Fight Aging!

As I'm sure you all know by now, mitochondria are swarming powerplants within the cell, descendants of symbiotic bacteria that bear their own DNA separate from the DNA in the cell nucleus. Mitochondrial DNA provides the blueprints for proteins making up the machinery of a mitochondrion, but it isn't as well protected or as well repaired as nuclear DNA. Given that a lot of reactive compounds are funneled through mitochondria in the processes that keep a cell powered, it is only to be expected that mitochondrial DNA becomes progressively more damaged over time. The range of mechanisms that have evolved to deal with that damage cannot keep up over the long term, and as a result a small but significant portion of our cells fall into ruin on the way to old age, becoming populated by dysfunctional, damaged mitochondria, and causing a great deal of harm to surround tissues and bodily systems by exporting a flood of reactive biochemicals. You can read a longer and more detailed description of this process back in the Fight Aging! archives.

So that is one side of the issue of mitochondrial DNA damage and its contribution to degenerative aging - and that in and of itself would be more than enough to make mitochondrial repair biotechnologies a research priority. There are many different potential ways of fixing or rendering irrelevant mitochondrial DNA damage, and allowing mitochondria to continue to function as well as they did at birth for an indefinite period of time. The sooner one of them is developed into a working therapy the better.

In considering mitochondrial damage there is another, more straightforward process at work, however. Many types of cell normally operate fairly close to the limit of the power provided by their mitochondria, including important cell populations in the brain and nervous system. As mitochondrial DNA damage accumulates with age, power production - meaning the pace at which adenosine triphosphate (ATP) is produced - falls off and cells either die or malfunction far more often than they did in youth. This is outlined in a recent open access review paper:

In aerobic cells the majority of ATP is produced by oxidative phosphorylation. This process takes place in the mitochondria where electrons that are donated from the Krebs cycle are passed through the four complexes (complex I-IV) comprising the electron transport chain (ETC), eventually reducing oxygen and producing water.

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Many cells operate at a basal level that only requires a part of their total bioenergetic capability. The difference between ATP produced by oxidative phosphorylation at basal and that at maximal activity is termed "spare respiratory capacity" or "reserve respiratory capacity" ... Under certain conditions a tissue can require a sudden burst of additional cellular energy in response to stress or increased workload. If the reserve respiratory capacity of the cells is not sufficient to provide the required ATP affected cells risk being driven into senescence or cell death.

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In this paper we hypothesize that mitochondria contributes to aging and age-related pathologies through a life-long continued decrease of the respiratory reserve capacity. The decrease sensitizes high energy requiring tissues to an exhaustion of the reserve respiratory capacity. This increases the risk of a range of pathologies that correspondingly are known to be age-related. Through a review of the effects of aging on the regulation of oxidative phosphorylation, we wish to substantiate this hypothesis. In addition, by using brain, heart, and skeletal muscle as examples, we will review how an age-related decrease of the reserve respiratory capacity is implicated in a variety of pathologies in the affected tissues.

Interestingly, there is a good case for arguing that it isn't just damage to mitochondria DNA (mtDNA) that reduces levels of power production in a cell's mitochondria - there are other changes taking place that turn down the dial, which in the absence of more definitive knowledge as to their causes could be classified either as programmed aging or as a programmed response to stochastic damage in other cellular systems:

Cumulative damage to the mtDNA is however, not the only contributor to the age-related decline of oxidative phosphorylation. Transcriptional profiling has revealed different regulation of nuclear genes encoding important peptides for oxidative phosphorylation when comparing young to old.

Either way, those mitochondria still need fixing. The biotechnologies capable of that job are on the horizon, and would be coming closer more rapidly if those involved in the work had a greater level of funding.

Steady progress in medicine has led to an ongoing reduction in many age-related conditions over the past few decades. Such as this, for example: "Today's senior citizens are reporting fewer visual impairment problems than their counterparts from a generation ago, according to a new [study]. Improved techniques for cataract surgery and a reduction in the prevalence of macular degeneration may be the driving forces behind this change, the researchers said. ... From 1984 until 2010, the decrease in visual impairment in those 65 and older was highly statistically significant. There was little change in visual impairments in adults under the age of 65. ... The [ study] shows that in 1984, 23 percent of elderly adults had difficulty reading or seeing newspaper print because of poor eyesight. By 2010, there was an age-adjusted 58 percent decrease in this kind of visual impairment, with only 9.7 percent of elderly reporting the problem. There was also a substantial decline in eyesight problems that limited elderly Americans from taking part in daily activities, such as bathing, dressing or getting around inside or outside of the home ... there are three likely reasons for the decline: (a) Improved techniques and outcomes for cataract surgery. (b) Less smoking, resulting in a drop in the prevalence of macular degeneration. (c) Treatments for diabetic eye diseases are more readily available and improved, despite the fact that the prevalence of diabetes has increased "

Link: http://www.northwestern.edu/newscenter/stories/2012/06/seniors-eyesight.html

Cryonics provider Alcor is holding a 40th anniversary conference in October, and the presently announced program looks much like this: "Sebastian Seung on testing how well cryopreservation (and alternatives) preserves the connectome. Todd Huffman on brain scanning. Panel discussion on long-term financial planning, including investing strategies, inflation protection, and personal trusts. Aschwin and Chana de Wolf from Advanced Neural Biosciences on advances in cryonics-relevant research. Greg Fahy from 21st Century Medicine on advances in cryoprotection. Aubrey de Grey from the SENS Foundation. Joshua Mitteldorf on programmed aging. Anders Sandberg on 'Handling the unknowable and undecidable: rational decision making about future technology.' Catherine Baldwin on advances at Suspended Animation. Panel on medical monitoring devices for improving your chances of a quick response in case of a critical physiological failure. Max More on how to improve your prospects for an optimal cryopreservation."

Link: http://www.alcor.org/conferences/2012/

If I mention medical nanorobotics, you might think of the designs put forward by Robert Freitas and others: molecular machines constructed largely from carbon that bear little relation to the cells and cellular system they are intended to interact with. Or you might think of the crude forerunners of those designs presently being tested in the laboratory, such as targeted nanoparticles and nanocontainers used to deliver drug compounds more precisely to where they are needed.

But you and I are built out of nanorobots: each of our cells is effectively a structured collection of cooperating, programmable nanoscale robots. They are evolved rather than designed, but still represent a vast preexisting parts library for researchers interested in building the first generation of medical nanorobots. While it is true that there are good reasons for reinventing this wheel, such as gaining far greater performance than is possible from anything similar to our present biology, given that time is of critical importance in developing the next generation of medicine, why not use these existing designs?

It seems likely that the first medical nanorobots (well, microrobots in this case) will be highly modified or even completely artificial cells. Why ignore the working blueprint that's right in front of you, after all?

Researchers are already building the prototypes, far more advanced than simple targeted nanoparticles. Here, for example, is news of progress towards nanofactories. These are programmable, artificial bacteria-like entities that can be set up to manufacture specific drug compounds in response to their local environment, or to signals from outside the body such as light or ingested chemicals.

Scientists are reporting an advance toward treating disease with minute capsules containing not drugs - but the DNA and other biological machinery for making the drug. ... development of nanoscale production units for protein-based drugs in the human body may provide a new approach for treating disease. These production units could be turned on when needed, producing medicines that cannot be taken orally or are toxic and would harm other parts of the body. Until now, researchers have only done this with live bacteria that were designed to make proteins at disease sites. But unlike bacterial systems, artificial ones are modular, and it is easier to modify them. That's why [this research group] developed an artificial, remotely activated nanoparticle system containing DNA and the other "parts" necessary to make proteins, which are the workhorses of the human cell and are often used as drugs.

They describe the nanoscale production units, which are tiny spheres encapsulating protein-making machinery like that found in living cells. The resulting nanoparticles produced active proteins on demand when the researchers shined a laser light on them. The nanoparticles even worked when they were injected into mice, which are stand-ins for humans in the laboratory, producing proteins when a laser was shone onto the animals.

The sky is the limit once biotechnology really takes off - and we're still in the early stages of this phase of progress. Much more is yet to come.

Why not aim to improve on blood? Its primary function is to carry oxygen, and it has evolved to do the bare minimum necessary on this front - separate any part of the body from a supply of oxygen for a minute or so and you're in trouble. It would be nice, for example, to have blood with a reserve capacity of a few hours, achieved using nanomachines that store the surplus oxygen that the body doesn't otherwise extract from air breathed in. Even if the heart stopped or blood stopped flowing in some vital tissue, you'd have those few hours to seek medical help. Here is a gentle first step towards the technologies of better blood: researchers "designed tiny, gas-filled microparticles that can be injected directly into the bloodstream to quickly oxygenate the blood. The microparticles consist of a single layer of lipids (fatty molecules) that surround a tiny pocket of oxygen gas, and are delivered in a liquid solution. ... report that an infusion of these microparticles into animals with low blood oxygen levels restored blood oxygen saturation to near-normal levels, within seconds. When the trachea was completely blocked - a more dangerous 'real world' scenario - the infusion kept the animals alive for 15 minutes without a single breath, and reduced the incidence of cardiac arrest and organ injury. The microparticle solutions are portable and could stabilize patients in emergency situations, buying time for paramedics, emergency clinicians or intensive care clinicians to more safely place a breathing tube or perform other life-saving therapies. ... The microparticles would likely only be administered for a short time, between 15 and 30 minutes, because they are carried in fluid that would overload the blood if used for longer periods ... the particles are different from blood substitutes, which carry oxygen but are not useful when the lungs are unable to oxygenate them. Instead, the microparticles are designed for situations in which the lungs are completely incapacitated. ... Intravenous administration of oxygen gas was tried in the early 1900s, but these attempts failed to oxygenate the blood and often caused dangerous gas embolisms. ... We have engineered around this problem by packaging the gas into small, deformable particles. They dramatically increase the surface area for gas exchange and are able to squeeze through capillaries where free gas would get stuck."

