulate a rule of psychology: a rational creature can not evolve with constant thoughts of death: [one can instead] forget, not think about it or deny it. [Forms] of psychological adaptation may also include [acceptance of] the inevitability of death, resignation, faith in the [continuation of life after death], confidence in the death benefit - a "just punishment", "punishment for sins, "an evolutionary necessity, "the engine of progress." [Apologism for] death is extensive [in] religious, philosophical and artistic literature, masterpieces of cinema.

Some psychologists, such as S. Belousov, in contrast, believe that only [by overcoming] the fear of death, [does a] person starts to live a full and authentic life. Confrontation with the fact of mortality [is, or should be] a natural phenomenon for man. As can be seen from the table, the desire to overcome the causes of death, along with a desire to improve the quality of life occurred in [antiquity] and became the principal engine of progress.

Period	Causes of death	Ways to counter
Past	Hunger	Gathering, hunting, animal husbandry and [farming]
	Supercooling	Clothing, fire, housing
	Trauma, parasites, infections	Folk healing, classical medicine
Today	Cardiovascular disease, cancer	Modern medicine
	Aging	[Biogerontology], transplantation, regenerative and nanomedicine, gene engineering
	Accidents	Improving the social and productive infrastructure

I should say that Moskalev's views on gerontology as a battle against death are representative of the Russian research community, but not of US gerontologists, many of whom are still doing their level best to deny any association with efforts to extend life span. As I've noted in the past, Russian culture seems far more amenable to the concept of engineered longevity than that of we English-language Westerners - and perhaps that difference starts with an aging research community whose members understand that the whole point of the exercise is to defeat death.

Some thoughts on hostile attitudes towards cryonics from Depressed Metabolism and Mark Plus:

One of the mysterious things about cryonics is that some of the arguments that are invoked against it would be considered ridiculous, or even insensitive, if they would be raised in the context of other live-saving technologies.

...

Why do we call engineering efforts to solve a hard problem which haven't worked so far "failures," while some people call cryonics' attempts at intervening into the death process "denial?" The difference seems to involve a double standard. We don’t call other efforts to save human life "denial" when they don’t work in some cases, and not just in a medical context. The effort to rescue those trapped miners in Chile may not work, for example; but nobody I know of calls the rescue project "denial," wants to stop it as a waste of resources, and admonishes the doomed miners to "Get over yourselves," as one of Ted Williams's relatives has said to cryonicists.

The same goes for medicine in general. How would we react if authority figures scolded us for seeking health care for serious illnesses or injuries, saying that we should instead deal with our "denial" and "fear of death" issues through, say, strength of character, rather than trying to stay alive and functional through modern medicine?

Sadly this prevailing double standard is also in force when it comes to life science research aimed at reversing aging and thereby greatly extending the healthy human life span. When listening knee-jerk reactions against engineered longevity and apologism for the suffering and death caused by aging, it's helpful to imagine the objecting person transported back in time to 1800 or thereabouts, and spouting the same nonsense about accepting the longevity we have - in an era with a far lower human life expectancy.

A person who ages to frailty is no less suffering and no less dead in the end than one who dies through accident or disease at a younger age. So many people are instinctively hostile to the prospect of anyone managing to live longer, just as they are instinctively hostile to those who make far more money - and this jealousy is, sadly, an important aspect of human nature. We primate hunter-gatherers are hardwired to hate and stamp out inequality wherever we see it, a tendency that isn't helpful at all in this day and age of great cities and complex economies. When acted upon, these urges help to hold back improvement for all:

Life is unfair, make no mistake. People are unequal in opportunity, capacity and the hand they were dealt at birth. To think that this truth can be removed in any way, shape or form is to betray a profound ignorance of economics and the human condition. You cannot make life better at the bottom by tearing down the top; the top is where progress happens, progress that lifts the quality of life for everyone. Punishing success in order to reward failure has predictable results - more failure and less success. The wealthy of 1950 were far worse off than the poor of today precisely because progress brings economic rewards to the successful.