Link: http://www.eurekalert.org/pub_releases/2012-06/chb-ilo_1062212.php

This demonstrated technology platform has wide-ranging uses beyond muscular dystrophy. The ability to generate altered versions of a patient's own stem cell populations and then deliver them as needed could be a useful therapy for many conditions: "scientists have turned muscular dystrophy patients' fibroblast cells (common cells found in connective tissue) into stem cells and then differentiated them into muscle precursor cells. The muscle cells were then genetically modified and transplanted into mice. ... In this study, scientists focused on genetically modifying a type of cell called a mesoangioblast, which is derived from blood vessels and has been shown in previous studies to have potential in treating muscular dystrophy. However, the authors found that they could not get a sufficient number of mesoangioblasts from patients with limb-girdle muscular dystrophy because the muscles of the patients were depleted of these cells. Instead, scientists in this study 'reprogrammed' adult cells from patients with limb-girdle muscular dystrophy into stem cells and were able to induce them to differentiate into mesoangioblast-like cells. After these 'progenitor' cells were genetically corrected using a viral vector, they were injected into mice with muscular dystrophy, where they homed-in on damaged muscle fibres. The researchers also showed that when the same muscle progenitor cells were derived from mice the transplanted cells strengthened damaged muscle and enabled the dystrophic mice to run for longer on a treadmill than dystrophic mice that did not receive the cells."

Link: http://www.sciencedaily.com/releases/2012/06/120627142514.htm

You might recall a recent Australian study that put forward a correlation between time spent sitting and mortality rate, independent of other factors - i.e. the claim there being that if you sit a lot but exercise moderately then you have a lower life expectancy than if you spent less time in a chair. My thought at the time was that this sort of result ties back into levels of activity:

This is not the first study to propose this correlation, of course. There are a range of others from past years. One has to wonder what the mechanism is here, however - my suspicion is that it actually does all come back down to the level of physical activity in the end. In these massive studies the level of exercise and activity is reported by the participants. A person who stands and works is going to be somewhat more active than a person who sits and works, even though that time may not be categorized as physical activity, or reported differently.

Here is a different study that proposes much the same sort of thing. These researchers - like the authors of another recent study on Alzheimer's disease and activity - used data gathered from worn accelerometer devices rather than the self-reporting of study participants, which in theory should lead to far more confidence in the results.

Association of Sedentary Time with Mortality Independent of Moderate to Vigorous Physical Activity:

Low physical activity levels are a well-known risk factor of mortality. Previous studies have shown that people who do not meet the physical activity recommendations or those who report less moderate to vigorous activity (MVPA) are at increased risk of death. Sedentary behavior has emerged as a potential risk factor independent of MVPA and is defined as engaging in behaviors during the waking day that are done while sitting or reclining and that result in little energy expenditure above rest, such as using the computer, watching television, driving a car, or sitting at a desk.

Recent studies with objectively measured sedentary time data have shown that prolonged time in sedentary behaviors is a cardiometabolic risk factor independent of moderate to vigorous physical activity. Additionally, self-reported sedentary time in several domains including sitting, riding in a car, and TV watching is positively associated with mortality.

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7-day accelerometry data of 1906 participants aged 50 and over from the U.S. nationally representative National Health and Nutrition Examination Survey (NHANES) 2003-2004 were analyzed. All-cause mortality was assessed from the date of examination through December 31, 2006.

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This study shows that time spent in sedentary behavior is positively associated with mortality in this representative sample of adults aged 50 and older. Participants in the highest quartile of percentage of time spent sedentary, which corresponds to more than 73.5% of time in men and more than 70.5% in women, had more than 5 times greater risk of death compared to those in the lowest quartile. Importantly, these associations were independent of MVPA.

At some point in the future we won't really have to worry too much about things like this, as medical science will progress to the point at which maintenance of long-term health regardless of lifestyle becomes as much a non-issue as protection from the infectious diseases that plagued our ancestors. But we have a way to go towards that goal, and in the meanwhile it doesn't seem wise to sit back and assume that biotechnology will rescue you from casual negligence. Maybe you'll get lucky, but for those of us in the middle stages of life it looks uncertain indeed. The coming decades are on the cusp between the era of aging as a fact of life and aging as a treatable and reversible medical condition - a lot of deaths will fall on the wrong side of that line, so why not try to shift the odds on whether yours is one of them? Every year gained is big deal in this sort of situation.

The flip side of that coin is, of course, helping to make rejuvenation biotechnology come about more rapidly. If you like being alive and in good shape, it makes sense to work on both (a) common sense health basics like exercise and calorie restriction, and (b) assisting scientific progress. You live in an age in which you can easily accomplish both of these things, thanks to a wealth of health knowledge at your fingertips, and the spread of volunteer, philanthropically funded organizations like SENS Foundation and Methuselah Foundation.

There is some ongoing interest in plastination (or chemopreservation) as a possible alternative to cryonics (or cryopreservation) - though not yet enough for an initiative to arise that offers that service. Here is commentary on this topic: "Even if chemopreservation can be demonstrated to preserve the intricate wiring of the brain, it can be safely assumed that there will not be a massive change in demand for brain preservation technologies ... As a consequence, providers of chemopreservation will most likely operate in the same environment as providers of cryonics. That means that, as a general rule, there will be a delay between pronouncement of legal death and the start of procedures. ... There is an understandable tendency to compare brain preservation protocols under ideal conditions and favor the method that produces the best preservation. But support for either technology cannot be solely based on results produces under controlled lab conditions. Personal survival technologies should be evaluated under conditions that are most likely to be encountered by organizations that will offer them. ... One interesting aspect of the cryonics vs chemopreservation debate, though, is that it appears that some people simply feel more comfortable with one of the approaches. People who have shown the slightest interest in human cryopreservation can get really excited about the idea of chemical brain preservation. This indicates that if both approaches would be pursued actively, the growth of chemopreservation would not necessarily be at the expense of cryonics but there would be a growth in the total number of people making bio-preservation arrangements aimed at personal survival. [But] chemopreservation is not at the stage where it can be responsibly offered. The growth of this field requires a committed group of individuals who will research, develop, and implement this program. Chemopreservation does not need to be perfected before being offered (neither was cryonics) but so far most advocacy has been mostly at the conceptual level."

Link: http://www.evidencebasedcryonics.org/2012/06/20/chemopreservation-in-the-real-world/

Another of the many benefits of calorie restriction is outlined in this paper: "The author focused on the functional decline of synapses in the brain with aging to understand the underlying mechanisms and to ameliorate the deficits. The first attempt was to unravel the neuronal functions of gangliosides so that gangliosides could be used for enhancing synaptic activity. The second attempt was to elicit the neuronal plasticity in aged animals through enriched environmental stimulation and nutritional intervention. Environmental stimuli were revealed neurochemically and morphologically to develop synapses leading to enhanced cognitive function. Dietary restriction as a nutritional intervention restored the altered metabolism of neuronal membranes with aging, providing a possible explanation for the longevity effect of dietary restriction. These results obtained with aging and dementia models of animals would benefit aged people."

Link: https://www.jstage.jst.go.jp/article/pjab/88/6/88_PJA8806B-04/_article

We life in an age of change and rapid scientific innovation in medicine. That in and of itself might be enough to explain why historical actuarial predictions of longevity have been low in comparison to the actual outcome: extrapolation of existing trends tends to do poorly in the face of consistently unpredictable innovation.

Nonetheless, a large industry is focused on getting these numbers right, or as close to right as is possible, as vast sums are promised to older folk, either as political entitlements or honestly obligated as a result of insurance contracts. Betting against increasing longevity seems like a fool's game, but nonetheless there is a lot of money to be made in that business - many large entities want to be protected from what is known as longevity risk, the risk that life spans will rise faster than expected and thus financial obligations will spiral out of control. Large entities are willing to pay for that insurance service, and taking on risk for a percentage is very much the core business of finance.

In theory the people taking on that risk for a percentage know what they are doing, and they are the ones funding efforts to understand the risk - which in this case means models for future increases in human longevity due to advances in medicine and biotechnology. In practice? The risk gets sliced and diced and parceled out among the players in finance, that much is true. But I'm sure we all see the present results of that undertaking in other large industries, such as housing: when there is enough money involved the business becomes one of lies and politics, the fine art of pocketing profits, taking on unknown risks for short term gain, steering government policies, and raiding the public treasury to cover losses when it all goes south. When buying politicians and policy is a reasonable cost judged against the cost of contracts, buying politicians and policy becomes a part of doing business - and very lucrative, since it allows risk-bearers to try for the upside with the expectation that they will be bailed out if it fails.

Thus a web of perverse incentives grows, benefiting the connected few at the expense of the many. In the course of all of this, there is an increasing pressure (and ability) to obscure or water down unfavorable data, especially when the interests of profiteers and government appointees coincide. Again, we've all seen this come to pass numerous times in recent years and prior decades. It is the way of the world, and just as much so when it comes to the future of human longevity:

In 1981, the United Kingdom (UK) Office for National Statistics estimated that male life expectancy at birth would rise to 74 by 2031. It hit that age in 1994. In 2002, the 2031 estimate was 81, but we are now expected to pass that in 2019. This systematic underestimation of official life expectancy increases occurs around the world. It is not an accident. It is deliberate. Politicians put pressure on official agencies to do this, so that the full cost of longevity increases does not fall on them or the current generation of voters. The reason is clear: If more accurate and hence higher projection of life expectancy were produced today, then social security contributions would have to rise now rather than later - and this would be politically very unpopular.

The powers that be and their predecessors have accomplished what powers that be always manage in the end: to set up a system of wealth transfers and entitlements that is both unsustainable and stands in opposition to true progress. Thus the modern spectacle of people trying to argue that increases in human longevity are a bad thing! The collapse will come, the promises that cannot be kept will be broken, that much is certain - although it is true that modern innovations in fiat currencies have allowed the game to go on for a good deal longer and become a good deal more destructive than was usually the case in the past. But eventually they will run out of other people's money to loot. Along the way to that end those who are trying to prop up the house of cards will undoubtedly build a great deal more in the ways of lies, waste, and other unpleasantness.

Mitochondria are the power plants of the cell and are important in aging: damage to their DNA contributes to degenerative aging through a complex process, and differences in mitochondrial resistance to damage is thought to go a long way towards determining variation in species life span. So it should not be surprising to see associations between different mitochondrial DNA haplogroups and human longevity, as is the case here: "Human longevity is an interesting and complicated subject, with many associated variations, geographic and genetic, including some known mitochondrial variations. The population of the Bama County of Guangxi Province of China is well known for its longevity and serves as a good model for studying a potential molecular mechanism. In this study, a full sequence analysis of mitochondrial DNA (mtDNA) has been done in ten Bama centenarians using direct sequencing. [Mitochondrial DNA was also] analyzed for a total of 313 Bama individuals with ages between 10 and 110 years. The results showed that there were seven mitochondrial variations [and] four haplogroups [in] 10 Bama centenarians. In the D-loop region of mtDNA, the mt146T occurred at a significantly lower frequency in those is the older age group (90-110 years) than in the middle (80-89 years) and in the younger (10-79 years) groups. The mt146T also had lower systolic blood pressure and serum markers such as total cholesterol, triglyceride and low density lipoprotein than did mt146C in the older age group. ... These results suggest that the mt146T/C polymorphisms in Guangxi Bama individuals may partly account for the Bama longevity."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22729909

Researchers are developing all sorts of methods for sifting through the mass of data on protein machinery used in our bodies, and some groups are finding novel ways to identify possible longevity-related proteins: "Despite a 10-100-fold difference in maximum lifespan (MLS), most known mammal species show similar phenotypes of aging. This observation suggests that the genetic determinants of mammalian aging and lifespan may be relatively plastic. The classical evolutionary theory of antagonistic pleiotropy posits that aging is an effect of the decrease in selection pressure that occurs after successful reproduction. Conversely, lifespan extension has been shown to occur when selection pressure increases in later age. Still relatively unexplored are the specific molecular mechanisms that determine differences in mammalian lifespan. Many mechanisms are possible and likely occur simultaneously, including changes in the sequence, structure, function, and expression of RNA and proteins. Here, we focus on changes in proteins caused by fixed substitutions. In this context, two recent studies predicted a simple consequence of the evolutionary theory: we might expect that proteins necessary for long mammalian lifespan would have fewer substitutions, i.e. show more conservation, in long-lived versus short-lived species. Thus, it may be possible to identify aging-related proteins [by] inferring and comparing some measure of such preferential substitutions, here called 'longevity-selected positions', among the several dozen mammal species whose proteomes are available. ... We analyzed 7,590 orthologous protein families in 33 mammalian species, accounting for body mass, phylogeny, and species-specific mutation rate. Overall, we found that the number of longevity-selected positions in the mammalian proteome is much higher than would be expected by chance. Further, these positions are enriched in domains of several proteins that interact with one another in inflammation and other aging-related processes, as well as in organismal development. We present as an example the kinase domain of anti-Müllerian hormone type-2 receptor (AMHR2). AMHR2 inhibits ovarian follicle recruitment and growth, and [its] longevity-selected positions cluster near a SNP associated with delayed human menopause. Distinct from its canonical role in development, this region of AMHR2 may function to regulate the protein's activity in a lifespan-specific manner."

Link: http://dx.doi.org/10.1371/journal.pone.0038595

SENS Foundation cofounder Aubrey de Grey presented last month at the humanity+ conference in Melbourne, Australia. Adam Ford, the conference coordinator, interviewed de Grey after the event, and later uploaded a slew of video segments from that interview to YouTube. You might take a look at the playlist of a dozen or so videos, divided by topic.

The longest of the segments is embedded below; it covers SENS, the research program that aims to repair the root biochemical causes of aging. Those of you who have heard this material before, and who are familiar with the recent updates on work in progress at the SENS Foundation, might choose to browse through the rest of the material instead.

The research program that takes us from where we are today, at the dawn of a revolution in biotechnology, to the point at which aging can be controlled through medicine just like any chronic disease is just about as straightforward as scientific research can ever be. The goals are known, the forms of damage to our biology that need to be fixed are known, a list of potential ways to fix them are known. The devil is ever in the details, but this isn't a case of speculative research that has yet to even find the problem it needs to solve.

At this point more money means more progress: there is a well defined list of things to work on and too little funding in this field of medical technology to work on them all to the degree that they merit.

As such, one might argue that the most important goal for the present is to explain all of this to the world at large, to grow the community of supporters and thus raise more funding. Most people still see aging as a mystery, set in stone, a thing that lies outside the bounds of medicine. Nothing could be further from the truth, but a much larger fraction of the populace must become educated and persuaded that rejuvenation biotechnology is a real, plausible, possible near term goal. Their support is needed in order to build the massive funding institutions and large research communities needed to make rapid progress towards the defeat of aging as the greatest cause of human death and suffering.

Building new organs from a patient's own cells is a goal that is gaining more attention from the wider public and the mainstream press: "What if dying patients waiting for an organ transplant could receive a custom, lab-grown replacement rather than waiting for a donor organ? To some, this may sound like science fiction - and in many ways, it still is. But the advances in the field of regenerative medicine that made headlines last week suggest such lab-grown organs may become reality in the future. ... The idea of using a patient's own cells rather than relying on those of a donor is important because it eliminates the need to find a 'match.' For any transplant procedure there is a concern that tissues from a donor will be rejected by a recipient's body. Even though doctors carefully analyze specimens under a microscope to find the most compatible individuals, and even despite the powerful drugs used to prevent the recipient's immune system from attacking the new body part, the risk of rejection still causes doctors to hold their breath in the days following a transplant. Custom-made organs from a patient's own tissues would solve this problem, obviating the need for strong immune-suppressing medications that come with significant side effects. The other potential benefit lies in availability. Growing a replacement tissue or organ in the lab eliminates the dependence on waiting for a donor to die. These parts cannot be grown overnight, but with people currently waiting months to years for donor organs, there might be a point at which the amount of time taken to grow a replacement is shorter than the wait for a donated one. It's a bright future. But many hurdles remain before widespread use becomes a reality."

Link: http://abcnews.go.com/Health/lab-grown-custom-organs-future-medicine/story?id=16631764

The logical progression for tissue engineering is to move to building inside the body rather than building outside and then transplanting the resulting new tissue. Here is an example of that trend: "The host site, the artery in this case, is an excellent source of cells and provides a very efficient growth environment. This is what inspired us to skip the cell culture altogether and create these cell-free synthetic grafts. ... [Researchers] designed the graft with three properties in mind. First, they chose a graft material - an elastic polymer called PGS - that is resorbed quickly by the body. Then, they examined graft porosity and selected parameters that allow immediate cell infiltration. [They wrapped] the vascular graft with a fibrous sheath to trap the cells. Finally, [researchers] wanted a coating for the grafts that would reduces blood clotting and bind many growth factors, so they used heparin, a molecule that does just that. ... [Researchers] made grafts as small as 1 mm in diameter and monitored the graft's transformation in vivo for three months. Because the graft was highly porous, cells were easily able to penetrate the graft wall, and mononuclear cells occupied many of the pores within three days. Within 14 days, smooth muscle cells - an important blood vessel builder - appeared. At 28 days, cells were distributed more evenly throughout the graft. At 90 days, most inflammatory cells were gone, which correlated with the disappearance of the graft materials. The artery was regenerated in situ and pulsed in sync with the host. Furthermore, the composition and properties of the new arteries are nearly the same as native arteries."

Link: http://www.eurekalert.org/pub_releases/2012-06/uop-pdb061912.php

An article from the New England Journal of Medicine has been doing the rounds: it looks at some of the changing causes of mortality over the past century. These changes are signs of success in the progress of medicine and technology: both might be thought of as the search for ways to prevent suffering and death - one cause at a time. With each passing generation in a time of progress, some of those causes are largely eliminated, leading to a shift in focus and new targets. The degree to which infectious disease has been tamed is very clear from the graphics in the article, though there is always much more to be done on that front:

The article itself really isn't worth reading - the authors burble about policy without really saying anything, and certainly nothing meaningful is put forward. It's exactly the sort of thing you don't want to hear from people involved in research or medicine. If you can't clearly say "it's a priority to build new and better medicine, and we're working on a portion of that goal right now," then probably best to leave the conversation about medicine to other people. Here the peanut gallery has more to offer in the way of occasional meaningful comments:

The first thing to notice here is how much our mortality rate has dropped over the course of a century, largely due to big reductions in infectious diseases like tuberculosis and influenza.

On the large scale, medicine chases the priorities of the now - and in wealthier regions of the world that has become cancer and heart disease. The size of the cancer and heart disease research communities reflects the present degree to which the two groups of conditions contribute to human mortality. What it does not yet reflect is the new and more meaningful unified way of looking at the conditions that kill the most people: that they are all caused by aging, and stem at root from a limited range of mechanisms and changes that happen over the years as a byproduct of our normal metabolism. We rust, and that rust blossoms into a thousand different failure modes. Yet medical science is still largely focused on end states, and patching over catastrophic damage rather than preventing its origins.

To keep reducing the human mortality rate, the research community has to start in on prevention in the form of repair biotechnologies - ways to halt and reverse the earliest development of the age-related conditions that kill most people. It is as much a cultural change in the life sciences as it is a technical challenge, as the path ahead is fairly clear. This is why organizations like the SENS Foundation, mixing aggressive advocacy with targeted research work where few others are making progress, are so important. It is not so much that they will get the work done by themselves, but that they will spawn a sea change in the research community, such that many, many groups will tomorrow be performing similar work with similar end goals: to to be able to treat and reverse the course of aging.

You might think of a focus on aging and its causes as the germ theory of today's medical community: a unifying set of ideas and resulting research strategies that will bring the bulk of the medical community onto a better path forward, one that will lead to a more rapid improvement in the human condition, and longer, healthier lives for all.