Via FuturePundit, the estimates for recent research funding: "The U.S. invested $139 billion last year in health research from all public and private sources, according to Research!America's latest annual estimate. That amount represents only 5.6% of the $2.47 trillion overall U.S. health spending in 2009 [which] varies no more than 0.2% from 2005 levels. ... We are all growing old. We are all aging and our parts are breaking down and wearing out. A portion of those billions of dollars flows toward science technologies that will eventually put an end to aging. Human bodies will become as repairable as cars. Replacement organs, cell therapies, gene therapies, and even nanobots will, at some point in the 21st century, halt and reverse the process of aging. Will you still be alive when that day is reached?" As has always been the case, funding for research is a tiny percentage of the flows of money in our culture. Funding for aging research is a tiny fraction of the figures given above, and funding for engineered longevity is in turn a tiny fraction of aging research. To fully realize the Strategies for Engineered Negligible Senescence in mice in the laboratory would probably cost in the vicinity of $1-2 billion over a decade or two. Food for thought.

Link: http://www.futurepundit.com/archives/007557.html

From the Australian: "Generating new body organs in the lab is the stuff of Hollywood fantasy. But judging by the latest experimental findings, science fiction may soon be science fact. ... Already, a bio-printer is cranking out three-dimensional tissues and Australian researchers are hard at work growing spare parts, with designer tissues proving their stuff in animal - and even human - trials. ... In animal experiments, [researchers have] made breast, fat, muscle and even pancreatic tissue that secretes insulin. They've also created tissue of a specialised immune system organ, the thymus, opening the way for multiple applications in immunology. That's because the thymus schools T-cells that help the immune system identify and fight infections and foreign cells. Using mice bred with no immune system, [researchers] found that after the mice received newly grown tissue they developed effective immune responses. ... the institute is engaged in a small number of human clinical trials with fat and breast tissue. The goal is to establish whether tissue can be created and used to replace tissue removed due to cancer. The trials have about six months to run. While creating living tissue is important, the larger aim is creation of functioning human organs."

Link: http://www.theaustralian.com.au/news/health-science/tailor-made-living-tissue-is-hot-off-the-press/story-e6frg8y6-1225935870396

Words carry baggage, a cloud of associated meaning that extends somewhat beyond what you'll find in the dictionary - and in some cases effectively supersedes the dictionary definition in common usage. Language is a living thing, and dictionaries are the conservative statements of a language's gatekeepers, not its primary and most numerous users.

It recently occurred to me that "rejuvenation" is a word whose primary meaning and baggage in common usage is no longer the first entry in the dictionary.

re·ju·ve·nate: to make young again.

This is important, because when we advocate engineered human longevity by using the word rejuvenation, to make young again is exactly what we mean. We are being precise, and using rejuvenation to mean "a hypothetical reversal of the aging process."

The problem here is that "rejuvenation" has long been a term of art and marketing brand for cosmetics manufacturers, the horrid "anti-aging" marketplace, dermatologists, and plastic surgeons - four communities with a significant overlap. They also boast very significant revenues, meaning their voices are loud and their presence hard to miss.

What all of these groups have in common is that they develop and sell products and services claiming to restore the appearance of youth to some degree: fake rejuvenation, in other words. At best it's a matter of papering over the cracks - but these folk use the term rejuvenation without qualification or reservation. In their eyes and publicity materials, "rejuvenation" means exactly "faking the appearance of rejuvenation."

Here is something I noticed only recently: head on over to PubMed, the reference repository for papers published in scientific journals, and search for "rejuvenation". You'll quickly see page after page of dermatologists and plastic surgeons talking about the tools and techniques by which they fake the appearance of rejuvenation in skin and facial structure. Every technical artifice, none of which do anything to intervene in the actual process of aging, is labeled as rejuvenation - because in their field, rejuvenation means artifice. It means fakery, deception, and alteration of appearance.

As I mentioned, this is a rich field. Throw enough money into marketing and the meanings you ascribe to words will spread into common usage. On the whole, this is a somewhat depressing state of affairs, but par for the course given human nature.