It is always a good idea to learn more about how the other half of the world thinks. Most people are closer to the values of social justice than the values of libertarianism, for all that that sort of "justice" (i.e. forced redistribution and mob envy) is just as destructive of wealth and progress as communism or fascism when put into earnest practice. It becomes a tyranny of egalitarianism, a leveling down, a tearing down of the high points of society, the groups that produce advances in technology. One of the values of reading In Search of Enlightenment is seeing the thinking that leads someone enmeshed in the culture of social justice - whose members characteristically belittle or reject scientific progress and the markets that drive it - come to advocate for longevity science and the defeat of aging: "Over the past decade I have worked at the intersection of issues in political philosophy/theory and the medical sciences. I have tried to help bridge what I take to be a troublesome divide between the field most concerned with ideals of justice and equality, and scientific advances (especially in the field of biogerontology) which could profoundly improve human health and prosperity. These two things are linked in important ways, but there is very little actually written by theorists on these kinds of topics. Bridging this gap is an up-hill struggle for a variety of reasons. The theoretical concepts and normative theories developed in political philosophy over the past 4 decades either ignored the realities of morbidity (e.g. like the fact that aging is a major risk factor for disease) or just assumed people went through their complete lives as 'healthy and productive members of society'. This meant the (almost exclusive) focus of theories of distributive justice was on the distribution of wealth and income. A fair society could be measured, so went the reasoning, to a large extent by the pattern of the distribution of a society's wealth. And the extent to which theories of justice have expanded, in the last 2 decades, to tackle topics like global justice and health, they are still constrained by the original assumptions and limited perspectives/concepts with which the dominant normative theories were originally devised. In other words, taking a theory of domestic justice designed to apply to a healthy and affluent society and then trying to make a few modifications once you take disease and debt seriously is not, imho, a recipe for success."

Link: http://colinfarrelly.blogspot.com/2012/06/how-to-put-aging-and-biogerontology-in.html

Decellularization involves stripping out the original cells from a donor organ and then repopulating it with cells grown from the recipient's tissue - thereby removing the possibility of immune rejection. One implication of this approach is that the donor doesn't necessarily have to be human: "In proof-of-concept research [a] team successfully used pig kidneys to make 'scaffolds' or support structures that could potentially one day be used to build new kidneys for human patients. The idea is to remove all animal cells - leaving only the organ structure or 'skeleton.' A patient's own cells would then be placed on the scaffold, making an organ that the patient theoretically would not reject. ... this is one of the first studies to assess the possibility of using whole pig kidneys to engineer replacement organs ... For the research, pig kidneys were soaked in a detergent to remove all cells, leaving behind the organ's 'skeleton,' including its system of blood vessels. In addition, the structure of the nephron - the kidney's functional unit - was maintained. The scaffolds were implanted in animals, where they were re-filled with blood and were able to maintain normal blood pressure, proving that the process of removing cells doesn't affect the mechanical strength of the vessels. ... It is important to identify new sources of transplantable organs because of the critical shortage of donor organs. These kidneys maintain their innate three-dimensional architecture, as well as their vascular system, and may represent the ideal platform for kidney engineering."

Link: http://www.eurekalert.org/pub_releases/2012-06/wfbm-lkp062112.php

Crowdfunding of commercial products is having a lengthy day in the sun at the moment. It has emerged from years of great success in small markets, such as the pen and paper gaming and indie publishing industries, and people are now applying the same models to fields where much more money is involved. Quite successfully too, some raising millions in what amount to well-run and timely preorder campaigns for products yet to be built. The range of endeavors open to crowdfunding of course includes scientific research, which is why it is a topic that shows up here every now and again:

If you can raise money for books, art projects, and widgets, why not for discrete life science research projects with determined goals? The LongeCity (previously the Immortality Institute) crowd have been trying this for some years, with a great deal of success considering the limited audience of this community in comparison to the audience available through Kickstarter. It is sad but true that far more people are brought to a state of excitedly opening their wallets for the development of an iPhone widget than for any sort of biotechnology project, even one that will contribute to the reversal of aging.

If you have a dedicated community, then you want to turn that dedication into professional organizations and the funds to run them. This is always going to be a messy, organic process of development, but which perhaps may be open to improvement through the spread of a more formalized crowdfunding culture. But in any case, I wanted to expand on the point made in the quote above - that crowdfunding for scientific research is a radically different undertaking from crowdfunding for development of a commercial product. This seems worth emphasizing, given that a whole range of startups and new ventures seem to be trying to port over crowdfunding into the sciences pretty much as-is, or with just a few embellishments. Like these, for example:

• EurekaFund
• FundaGeek
• GeekFunder
• Microryza
• Petridish
• Rockethub
• Sciflies

What we can hope for from this wealth of effort is that some groups figure out the magic formula that will make science funding work in this environment - and make it work with the same degree of liquidity and interest as in commercial projects. Experimentation is clearly needed, however.

The basic point of divergence between crowdfunding a product versus crowdfunding research is that in the former case the funders are definitively buying something concrete: that is their motivation and incentive. They are putting down money in expectation that what they are doing is submitting a preorder. Variations on the preorder theme are legion, but they all boil down to paying for a definitive item, a which will usually have fairly solid delivery date. Scientific research is notoriously bad when it comes to delivering on both those points, however. The work that is most amenable to crowdfunding consists of small projects that only incrementally add value to their fields - and which may not even do that, given the necessarily high failure rate for research.

The challenge facing science crowdfunding is the same challenge faced by scientific advocates at all times: they do their part to grow communities of supporters and encourage those supporters to pay for research work. That work will give no immediate result, the eventual result may be hard for supporters to understand, it will likely not benefit them for some time, if ever, and in addition to all of that the undertaking will quite likely fail. Science is a high risk endeavor, with few short-term payoffs that people find rewarding - and thus it is a hard sell when held up against the allure of immediate gratification, candy, and shiny objects.

But technological progress is the only thing that matters, not today's pretty baubles that are made possible by past successes in science. Funding of science has to be made to work if we want to continue on this upward curve to longevity, wealth, and expansion of what it means to be human.

Despite all of the challenges, the old messy, organic way of funneling money into scientific projects does in fact make progress. People who care about the end result, something decades away, do step up to fund science. You might look at our little community of longevity science enthusiasts for example, making noise and raising somewhere north of $14 million over the past eight years for organizations and initiatives like the Methuselah Foundation, the New Organ Prize, and the SENS Foundation. Knowing that this is possible, and regardless of the fact that it is hard, very hard, to convince people to open their wallets for science, you have to look at what's happening in the crowdfunding space right now and think that fundraising for science could all be made easier - if someone just goes about it in the right way, builds the right tools, hits the right business model, pulls together the right sort of seed community.

And maybe so. I've watched most of a decade of a small community funding research, and the cryonics advocates have watched much the same thing for far longer, but I don't have any good answers - and I'm not sure that they do either. So it is a good thing that a number of venture funded and bootstrapped groups are working on this; they'll have a few years of runway to work on finding the key to the problem, and we'll all benefit should one of them come up with a good way forward.

To go along with a recent post on cell therapies for nerve regeneration, here researchers investigate a different set of mechanisms: "A protein required to regrow injured peripheral nerves has been identified by researchers. ... The finding, in mice, has implications for improving recovery after nerve injury in the extremities. It also opens new avenues of investigation toward triggering nerve regeneration in the central nervous system, notorious for its inability to heal. ... scientists show that a protein called dual leucine zipper kinase (DLK) regulates signals that tell the nerve cell it has been injured - often communicating over distances of several feet. The protein governs whether the neuron turns on its regeneration program. ... How does an injured nerve know that it is injured? How does it take that information and turn on a regenerative program and regrow connections? And why does only the peripheral nervous system respond this way, while the central nervous system does not? We think DLK is part of the answer. ... If an axon is severed somewhere between the cell body in the spinal cord and the muscle, the piece of axon that is no longer connected to the cell body begins to disintegrate. Earlier work showed that DLK helps regulate this axonal degeneration. And in worms and flies, DLK also is known to govern the formation of an axon's growth cone, the structure responsible for extending the tip of a growing axon whether after injury or during development. The formation of the growth cone is an important part of the early, local response of a nerve to injury. But a later response, traveling over greater distances, proves vital for relaying the signals that activate genes promoting regeneration. This late response can happen hours or even days after injury. But in mice, unlike worms and flies, [DLK] is not involved in an axon's early response to injury. Even without DLK, the growth cone forms. But a lack of DLK means the nerve cell body, nestled in the spinal cord far from the injury, doesn't get the message that it's injured. Without the signals relaying the injury message, the cell body doesn't turn on its regeneration program and the growth cone's progress in extending the axon stalls. ... A neuron that has seen a previous injury now has a different regenerative program than one that has never been damaged. We hope to be able to identify what is different between these two neurons - specifically what factors lead to the improved regeneration after a second injury. We have found that activated DLK is one such factor. We would like to activate DLK in a newly injured neuron to see if it has improved regeneration."

Link: http://www.sciencedaily.com/releases/2012/06/120620132926.htm

Here is another paper suggesting that resveratrol isn't necessarily a great place to be spending hundreds of millions of dollars on research and development, given the poor results in studies that evaluate its effects. In an ideal world this money that would go towards improving biotechnology rather than the old-school approach of mining the natural world for compounds that maybe do more good than harm: "Resveratrol has shown evidence of decreasing cancer incidence, heart disease, metabolic syndrome and neural degeneration in animal studies. However, the effects on longevity are mixed. We aimed to quantify the current knowledge of life extension from resveratrol. We used meta-analytic techniques to assess the effect resveratrol has on survival, using data from 19 published papers, including six species: yeast, nematodes, mice, fruitflies, Mexican fruitflies and turquoise killifish. Overall, our results indicate that resveratrol acts as a life-extending agent. The effect is most potent in yeast and nematodes, with diminished reliability in most higher-order species. Turquoise killifish were especially sensitive to life-extending effects of resveratrol but showed much variation. Much of the considerable heterogeneity in our analysis was owing to unexplained variation between studies. In summary, we can report that few species conclusively show life extension in response to resveratrol. As such, we question the practice of the substance being marketed as a life-extending health supplement for humans."

Link: http://dx.doi.org/10.1098/rsbl.2012.0316

A fellow that you met today will, forty years from now, have an entirely artificial immune system. It is an early model, a prosthetic replacement that is a mix of synthetic cells and less organic medical nanomachines, and requires frequent work and an open data channel to keep in line. Obtaining it wasn't a choice - it is a new treatment for a small class of acquired autoimmune conditions that somehow manage to persist through complete removal and replacement of immune cell populations. It works; he doesn't get sick, at all. Ever.

Nonetheless, you shook this man's hand today. That future lies in waiting.