Mitochondrially targeted antioxidants - such as gene engineering of increased amounts of catalase - are shown to extend life in mice, but here researchers find no such effect (or a negative effect) in flies: "The simultaneous overexpression of multiple copies of Mn superoxide dismutase (SOD) and ectopic catalase (mtCat) transgenes in the mitochondria of the fruit fly, Drosophila melanogaster, was shown previously to diminish the life span. The hypothesis tested in the present study was that this effect was due primarily to the presence of one or the other transgene. An alternative hypothesis was that both transgenes have additive, negative effects. Crosses were performed between five pairs of transgenic lines containing single-copy insertions of either mtCat, Mn SOD, or P element vector control transgenes at unique loci, and the life spans of progeny containing two mtCat, Mn SOD or vector insertions were determined. Increasing amounts of mitochondrial catalase activity tended to be associated with decreases in mean life span. Overexpression of two copies of the genomic Mn SOD transgene had no effect on life span. The results do not support the hypothesis that enhanced mitochondrial SOD or catalase activity promotes longevity in flies." This suggests that it's possible to set up a situation in mammals wherein mitochondrially targeted antioxidants are harmful to life span, but I'm not aware of any examples.

Link: http://www.ncbi.nlm.nih.gov/pubmed/20923705

CALERIE is the largest present study of calorie restriction in humans: "In a robust and consistent manner, sustained caloric restriction (CR) has been shown to retard the aging process in a variety of animal species. Nonhuman primate studies suggest that CR may have similar effects in longer-lived species. The CALERIE (Comprehensive Assessment of the Long-term Effects of Reducing Intake of Energy) research program is the first systematic investigation of CR in nonobese human beings. In the phase 2 study, it is hypothesized that 2 years of sustained CR, involving a 25% reduction of ad libitum energy intake, results in beneficial effects similar to those observed in animal studies. ... The study is a multicenter, parallel-group, randomized controlled trial. A sample of 225 participants [is] being enrolled with 2:1 allocation to CR. ... An intensive dietary and behavioral intervention was developed to achieve 25% CR and sustain it over the 2 years. Adherence is monitored using a doubly labeled water technique. Primary outcomes are resting metabolic rate and core temperature, and are assessed at baseline and at 6-month intervals. Secondary outcomes address oxyradical formation, cardiovascular risk markers, insulin sensitivity and secretion, immune function, neuroendocrine function, quality of life and cognitive function. ... The results will provide insight into the detrimental changes associated with the human aging process and how CR mitigates these effects."

Link: http://www.ncbi.nlm.nih.gov/pubmed/20923909

The next decade or two of medical science will be dominated by progress in cell engineering. Today that field is still largely a matter of building low cost and reliable research tools, with first generation therapies as a secondary benefit rather than a primary goal. Much of that work involves stem cells: understanding them, and then figuring out how to create and control them as needed. Stem cells are comparatively rare cells in the body, of many different types, that maintain and build tissue. All descend from the original embryonic stem cells that build the body in the first place:

In a developing embryo, stem cells can differentiate into all of the specialized embryonic tissues. In adult organisms, stem cells and progenitor cells act as a repair system for the body, replenishing specialized cells, but also maintain the normal turnover of regenerative organs, such as blood, skin, or intestinal tissues.

Somewhere along this road stand a complete toolkit for repair of injuries that do not normally heal, technology to build replacement organs as needed, and other feats of medical science. This is one of the technology platforms needed to reverse the course of aging - to be able to build replacement cell populations for those that have become worn and dysfunctional with age.

Embryonic stem cells are important in stem cell research because they are pluripotent: able to create all cell types. A few years ago, researchers figured out how to turn ordinary cells into pluripotent cells that seemed to be as powerful as embryonic cells - a much cheaper and more readily available source than embryonic cells, and with the added possible benefit of using a patient's own cells to grow any form of tissue desired. These engineered stem cells are called induced pluripotent stem cells, and one present focus of research efforts is to understand whether they are, in fact, the same as embryonic stem cells.

For example, see this open access paper:

After the hope and controversy brought by embryonic stem cells two decades ago for regenerative medicine, a new turn has been taken in pluripotent cells research when, in 2006, Yamanaka's group reported the reprogramming of fibroblasts to pluripotent cells with the transfection of only four transcription factors. Since then many researchers have managed to reprogram somatic cells from diverse origins into pluripotent cells, though the cellular and genetic consequences of reprogramming remain largely unknown. Furthermore, it is still unclear whether induced pluripotent stem cells (iPSCs) are truly functionally equivalent to embryonic stem cells (ESCs) and if they demonstrate the same differentiation potential as ESCs.

...

When compared to ESCs, iPSCs, as expected, share a common pluripotency/self-renewal network. Perhaps more importantly, they also show differences in the expression of some genes. We concentrated our efforts on the study of [a range of genes] (in ESCs) which are not expressed in ESCs, as they are supposedly important for differentiation and should possess a poised status in pluripotent cells, i.e. be ready to but not yet be expressed. We studied each iPSC line separately to estimate the quality of the reprogramming and saw a correlation of the lowest number of such genes expressed in each respective iPSC line with the stringency of the pluripotency test achieved by the line.

Cells are complex and wayward little beasts, and many similar but different methodologies are presently being using to produce iPSCs. The end results vary in some way from laboratory to laboratory because that is true of almost every form of cell engineering. Cells change their gene expression profiles in minor ways at the drop of a hat. But these researchers are at least demonstrating that there are ways in which iPSCs can be methodically assessed and rated against ESCs.

A related paper:

The purpose of this study was to determine the degree of molecular similarity [between] differentiated cell types [derived] from human iPS cells and conventional ES cells. Our data indicates that [iPS cells] are transcriptionally highly similar to [ES cells].

This is how the sausage is made in the life sciences: a lot of very painstaking measurement and assessment of complex, shifting cellular machinery.

Inevitably, researchers who focus on slowing aging through metabolic manipulation will uncover ingested compounds that alter metabolism in beneficial ways, and thus very modestly raise life expectancy. Here is an example in mice: "Recent evidence points to a strong relationship between increased mitochondrial biogenesis and increased survival ... Branched-chain amino acids (BCAAs) have been shown to extend chronological life span in yeast. However, the role of these amino acids in mitochondrial biogenesis and longevity in mammals is unknown. Here, we show that a BCAA-enriched mixture (BCAAem) increased the average life span of mice. BCAAem supplementation increased mitochondrial biogenesis and sirtuin 1 expression in primary cardiac and skeletal myocytes and in cardiac and skeletal muscle, but not in adipose tissue and liver of middle-aged mice, and this was accompanied by enhanced physical endurance. Moreover, the reactive oxygen species (ROS) defense system genes were upregulated, and ROS production was reduced by BCAAem supplementation. All of the BCAAem-mediated effects were strongly attenuated in [mice engineered to lack] endothelial nitric oxide synthase." Nitric oxide is important to stem cell and blood vessel function; it is interesting that this effect depends upon that component of metabolism.

Link: http://dx.doi.org/10.1016/j.cmet.2010.08.016

A brief summary of recent research into risk factors for disease and human longevity: "A set of currently known alleles increasing the risk for coronary artery disease, cancer, and type 2 diabetes as identified by genome-wide association studies was tested for compatibility with human longevity. Here, we show that nonagenarian siblings from long-lived families and singletons older than 85 [years] of age from the general population carry the same number of disease risk alleles as young controls. Longevity in this study population is not compromised by the cumulative effect of this set of risk alleles for common disease." The way in which you choose to lead your life is a more important determinant - for example, being sedentary and fat raises your risk of suffering the common diseases of aging far more than most known genetic variants. It is true that there are many gene variants associated with exceptional human longevity, but it still seems to be the case that environment and choice trumps small variations in your biology.