Earlier you passed by a kid who will outlive you, your plans, your memory, your immediate descendants, and the first phase of terraforming to take place on Mars. The young have it good these days: a solid eighty years of probable-worst-case life expectancy at birth that will take them well into the first age of radical life extension - and that even if the next twenty years take us through a miserable economic depression coupled with a spread of repressive regulatory regimes that effectively stifle life science research and its application. Many of the youngest children of today will live for centuries, and many of those will go on to live for thousands of years.

You walked right by that kid. In fairness, he doesn't know either, of course.

Then there's that new face at the office, fresh out of college: by the 2070s she'll be a shell of the person she was. A happy shell, however, the original exterior polished up by gene, cell, and enzyme therapies to minimize the changes of aging in skin and musculature, but all of the interior organs below the neck new from labs in Thailand and Vietnam over the years, grown from her own genetic material. That took money, even though it's second string organ biotechnology by that time - but the sharp average worker you can save enough to afford that sort of thing over a lifetime. It's not as though she'll be retiring any time soon, and better low on funds than living like a 80-year old from a century past.

That probably didn't cross your mind today when the two of you happened to be in the same meeting.

The point here is this: the next half century is shaping up to be a transformation to match the last, but this time in biotechnology and medicine as well as in computing. These little snapshot nascent futures are no different than my 1960s analog describing to you the future of a then-20-something-and-now-70-something individual: surrounded by monitors; in touch with distant corners of the world at the click of a button; the world's encyclopedias and research institutions available at a moment's notice; living drenched in a wealth of knowledge, and connected to half the world's population in near-instant communication; possessing such massive reserves of computation power that enormous multi-machine simulations run for little more than entertainment value; connected to this web of knowledge and communication by radio, microwave, and pocket-devices that can be used near anywhere; amidst a sea of surging culture, charged by a hundred million voices all talking at once.

This is an age of change, and much lies ahead of us. The potential for what sounds like science fiction - radical life extension, artificial organs and bodily systems, the defeat of disease and aging - lies nascent and dormant, awaiting those who will carve it from the passage of time, who will do the work to make these dreams a reality.

This is the time for it.

You might recall the species of clam that can live for at least four centuries. Similarly, you might also recall the membrane pacemaker hypothesis that explains differences in longevity between species in terms of the resistance of cell membranes - and especially mitochondrial membranes - to damage. Here, the two topics are linked: "The deleterious reactive carbonyls released upon oxidation of polyunsaturated fatty acids in biological membranes are believed to foster cellular aging. Comparative studies in mammals and birds have shown that the susceptibility to peroxidation of membrane lipids (peroxidation index, PI) is negatively correlated to longevity. Long-living marine molluscs are increasingly studied as longevity models, and the presence of different types of lipids in the membranes of these organisms raises questions on the existence of a PI-longevity relationship. We address this question by comparing the longest-living metazoan species, the mud clam Arctica islandica (maximum reported longevity = 507 y) to four other sympatric bivalve molluscs greatly differing in longevity (28, 37, 92, and 106 y). We contrasted the acyl and alkenyl chain composition of phospholipids from the mitochondrial membranes of these species. The analysis was reproduced in parallel for a mix of other cell membranes to investigate if a different PI-longevity relationship would be found. The mitochondrial membrane PI was found to have an exponential decrease with increasing longevity among species and is significantly lower for A. islandica. The PI of other cell membranes showed a linear decrease with increasing longevity among species and was also significantly lower for A. islandica. These results clearly demonstrate that the PI also decreases with increasing longevity in marine bivalves and that it decreases faster in the mitochondrial membrane than in other membranes in general. Furthermore, the particularly low PI values for A. islandica can partly explain this species' extreme longevity." This emphasizes the importance of mitochondrial damage in aging and longevity, and thus the importance of research into mitochondrial repair biotechnologies for humans.

Link: http://www.ncbi.nlm.nih.gov/pubmed/22708840

There's a fair amount of evidence implicating cytomegalovirus (CMV) in immune system decline, rhe theory here being that the immune system devotes ever more of its fixed resources to dealing with the largely harmless variants of this virus that it cannot clear. Here researchers argue against that view: "Aging is accompanied by the development of low grade systemic inflammation, termed 'inflammaging', characterised by raised serum C-reactive protein (CRP) and pro-inflammatory cytokines. Importantly, inflammaging is implicated in the pathogenesis of several of the major age-related diseases including cardiovascular disease, type 2 diabetes and dementia and is associated with increased mortality. The incidence of infection with the persistent herpes virus cytomegalovirus (CMV) also increases with age. Cross-sectional studies have proposed CMV infection as a significant driver of inflammaging, but a definitive case for CMV as a causative agent in inflammaging has not yet been made. We studied longitudinally 249 subjects (153 men, 96 women) who participated in the Hertfordshire Ageing Study at baseline (1993/5, mean age 67·5 years) and at 10 year follow up. At both times [subjects] provided blood samples for analysis of inflammatory status and CMV seropositivity. In the cohort as a whole, serum CRP and pro-inflammatory cytokines [were] increased between baseline and follow up ... These changes to cytokine status over time occurred equally in the 60% of subjects who were seropositive for CMV at baseline and follow up, the 8% who were CMV negative at baseline but who became CMV positive by the 10 year follow up, and also in the 32% who were CMV seronegative throughout. We conclude that CMV infection is not a primary causative factor in the age-related increase in systemic inflammation."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22708923

A fair number of research groups are working to develop a technology platform for effective and rapid nerve repair. One of the many parallel lines of research involves the use of Schwann cells, a part of the supporting infrastructure for the nervous system. As for much of the field of regenerative medicine, work has progressed through stages of increasing sophistication: learning how to isolate and culture useful cells, and then introducing those cells into damaged areas, or incorporating them into existing therapies.

Here is a very readable review paper on this topic, entitled Peripheral Nerve Repair with Cultured Schwann Cells: Getting Closer to the Clinics:

Peripheral nerve injuries are a frequent and disabling condition, which affects 13 to 23 per 100,000 persons each year. Severe cases, with structural disruption of the nerve, are associated with poor functional recovery. The experimental treatment using nerve grafts to replace damaged or shortened axons is limited by technical difficulties, invasiveness, and mediocre results. Other therapeutic choices include the adjunctive application of cultured Schwann cells and nerve conduits to guide axonal growth. The bone marrow is a rich source of mesenchymal cells, which can be differentiated in vitro into Schwann cells and subsequently engrafted into the damaged nerve.

...

Cell-based therapy associated with scaffolds is a promising branch of regenerative medicine. ... The idea of using nerve conduits filled with bone-marrow mesenchymal cells may be an attractive alternative to more aggressive therapies. If successful, the treatment may lead to functional improvement, avoiding the hurdles of additional surgeries and use of immunosuppressive drugs. A hypothetical scenario would be a patient with a traumatic limb injury, including extensive and severe damage of a motor nerve, resulting in acute disability. There would be a nerve gap, precluding any attempt of direct nerve suture. The use of a nerve conduit filled with allogeneic bone marrow-derived MSCs would be proposed, as an alternative to the standard autologous nerve graft implant. The acute nature of the condition would require a readily available source of cells, and since MSCs are immunoprivileged, indicating poor alloimmune response and therefore delayed rejection, allogeneic sources would be ideal. The cells would be already isolated from donated bone marrow, expanded in culture without further manipulation, tested for safety and quality, cryopreserved and ready for clinical use. The necessary amount of cells would then be thawed and inserted into biodegradable nerve conduits, readily implanted between nerve stumps during microsurgery.

The therapy would require no immunosuppression and sequential functional and electromyographical evaluations would determine the outcomes. Expected results would be axonal repair, remyelination, and progressive functional improvement, either through differentiation of the transplanted into Schwann-like cells or, most probably, through paracrine effects of the bone-marrow-derived MSCs on the proximal axonal stump and remaining endogenous Schwann cells, stimulating regeneration.

...

Schwann cell cultures have demonstrated favorable results in the experimental setting; however, the ideal source of cells has not yet been established. Bone-marrow-derived mesenchymal cells present encouraging results and may become the ideal cell for clinical translation. These cells have been exhaustively investigated during the last two decades and approved for use in numerous clinical trials

It is interesting to note that there are areas of stem cell medicine in which cell transplants from other people are just as useful as autologous cells obtained from the patient, this being one of them. So there is less of a motivation in this line of work to develop the techniques of culturing patient cells versus the long-established use of donor tissue.

From Nature: researchers have "grown the precursor of a human eye in the lab. The structure, called an optic cup, is 550 micrometres in diameter and contains multiple layers of retinal cells including photoreceptors. The achievement has raised hopes that doctors may one day be able to repair damaged eyes in the clinic. ... the most exciting thing is that the optic cup developed its structure without guidance from [the] team. ... Until recently, stem-cell biologists had been able to grow embryonic stem-cells only into two-dimensional sheets. But over the past four years, [this group] has used mouse embryonic stem cells to grow well-organized, three-dimensional cerebral-cortex, pituitary-gland and optic-cup tissue. His latest result marks the first time that anyone has managed a similar feat using human cells. ... The various parts of the human optic cup grew in mostly the same order as those in the mouse optic cup. This reconfirms a biological lesson: the cues for this complex formation come from inside the cell, rather than relying on external triggers. ... retinal precursor cells spontaneously formed a ball of epithelial tissue cells and then bulged outwards to form a bubble called an eye vesicle. That pliable structure then folded back on itself to form a pouch, creating the optic cup with an outer wall (the retinal epithelium) and an inner wall comprising layers of retinal cells including photoreceptors, bipolar cells and ganglion cells. ... This resolves a long debate [over] whether the development of the optic cup is driven by internal or external cues."