Link: http://www.ncbi.nlm.nih.gov/pubmed/20921414

Let me be far from the first to observe that humans, collectively, are grandly and suicidally irrational. I point to war and destructive waste of institutional government as the primary symptoms, but there countless others. We humans are instinctive builders of social hierarchy, and aggressive optimizers in short-sighted search of the local maxima of our personal wellbeing. We'll ignore any number of fascinating mountains on the the horizon to climb to the top of the pitcher's mound right in front of us.

These two aspects of human nature - the short-sighted quest for gain and the need for hierarchy - combine to form a collective insanity, and are the root of the grand and depressing cycle of human societies. Production of wealth in a free society leads to the creation of a violence-backed hierarchy of rulership - the state - which in time bloats to become a police state or an empire. In either case power is concentrated enough for those at the top to destroy their society through the simple exercise of human nature. Corruption, destruction, unintended consequences, and the urge to personal enrichment. The resulting collapse removes the hand of the state to at least some degree, leading to the freedom needed to create wealth once more. And so it begins again.

This is the way it will be until some faction of humanity engineers changes in human nature: which will happen, probably near the advent of strong artificial intelligence, but not on a timescale useful to a discussion of what will happen to present to the present dominant empires, such as the US.

In any case, I'd like to point out a different form of insanity that springs from our human lust for local maxima and blindness of distant mountains: in this day and age, the rational use for any amount of money - beyond that needed to get by, for whatever definition of "get by" you care to use - is longevity science. Research into extending the healthy human life span by repairing and reversing the biochemical damage of aging. Why is this? Because time is limited, and money is not.

Time spent alive is the root of all property, all human action, and thus all wealth - both the silver in your pocket that provides for present choice, and the wealth of possible choices created by past investment. Time is everything. How much have time you spent reading this far? Could you have been doing something more useful, more optimal from your perspective? We make these small evaluations constantly, because time is the most valuable thing we have.

A hundred years ago, additional time was a limited commodity. You could spend resources to have a little more of it - doctors, a good life, the learning needed to take advantage of these items - but after a certain point there was no amount you could spend that would let you live for even one additional day.

This is no longer the case.

A sufficiently massive directed research program could, for example, realize the SENS program for rejuvenation within a couple of decades, to produce the planned and presently understood methods for repairing the biochemical and cellular damage that causes aging. Say $2 billion spent at $100 million a year, and you'll have working rejuvenation in mammals in the laboratory, ready to move to development in humans. It really is that cheap to go from where the research community stands now to completed proof of concept, and that would fund the full spectrum of development: replacement of mitochondrial DNA, safe breakdown of AGEs, amyloids, lipofuscin, and other unwanted chemical gunk, replacement of damaged stem cell populations, immune system restoration, and so forth. Cures for all cancers are in that list as well, but I'm actually fairly confident that will happen anyway before 2040 rolls around.

If you have time and health, you can always make more money. If you have neither time nor health, then money is worthless. So it seems fairly obvious where a rational person should direct the money not needed to get by. It should all go to longevity science: increasing the chance of you personally living into an age of indefinite healthy, youthful life spans, brought about by medical technologies of maintenance and repair that can reverse the course of aging.

But of course, we're all irrational seekers after local maxima, and so longevity science is largely unknown and unfunded. It's that mountain on the horizon - the biggest of them all. But that just seems to make it easier to ignore. So we keep climbing that pitcher's mound while the empire rolls towards its demise around us.

Your cells are constantly creating and destroying the protein components of their machinery. All of the known metabolic alterations that enhance longevity affect these processes in some way: "Cellular homeostasis, which is needed for the cells to survive, requires a well-controlled balance in protein turnover. Both protein synthesis and degradation are influenced by distinct genetic pathways that control aging in divergent eukaryotic species. ... In addition to providing building blocks for generation of new proteins and fuelling the cell with energy under starvation, the protein degradation processes eliminate damaged, nonfunctional proteins, the accumulation of which serves as the primary contributory factor to aging. Interestingly, a complex, intimate regulatory relationship exists between mechanisms promoting protein synthesis and those mediating protein degradation: under certain circumstances the former downregulate the latter. Thus, conditions that favor protein synthesis can enhance the rate at which damaged proteins accumulate. This may explain why genetic interventions and environmental factors (e.g., dietary restriction) that reduce protein synthesis, at least to tolerable levels, extend lifespan and increase resistance to cellular stress in various experimental model organisms of aging."

Link: http://www.ncbi.nlm.nih.gov/pubmed/20886758

Looking back at historical data on life span in human lineages, researchers find the result you might expect from centenarian studies - the most long-lived families tend to have more long-lived offspring, while for everyone else lifestyle choices and accident are more important determinants: "Although genetic factors are known to influence the human aging process, the proportion of life span and longevity variation explained by them is still controversial. We evaluated the genetic contribution to life span using historical data from three Alpine communities in South Tyrol, Italy. We estimated the heritability of life span and survival to old age (longevity), and we assessed the hypothesis of a common genetic background between life span and reproduction. The heritability of life span was [low], whereas the heritability of longevity [increased] as the longevity threshold increased. Heritability estimates were little influenced by shared environment, most likely due to the homogeneity of lifestyle and environmental factors in our study population. Life span showed both positive association and genetic correlation with reproductive history factors. Our study demonstrates a general low inheritance of human life span, but which increases substantially when considering long-living individuals, and a common genetic background of life span and reproduction, in agreement with evolutionary theories of aging."

Link: http://www.ncbi.nlm.nih.gov/pubmed/20884848

I don't think I can better the title of a recent post by Maria Konovalenko, so I'll quote it instead: "I refuse the invitation to my grave." You might read it with the accent of a weary but determined Russian spy in a late black and white era film, but the topic is the way in which so many people encourage us to turn our backs on longevity science.

I fundamentally disagree with the following idea made by [researcher Tom Kirkwood in a recent issue of Scientific American]: "The goal of gerontology research in humans, however, is always improving health at the end of life, rather than achieving Methuselean life spans."

This is a traditional stance taken by the hawks of the conservative wing of gerontologists: to [set quality of life and longevity as distinct research goals that are in opposition]. This is the biggest mistake in gerontology. The quality of life and longevity are closely related. If the quality of life is high in the biomedical sense, then why would the person suddenly die? Besides, many experiments on model animals show that the interventions leading to life extension also led to improved reproduction and increased activity. Essentially, an improved quality of life for the animal.

The reasoning behind such statements is based on an "acceptance of one’s own death", which the author is calling for. Since we cannot radically increase longevity right now, then let’s consider it as 'unnecessary'.

...

Denial of the radical life extension idea amounts to intellectual cowardice or fear to be perceived as a 'black sheep', and ignoring the advances of modern science.

Which is exactly the case. It is unfortunate that it is hard to steer more research efforts and funding towards the very plausible goal of reversing aging by repairing biochemical damage. As soon as you point out that the natural consequence of working repair technologies is a very, very long human life span, much of the audience tunes out - simply refusing to look at the evidence and the science. Yet this is nothing more than an engineering problem in biotechnology, just like many others undertaken in the fight to cure disease, and which could be brought to completion in just a few decades.

At some point in the future, sociologists of history will have their work cut out trying to understand why it was that their ancestors took so long to build the technologies of radical life extension. Why did they ignore the possibilities, embrace delay, and fail to rapidly fund the work that would have saved them - billions of people - from suffering and death by aging?