Link: http://www.nature.com/news/biologists-grow-human-eye-precursor-from-stem-cells-1.10835

There is some debate over the degree to which accumulated nuclear DNA damage contributes to aging. Here researchers propose a class of mechanisms: "Aging is characterized by the inability of tissues to maintain homeostasis. This leads to an impaired response to stress and, as a consequence, an increased risk of morbidity and mortality. ... Aging is thought to be driven, at least in part, by the accumulation of stochastic damage in cells. ... However, the mechanism by which cellular damage drives aging is not known. The simplest model is that damage causes attrition of functional cells. But this is inadequate in light of emerging evidence that aging-related degenerative changes in old and damaged organisms can be delayed or reversed by circulating factors. These observations point instead toward the cellular response to damage being the key driver of aging. The transcription factor NF-κB is a central component of the cellular response to damage, stress, and inflammation ... Numerous studies report increased NF-κB activity with aging. ... Genetic depletion of NF-κB in the skin of transgenic mice reversed age-related gene expression and histologic changes, providing support for NF-κB activation playing a causal role in skin aging. ... it remains to be determined whether NF-κB activation drives systemic aging and whether NF-κB is a therapeutic target for attenuating and/or delaying aging-related degenerative changes. ... We found that NF-κB is stochastically activated in a variety of cell types with normal and accelerated aging and that genetic or pharmacologic inhibition of NF-κB activation delays the onset of numerous aging-related symptoms and pathologies. Inhibition of IKK/NF-κB activity reduced cellular senescence and oxidative damage, including DNA and protein damage, revealing that cellular stress responses promote further cellular damage. Our findings strongly suggest that inhibitors of the IKK/NF-κB pathway may delay damage and extend healthspan in patients with accelerated aging and chronic degenerative diseases of old age."

Link: http://dx.doi.org/10.1172/JCI45785

You might recall that I've mentioned the Brain Preservation Prize as a worthy endeavor. Research prizes are in general a very effective means of spurring progress in fields that would not otherwise move all that much. Sufficiently accurate preservation of the brain ties in to a range of topics important to those of us interested in radical life extension - such as how to help the billions who will die prior to the emergence of effective and widespread medical technologies capable of reversing aging.

The nonprofit Brain Preservation Foundation (BPF) hereby officially announces a cash prize for the first individual or team to rigorously demonstrate a surgical technique capable of inexpensively and completely preserving an entire human brain for long-term (more than 100 years) storage with such fidelity that the structure of every neuronal process and every synaptic connection remains intact and traceable using today's electron microscopic (EM) imaging techniques.

Cryonics is one existing way of preserving a human brain sufficiently well to enable a future resuscitation with more advanced technologies than are available today. Plastination is another possibility, but one that was never developed into a commercial service such as that offered by cryonics providers - arguably for no reason other than historical accident and the specialties of those who founded the cryonics movement. Interestingly there are currently a pair of teams competing in the Brain Preservation Prize, and they are employing quite different methods from cryonics and plastination:

Our first team, led by Shawn Mikula (working in the laboratory of Winfried Denk at the Max Planck Institute in Heidelberg), has developed a whole mouse brain chemical preservation and plastic embedding technique. ... As part of the Brain Preservation Technology Prize competition, Dr. Mikula has agreed to demonstrate the quality of ultrastructure preservation which his protocol can achieve. ... 21st Century Medicine's main research has been focused on the cryopreservation of transplantable organs (kidney, heart) and toward decreasing the toxicity of the process to such organs. However, as part of the Brain Preservation Technology Prize competition, they have agreed to demonstrate the quality of ultrastructure preservation that their low temperature vitrification technique can achieve when applied to whole rabbit brains.

I see that economist Robin Hanson of Overcoming Bias is in favor of this initiative, as one might expect from his views on cryonics.

Plastination is Near:

The biggest single charity donation I've made so far is ~$100. But now I'm donating $5000 to an exceptionally worthy cause. And I suggest you donate too. Here's my cause: People who "die" today could live again in the future, perhaps forever, as brain emulations (= uploads, ems), if enough info were saved today about their brains.

...

Today, the main way folks try to save such brain info is to pay a cryonics org to freeze their brain in liquid nitrogen, and keep it so frozen for a long time. Alas, this approach fails if this org ever even briefly fails at this task, letting brains thaw, an event I expect is more likely than not over a century timescale.

...

An anonymous donor has actually funded a $100K Brain Preservation Prize, paid to the first team(s) to pass this test on a human brain, with a quarter of the prize going to those that first pass the test on a mouse brain. Cryonics and plastination teams have already submitted whole mouse brains to be tested. The only hitch is that the prize organization needs money (~25-50K$) to actually do the tests!

This is the exceptionally worthy cause to which I am donating $5K, and to which I encourage others to donate. (More info here; donate here.) We seem close to having a feasible plastination technique, where for a few 10K$ or less one could fill a brain with plastic, saving its key brain info for future revival in an easily stored form. We may only lack donations of a similar amount to actually test that it does save this key brain info. (And if the first approach fails, perhaps to test a few revisions.)

I don't understand why the cryonics community isn't already all over this. To express my opinions to them more forcefully, I offer to bet up to $5K that plastination is more likely to win this full prize than cryonics. That is, if plastination wins but cryonics fails, I win the bet, and if cryonics wins but plastination fails, I lose. If they both win or both fail, the bet is called off. Any takers?

Hanson would be far from the only person to have doubts as to the viability of cryonics, either from an organizational or technical perspective - though he really should use "vitrify" in place of "freeze", as that is what cryonics organizations do these days. Quite different.

My own opinions on the matter are that plastination is well worth exploring - but I would expect any plastination-based community initiative to take a few decades to come to some form of stability and sort out its presently unforseen technical issues. Just because you don't need liquid nitrogen doesn't mean you can handwave away costs and challenges in long term storage. Do insects or forms of microbe like to eat any of the known plastination compounds, for example? Does storage in need to be maintained in a regulated temperature range to preserve structure for the long term? Either of those immediately raises both costs and risks considerably. Cryonics as an industry has the big advantage of having already demonstrated decades of staying power.

That said, it is of course the case that more exploration and more competition is always better. The same is true for technical validation and bulletproofing of the technologies presently used in cryonics. Competition drives progress to a greater degree than aspiration: humans move when they must more than when they want to.

I should also note that, as is often the case in these matters, Hanson's commentary touches on whether a copy of your mind is you. I say no, which is one of the reasons to go into cryopreservation with a tattoo or other permanently attached note to say "Do not copy, restore the original." Copying of a preserved mind is likely to be somewhat easier, so will probably happen unless you ask for some other option.

One portion of the Alzheimer's research field is focused on immune therapies - training the immune system to attack and break down amyloid beta plagues characteristic of Alzheimer's disease. It is important to note that the buildup of signs of Alzheimer's, such as amyloid beta, occurs in most people to a lesser degree, whether or not they go on to develop the condition, and that the level of this sort of damage is associated with level of mental decline with aging. Here researchers show that this may all have something to do with how effective the immune system is in clearing out unwanted junk from the brain: "Recent work in mice suggested that the immune system is involved in removing beta-amyloid, the main Alzheimer's-causing substance in the brain. Researchers have now shown for the first time that this may apply in humans. [Researchers] screened the expression levels of thousands of genes in blood samples from nearly 700 people. The telltale marker of immune system activity against beta-amyloid, a gene called CCR2, emerged as the top marker associated with memory in people. The team used a common clinical measure called the Mini Mental State Examination to measure memory and other cognitive functions. The previous work in mice showed that augmenting the CCR2-activated part of the immune system in the blood stream resulted in improved memory and functioning in mice susceptible to Alzheimer's disease. ... This is a very exciting result. It may be that CCR2-associated immunity could be strengthened in humans to slow Alzheimer's disease, but much more work will be needed to ensure that this approach is safe and effective."

Link: http://www.eurekalert.org/pub_releases/2012-06/tpco-ism061512.php

Via the IEET: "Louis Begley vividly describes the last years of his mother's life, who had been a widow for the previous 40 years before her death. Begley lets us feel the pain in her joints and in her heart. He obviously sees aging as nothing but misery and loneliness. But I think he misses the point - he believes his mother's solitude is the reason of her woes, but it actually is aging, her declined health, pain and suffering - these are the real reasons of her tragedy. If she had been young she would have had no diseases, but only good looks and the opportunity to start over, but alas! she rots alive. Louis Begley caught the very overwhelming in its inevitability, horrifying feeling that it's all over, no need to buy new costumes. They will not be worn for a long time and they're not worth spending time and money. Mr. Begley was widely criticized - and by whom? Who do you think justified aging? The Executive Director and chief scientific officer of the Alzheimer's Drug Discovery Foundation wrote: 'Mr. Begley's bitter portrayal of aging is neither universal nor inevitable... Old age should never be measured by the metrics of youth. An adaptive rather than a maladaptive response to old age and even frailty is possible.' This is unbelievable. So wrong. In reality it's exactly the opposite - aging is universally debilitating and inevitable. While this type of words are coming out of the mouths of people who are the advocates for aging research, nothing good will happen. There will be no money for research to live longer in a younger body. And the reason is the faulty idea that aging can be healthy, productive, or enjoyable. It can't by definition."

Link: http://ieet.org/index.php/IEET/more/konovalenko20120614

Mikhail Blagosklonny might be, to my eyes, a little too focused on mTOR as the be-all and end-all of aging, but he certainly writes a good paper when he puts his mind to it. This one is a thought-provoking look at similarities and differences in mechanisms that come into play at the opposite ends of the calorie intake spectrum. Differences in dietary habits lead, on average, to a longer, healthier life when eating less and a shorter, more unhealthy life when eating more. Naturally, the mechanisms underlying these changes are of interest to researchers who work on calorie restriction mimetic drugs, seeking to understand and then recreate the health benefits through medical technology:

Once again on rapamycin-induced insulin resistance and longevity: despite of or owing to:

Calorie restriction (CR), which deactivates the nutrient-sensing mTOR pathway, slows down aging and prevents age-related diseases such as type II diabetes. Compared with CR, rapamycin more efficiently inhibits mTOR. Noteworthy, severe CR and starvation cause a reversible condition known as "starvation diabetes." [and] chronic administration of rapamycin can cause a similar condition in some animal models. ... Here I introduce the notion of benevolent diabetes and discuss whether starvation-like effects of chronic high dose treatment with rapamycin are an obstacle for its use as an anti-aging drug.

...