An open access paper that is representative of much of the present day investigation of the genetics of longevity: "Animal life span is regulated in response to developmental and environmental inputs through coordinate changes in gene expression. Thus, longevity determinants include DNA-binding proteins that regulate gene expression by controlling transcription. Here, we explored the physiological role of the transcriptional regulator, ETS-4, in the roundworm Caenorhabditis elegans. Our data showed that worms that lack ETS-4 lived significantly longer, revealing ETS-4's role in the transcription network that regulates life span. We identified 70 genes whose expression was modulated by ETS-4 that function in lipid transport, lipid metabolism and innate immunity. Some of the ETS-4-regulated genes were also controlled by two other regulators of aging, the FOXO and GATA factors. We concluded that a common set of transcriptional targets orchestrate the network of physiological factors that affect aging. ETS-4 is closely related to the human ETS protein SPDEF that exhibits aberrant expression in breast and prostate tumors. Because the genetic pathways that regulate aging are well conserved in other organisms, including humans, our findings could lead to a better understanding of SPDEF function and longevity regulation in mammals."

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2940738/

As a companion piece to recent work on histones and aging in yeast, these researchers investigate further the connections between cell aging and histones: "as cells count down to senescence and telomeres wear down, their DNA undergoes massive changes in the way it is packaged. These changes likely trigger what we call 'aging'. ... Prior to this study we knew that telomeres get shorter and shorter as a cell divides and that when they reach a critical length, cells stop dividing or die. Something must translate the local signal at chromosome ends into a huge signal felt throughout the nucleus. But there was a big gap in between. ... [researchers compared] levels of proteins called histones in young cells - cells that had divided 30 times - with 'late middle-aged' cells, which had divided 75 times and were on the downward slide to senescence, which occurs at 85 divisions. Histone proteins bind linear DNA strands and compress them into nuclear complexes, collectively referred to as chromatin. ... aging cells simply made less histone protein than do young cells. ... These proteins are required throughout the genome, and therefore any event that disrupts this production line affects the stability of the entire genome. ... Comparisons of histone patterns in cells taken from human subjects-a 9- versus a 92-year-old-dramatically mirrored histone trends seen in cell lines. ... These key experiments suggest that what we observe in cultured cells in a laboratory setting actually occurs and is relevant to aging in a population." This might be thought of as another line of evidence in the debate over the degree to which nuclear DNA damage contributes to aging.

Link: http://www.eurekalert.org/pub_releases/2010-10/si-toc092810.php

Our cells are very versatile and complex machines, really an assemblage of many such machines. As researchers make inroads into understanding the details of the mechanisms, they will become ever more capable of manipulating and engineering cells. The earliest meaningful efforts here are focused on (a) trying to change the high level state of the cell, to turn an ordinary cell into a stem cell, for example, and (b) directing cells to undertake specific actions by issuing chemical signals, such as efforts to spur stem cells into greater feats of regeneration.

In the future, engineering cellular state and behavior will become a very broad technology platform indeed. Almost any part of the cell is open to change, enhancement, or outright replacement if fully understood. We couldn't possibly predict all of what will be accomplished here: engineered cells may be turned into medical instruments, for example, programmed to construct drugs and move through the body to where those drugs are needed. Entire classes of cells, such as immune system cells, may be retired to be replaced with more efficient versions. And so forth.

Here and now, however, this line of research is still just beginning. The cutting edge today is focused on infrastructural needs, such as low cost and reliable production of stem cells. Half the battle here is finding ways to build the tools of research cheaply enough to allow a much larger research community to join in - a hundred labs produce a far greater diversity of results than ten.

With that in mind, here are a couple of recent examples of new progress and discovery in stem cell engineering:

New method for generating human stem cells is remarkably efficient

The ability to efficiently generate patient-specific stem cells from differentiated cells and then reliably direct them to form specialized cells (like neurons or muscle) has tremendous therapeutic potential for replacing diseased or damaged tissues. However, despite some successes, there have been significant limitations associated with existing methods used to generate human induced pluripotent stem cells (iPSCs).

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Dr. Rossi and colleagues did not take the standard approach to permanently alter the genome to achieve expression of protein factors known to reprogram adult cells into iPSCs. Instead, they developed synthetic modified messenger RNA molecules (which they termed "modified RNAs") that encoded the appropriate proteins but did not integrate into the cell's DNA.

Repeated administration of the modified RNAs resulted in robust expression of the reprogramming proteins in mature skin cells that were then converted to iPSCs with startling efficiency. "We weren't really expecting the modified RNAs to work so effectively, but the reprogramming efficiencies we observed with our approach were very high," says Dr. Rossi.

Use of RNA in place of gene alteration is a theme of late, and you should expect to see more of it in the future. Gene expression, the production of proteins from genetic blueprints, is a multi-step process: firstly, RNA is formed through transcription, and that RNA in turn produces the final protein product. If you introduce the appropriate RNA, then the genetic change is unnecessary, as the production of the protein picks up at a later stage. There are other advantages to working in RNA rather than gene therapy as well, such as easier control over turning a change on and off.

Researchers engineer adult stem cells that do not age

Biomedical researchers at the University at Buffalo have engineered adult stem cells that scientists can grow continuously in culture, a discovery that could speed development of cost-effective treatments for diseases including heart disease, diabetes, immune disorders and neurodegenerative diseases. ... the breakthrough overcomes a frustrating barrier to progress in the field of regenerative medicine: The difficulty of growing adult stem cells for clinical applications.

Because mesenchymal stem cells have a limited life span in laboratory cultures, scientists and doctors who use the cells in research and treatments must continuously obtain fresh samples from bone marrow donors, a process both expensive and time-consuming.

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The cells that UB researchers modified show no signs of aging in culture, but otherwise appear to function as regular mesenchymal stem cells do - including by conferring therapeutic benefits in an animal study of heart disease. Despite their propensity to proliferate in the laboratory, MSC-Universal cells did not form tumors in animal testing.

This second item is a most interesting discovery: immortal cell populations exist in the germ line and in certain cancers, so immortality is clearly a characteristic that cells are capable of. But I don't think anyone was expecting to just flip a switch and have this show up cleanly and distinctly in other cell types. The most promising aspect of this research is that the cells seem otherwise normal, no more capable of causing havoc than an ordinary germ cell.

The Economist looks at an intriguing research discovery: "The one sure way to prolong an animal's life is, paradoxically, to starve it. 'Caloric restriction', as it is known in the trade, works for everything from threadworms to mammals (people included, as far as can be ascertained without the luxury of controlled experiments). So it is no surprise that it also works for a group of small creatures known as rotifers. ... What makes this news is that the offspring of the rotifers in question also lived longer than normal. And that - the inheritance of an acquired characteristic - is quite startling. ... the offspring of calorie-restricted mothers have more catalase than those of mothers who were fed without restriction. The researchers also detected higher levels of the enzyme in the eggs of calorie-restricted mothers, so it could be that their offspring are simply endowed with the stuff. A more intriguing possibility, though, is that the relevant genes are affected by epigenesis, a process in which chemicals attached to the DNA control its activity. Epigenetic modifications are often retained when cells divide, and can sometimes be passed on to offspring." You'll recall that catalase gene engineered to localize in mitochondria can be used to extend life in mice. Researchers will now have to check to see if mammals reproduce any of this inherited catalase effect seen in rotifers.

Link: http://www.economist.com/node/17144833?story_id=17144833

Here, an Australian radio show looks at Werner syndrome, an accelerated aging condition that appears to be one aspect of normal aging run amok: "People with Werner syndrome age quickly in their early 20s and at this age can look as though they are 70 years old. They die prematurely of old age and show all the signs of normal ageing. There are only 200 known cases in the world. It is caused by the loss of function of one gene and is a perfect model for ageing. This research is assisting in understanding the biochemical pathways of older people's health and may lead to treatments to improve the health of older people." As is the case for progeria, it is possible that therapies for the accelerated aging conditions may have some application in normal aging - it depends on how greatly the specific biochemical dysfunctions involved contribute to "normal" age-related degeneration. My own sense is that they are not in fact important in comparison to the forms of biochemical and cellular damage outlined in the Strategies for Engineered Negligible Senescence, but I'm not aware of any rigorous analysis to back that up that sentiment.

Link: http://www.abc.net.au/rn/scienceshow/stories/2010/3027370.htm