[You] might wonder whether rapamycin extends lifespan despite or because of "starvation-like diabetes". ... Rapamycin, which inhibits mTOR, is a "starvation-mimetic", making the organism "think" that food is in a short supply. The most starvation-sensitive organ is the brain. The brain consumes only glucose and ketones. Therefore, to feed the brain during starvation, the liver produces glucose from amino acids (gluconeogenesis) and ketones from fatty acids (ketogenesis). Since insulin blocks both processes, the liver needs to become resistant to insulin. Also secretion of insulin by beta-cells is decreased. And adipocytes release fatty acids (lipolysis) to fuel ketogenesis by the liver. Thus, there are five noticeable metabolic alterations of starvation: gluconeogenesis, ketogenesis, insulin resistance, low insulin levels and increased lipolysis. This metabolic switch is known as starvation diabetes, a reversible condition, described 160 years ago.

...

Starvation-diabetes is not a true type II diabetes. Type II diabetes is a consequence of insulin-resistance in part due to excessive nutrients and obesity. ... Type II diabetes and starvation diabetes seem to be the two opposite conditions: the first is associated with activation of nutrient-sensing pathways, whereas the second is associated with deactivation of nutrient sensing pathways such as mTOR. Type II diabetes is dangerous by its complications such as retinopathy, neuropathy and accelerated atherosclerosis and cancer. Long-term effects of prolonged "starvation diabetes" is not known of course: it could not last for a long time, otherwise an animal (or human) would die from starvation. Or would not? ... Among individuals who had been practicing severe CR for an average of 7 years, 40% of CR individuals exhibited "diabetic-like" glucose intolerance, despite low levels of fasting glucose, insulin and inflammatory cytokines as well as excellent other metabolic profiles. In comparison with the rest CR individuals, they had lower BMI, leptin, circulating IGF-I, testosterone, and high levels of adiponectin, which are key adoptations to CR in rodents, suggesting severe CR.

The authors speculated that the "insulin resistance" in this severe CR group might have the effect of slowing aging, also based on the finding that a number of insulin-resistant strains of mice are long-lived. The same conclusion could be reached from the mTOR perspective

Metabolism is a complex thing, is it not? The benefits of calorie restriction in humans are legion, per the research to date, and it's well worth your time to look into it and give it a try. Heart health vastly improved, near every measure of aging slowed, greater resistance to age-related diseases, and much more - far more than any medical technology can yet accomplish for a basically healthy individual, in fact.

The continued search for ways to more quickly determine differences in expected longevity between members of the same species finds a potential marker: "Xenobiotic metabolism has been proposed to play a role in modulating the rate of aging. Xenobiotic-metabolizing enzymes (XME) are expressed at higher levels in calorically restricted mice (CR) and in GH/IGF-I-deficient long-lived mutant mice. In this study, we show that many phase I XME genes are similarly upregulated in additional long-lived mouse models, including "crowded litter" (CL) mice, whose lifespan has been increased by food restriction limited to the first 3 weeks of life, and in mice treated with rapamycin. Induction in the CL mice lasts at least through 22 months of age, but induction by rapamycin is transient for many of the mRNAs. Cytochrome P450s, flavin monooxygenases, hydroxyacid oxidase, and metallothioneins were found to be significantly elevated in similar proportions in each of the models of delayed aging tested, whether these are based on mutation, diet, drug treatment, or transient early intervention. The same pattern of mRNA elevation can be induced by 2 weeks of treatment with tert-butylhydroquinone, an oxidative toxin known to active Nrf2-dependent target genes. These results suggest that elevation of phase I XMEs is a hallmark of long-lived mice and may facilitate screens for agents worth testing in intervention-based lifespan studies."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22693205

Researchers here report on another way to tell old stem cells to get back to work on maintaining muscle tissue - though not one that has immediate application, as it requires removal of an important component of immune system function. Thus this is only promising if researchers can pick apart the different functions of this component and interfere only where it suppresses stem cell activity in muscle regeneration: "Wnt signaling plays critical roles in development of various organs and pathogenesis of many diseases, and augmented Wnt signaling has recently been implicated in mammalian aging and aging-related phenotypes. We here report that complement C1q activates canonical Wnt signaling and promotes aging-associated decline in tissue regeneration. Serum C1q concentration is increased with aging, and Wnt signaling activity is augmented during aging in the serum and in multiple tissues of wild-type mice, but not in those of C1qa-deficient mice. ... Skeletal muscle regeneration in young mice is inhibited by exogenous C1q treatment, whereas aging-associated impairment of muscle regeneration is restored by C1s inhibition or C1qa gene disruption. Our findings therefore suggest the unexpected role of complement C1q in Wnt signal transduction and modulation of mammalian aging."

Link: http://www.cell.com/retrieve/pii/S0092867412005314

Whole brain emulation is the topic for today: being able to run all of the processes of a brain on some form of computing machinery other than the evolved biological structures we presently possess. Considered in the long term this is an important line of research, as radical life extension will ultimately require moving away from flesh and into some more robust form of machinery in order to better manage the risk of fatal accidents. 'Ultimately' here is a long way into the future, centuries or more, long after we have solved the basic problems of repairing our aging biology so as to attain continual youth. Some people will be satisfied with copying themselves from their biological substrate into a machine substrate and letting that machine copy continue on, but that seems to me little more than an expensive form of procreation - continuation of the self requires a slow transformation of the original, not a quick cut and paste of data to a new computing device. But this is an old and often rehashed argument between identity as pattern and identity as continuity.

Here are some past posts on whole brain emulation if you'd like to do some background reading:

• A Preliminary Roadmap to Whole Brain Emulation
• The Age of Artificial Brains

Regardless of how people decide to use the ability to host a conscious individual somewhere other than a human brain, the technologies of whole brain emulation will have to be built. They are a precursor to any program of replacing the brain's present biological machinery with something better. From where I stand, brain emulation is also the most plausible path to true artificial intelligence, which at this time looks far more likely to arise from attempts to duplicate and then improve on the operation of human brains than from efforts to improve expert systems of varying sorts.

Reasonable people differ on this, of course, as even a brief survey of publications on artificial intelligence will tell you.

If you find this topic interesting, you might look at the latest issue of the International Journal of Machine Consciousness, featuring many of the usual suspects from the transhumanist community - folk who have been putting in time on AI and molecular nanotechnology research for some years. A couple of the more intriguing items:

Non-Destructive Whole-Brain Monitoring Using Nanorobots: Neural Electrical Data Rate Requirements

Neuronanorobotics, a promising future medical technology, may provide the ultimate tool for achieving comprehensive non-destructive real-time in vivo monitoring of the many information channels in the human brain. This paper focuses on the electrical information channel and employs a novel electrophysiological approach to estimate the data rate requirements, calculated to be (5.52 ± 1.13) × 10^16 bits/sec in an entire living human brain, for acquiring, transmitting, and storing single-neuron electrical information using medical nanorobots, corresponding to an estimated synaptic-processed spike rate of (4.31 ± 0.86) × 10^15 spikes/sec.

Why Uploading Will Not Work, or, the Ghosts Haunting Transhumanism

Transhumanists tend to have a commitment to materialism and naturalism but nonetheless pursue goals traditionally associated with religious ideologies, such as the quest for immortality. Some hope to achieve immortality through the application of a technology whereby the brain is scanned and the person "uploaded" to a computer. This process is typically described as "transferring" one's mind to a computer.

I argue that, while the technology may be feasible, uploading will not succeed because it in fact does not "transfer" a mind at all and will not preserve personal identity. Transhumanist hopes for such transfer ironically rely on treating the mind dualistically - and inconsistently with materialism - as the functional equivalent of a soul, as is evidenced by a carefully examination of the language used to describe and defend uploading. In this sense, transhumanist thought unwittingly contains remnants of dualistic and religious concepts.

A Framework for Approaches to Transfer of a Mind's Substrate

I outline some recent developments in the field of neural prosthesis concerning functional replacement of brain parts. Noting that functional replacement of brain parts could conceivably lead to a form of "mind-substrate transfer" (defined herein), I briefly review other proposed approaches to mind-substrate transfer then I propose a framework in which to place these approaches, classifying them along two axes: top-down versus bottom-up, and on-line versus off-line; I outline a further hypothetical approach suggested by this framework. I argue that underlying technological questions about mind-substrate transfer, there is a fundamental question which concerns our beliefs about continuity of identity.

On this last topic, present developments in neural prosthetics are well worth the time taken to investigate. Being able to replace some lesser pieces of the brain in the event of damage is on the verge of being a going concern - sometime within the next twenty years there will be a fair number of people walking around with implanted medical devices in their brains. Those devices will replace or augment the function of one or more component parts of the brain, allowing these patients to live where they would otherwise have died or suffered a lower quality of life. This is the start of the next wave of mapping the physical structure of the brain to its function, and that field of research will expand and accelerate just like all other areas of medicine, driven by the ongoing biotechnology revolution.

Via EurekAlert!: "Regenerative medicine, or the use of specially grown tissues and cells to treat injuries and diseases, has been successful in treating disorders of a number of organs, including heart, pancreas, and cartilage. However, efforts to treat disorders of the corneal endothelium, a single cell layer on the inner surface of the cornea, with regenerative techniques have been less effective. Now, a group of scientists has developed a method that enhances the adhesion of injected corneal endothelial cells (CECs), allowing for successful corneal transplantation to repair pathological dysfunctions. ... Previous studies demonstrated that Rho-associated kinase (ROCK) signaling interferes with adhesion. We found that transplanting cultivated CECs in combination with a low-molecular weight compound that inhibits ROCK (ROCK inhibitor Y-27632), successfully achieved the recovery of corneal transparency. ... Using rabbit cells, researchers cultivated CECs in the lab and injected them into the anterior chamber of rabbit eyes with damaged corneal endothelia. Based on the recovery of the corneal endothelial function, they found that when the cultivated cells were injected along with Y-27632, the rabbit corneas regained complete transparency 48 hours after injection. ... Since rabbit CECs are highly prolific in vivo, the scientists performed another round of experiments with monkey CECs, which are more similar to those in humans. The transplantation of CECs in these primates also achieved the recovery of long-term corneal transparency with a monolayer of hexagonal cells, suggesting that cell adhesion modified by ROCK inhibitor may be an effective treatment for human corneal endothelial disorders."

Link: http://www.eurekalert.org/pub_releases/2012-06/ehs-rcm061112.php

From the BBC: "A 10-year-old girl has had a major blood vessel in her body replaced with one grown with her own stem cells. ... A vein was taken from a dead man, stripped of its own cells and then bathed in stem cells from the girl, according to a study published in the Lancet. Surgeons said there was a "striking" improvement in her quality of life. This is the latest is a series of body parts grown, or engineered, to match the tissue of the patient. Last year, scientists created a synthetic windpipe and then coated it with a patient's stem cells. ... In this case, other options such as using artificial grafts to bypass the blockage, had failed. ... It used a process known as "decellularisation". It starts with a donor vein which is then effectively put through a washing machine in which repeated cycles of enzymes and detergents break down and wash away the person's cells. It leaves behind a scaffold. This is then bathed in stem cells from the 10-year-old's bone marrow. The end product is a vein made from the girl's own cells. ... The young girl was spared the trauma of having veins harvested from the deep neck or leg with the associated risk of lower limb disorders."

Link: http://www.bbc.co.uk/news/health-18428889

Sarcopenia is the umbrella name for the progressive loss of muscle mass and strength with age - which may turn out to cover a range of separate mechanisms. The progression of sarcopenia appears to be reduced by the practice of calorie restriction, and might also be slowed by a range of possible therapies such as exercise and dietary leucine supplementation or targeting the myostatin gene and its protein product. Levels of inflammation also show up as a possible contributing factor - more chronic inflammation is a bad thing across the board.

Here is an open access paper that touches on much of what the mainstream research community is investigating when it comes to sarcopenia.

Sarcopenia, the age-related loss of skeletal muscle, is characterized by a deterioration of muscle quantity and quality leading to a gradual slowing of movement, a decline in strength and power, and an increased risk of fall-related injuries. Since sarcopenia is largely attributed to various molecular mediators affecting fiber size, mitochondrial homeostasis, and apoptosis, numerous targets exist for drug discovery. In this paper, we summarize the current understanding of the endocrine contribution to sarcopenia and provide an update on hormonal intervention to try to improve endocrine defects. Myostatin inhibition seems to be the most interesting strategy for attenuating sarcopenia other than resistance training with amino acid supplementation.

...

Several researchers have investigated the effect of inhibiting myostatin to counteract sarcopenia using animals. Lebrasseur et al. found that treatment with a mouse chimera of antihuman myostatin antibody (24 mg/Kg, 4 weeks), a drug for inhibiting myostatin, elicited a significant increase in muscle mass and in running performance ... More recently, Murphy et al. showed, by way of once weekly injections, that a lower dose of this anti-human myostatin antibody (10 mg/Kg) significantly increased the fiber cross-sectional area (by 12%) and in situ muscle force (by 35%) of aged mice (21 mo old). These findings highlight the therapeutic potential of antibody-directed myostatin inhibition for sarcopenia by inhibiting protein degradation.

Work on myostatin therapies is one of the topics worthy of greater attention here, as this seems like it would be a generally beneficial gene therapy for everyone - something that, given a good safety profile, most people would want to undergo earlier in life. The first step towards widespread availability for this sort of human enhancement is to develop the necessary medical technology in in the first place, of course, and these days that's only going to happen in the service of treating a specific medical condition.

An article from Cryonics Magazine: "Cryopreserved patients must be cared for for at least decades and some anticipate centuries. During this time, some caretaker organization must look after the patients. This involves paying the rent and utilities, replacing liquid nitrogen, maintaining and replacing dewars, hiring and paying staff, and a host of other activities that must be done reliably and economically. The usual arrangement is for the patient to make a lump sum payment into a common fund, the interest from which will then pay the expenses of maintaining a group of patients in cryopreservation for whatever period of time might be required. At Alcor, the lump sum payment is made into the PCT (Patient Care Trust), and the payment made by each patient is the 'PCT allocation,' taken from the total payment made by the patient at the time of cryopreservation. Determining the appropriate amount of the PCT allocation can raise questions whose answers are not always obvious and can sometimes be quite dilemmatic. ... Contractual and financial arrangements must usually be in place before a patient can be cryopreserved. The financial arrangements involve payment for both the up-front procedures and long term care. These payments are usually bundled, and at Alcor the total amount of money that is required is called the 'funding minimum'. The funding minimum is usually paid with life insurance. ... The focus of this article is on the lump sum payment made into the common fund from the funding minimum by the patient at the time of the patient's cryopreservation."

Link: http://www.alcor.org/magazine/2012/06/11/the-allocation-of-long-term-care-costs-at-alcor/

The build up of senescent cells is one of the contributing causes of aging, and is partially due to the progressive failure of the immune system to destroy these cells as they crop up. Many of the changes that come with aging accelerate as they progress, and this piece provides one example as to why this is the case; for senescent cells, the more you have the faster they accumulate: "Cells may become senescent in an effort to protect the body such as when tumor suppressor genes shut down division to prevent cancer. However other sorts of damage may lead cells to stop dividing as well. A pivotal study last year showed elegantly using a trangenic approach that if senescent cells were regularly cleared from the body of mice, signs of aging in many tissues were dramatically reduced. The explanation for this result was that somehow senescent cells were damaging nearby cells, perhaps by excreting toxic materials. ... A newly published study [proves] or the first time that senescent cells do indeed damage nearby cells causing them to become senescent too. It also shows this occurs through direct cell to cell contact and resultant spread of reactive oxygen species. Furthermore it shows evidence this process occurs in the living organism as clusters of cells bearing senescent makers are found in mice livers. Clearly the next and important step for helping to reduce aging in humans is developing a safe and effective method presumably using a pharmacological agent in which senescent cells can be removed from the body."

Link: http://extremelongevity.net/2012/06/11/study-proves-senescent-cells-cause-nearby-cells-to-become-senescent/

DNA methylation is a part of epigenetics, one of the mechanisms by which protein machinery produced from DNA creates feedback loops to change the production levels of many different proteins. Genes are decorated with a continually altering array of chemical signals, changing with circumstances and environment. The cell nucleus is a factory, DNA the component blueprints, and DNA methylation one portion of the chaotic parts order list: from moment to moment, how much to make of each piece of protein machinery encoded in the genome.

DNA methylation changes with age, location within the body, and type of cell, a fuzzy and very complicated pattern of decorated genes. Some of the myriad changes are sufficiently similar from person to person to be a possible method to determine age quite accurately. Others are known to reflect the degree to which a person becomes frail with age. Many more are not understood at all, or may be largely random.

A great many debates within aging science revolve around the difference between cause and consequence - and so too with DNA methylation. Is it a part of the expected attempts by the body to adapt to increasing levels of cellular damage caused by aging, or is at least some alteration in DNA methylation a form of damage in and of itself? Good arguments can be made either way, but for my money I'd be surprised to see significant levels of epigenetic changes that were anything other than the results of underlying damage and evolutionary adaptations that try (and ultimately fail) to cope with that damage.

This debate is significant, of course, because of how it directs research and development funding. Will scientists try to patch over the root causes of aging by altering its secondary effects - inevitably doomed to be expensive and comparatively ineffective - or will they work to repair the true causes, and thereby remove the secondary effects for free? There's been a great deal too much work on patching over the cracks in the medicine of past decades, and in this age of biotechnology it seems a sin to continue that way when we don't have to.

In any case, here is news of more recent work on DNA methylation that has been doing the rounds:

DNA Switches Discovered to Decline Significantly with Age

An important element of the DNA is what is known as the epigenome. This refers to the pattern of added chemical tags on the DNA called methyl groups. These tags may alter the expression of genes near or on which they reside. Usually they turn off expression of the gene on which they reside.

...

A team of researchers decoded and compared the entire epigenome from blood cells in a neonate, a 26 year old, and a 103 year old. The results were striking. The researchers discovered that as the cells aged, the epigenome changed dramatically. They found 80% of all cysteine residues were methylated in the newborn compared to just 73% of them in the centenarian. A 26 year old subject had 78% of them methylated. They also found almost 18,000 locations in the genome where methylation varied the most. About one third of those regions occurred in genes linked to increase risk of cancer. Mostly aging involved loss of methyl groups.

Why do we age? Genomes of baby and 103-year-old may offer clue

The researchers analyzed the genome of the baby's white blood cells (obtained from cord blood). They found more than 16 million spots where methyl groups had been attached to the baby's DNA. But when they did the same thing with the old man's DNA (obtained from his white blood cells), they found nearly 500,000 fewer sites with methyl groups attached. The sites weren't as densely methylated either.

The scientists got a similar result when they looked in a larger group of 19 Caucasian newborns and 19 Caucasian nonogarians (average age 92.6). And they found an intermediate level of methylation when they examined the white-blood-cell DNA of 19 middle-aged people (average age about 60).

The scientists went on to take a closer look at a few specific genes where they'd spotted changes in methylation in their samples and found that the activity of the genes that had been depleted in methyl groups was, indeed, changed. And they noted that some of the genes - such as two called Sirtuin 5 and Sirtuin 7 - are thought from other studies to be involved in the biology of aging.

As I said above, I don't think epigenetic changes have much to say about why we age, as they are not a fundamental change. They may encode many of the details of how we age, however - ways in which low-level damage translates into characteristic changes in the way that cells, systems, and organs operate. This may be very valuable, but equally it doesn't change the basic goal, which is to repair the fundamental forms of damage that drive aging.

A finding here ties into research suggesting that life can be lengthened through selective breeding at later ages - this, like the response to calorie restriction, is a form of metabolic variability that may have evolved to make a species better able to adapt to changing environmental circumstances: "Children and even grandchildren of older fathers may live longer than children of younger men. ... Scientists found that children born to fathers between the ages of late 30s to early 50s inherit longer 'telomeres' or tiny protective caps on the ends of chromosomes that protect against aging degeneration and disease. ... Researchers measured the telomere length of DNA by using blood samples collected from 1,779 young Filipino adults and their mothers and determined the ages of the children's fathers and grandfathers. Study results show that a person's telomeres became longer not only with their father's age at birth, but also with their paternal grandfather's age at their father's birth, meaning that the longevity effect is amplified over the generations. ... The findings suggest that delayed paternal reproduction can lead to cumulative, multi-generational increases in telomere length in offspring which may promote longer life. Researchers also believe that longer telomeres may delay sexual development, and instead invest energy into the extra resources necessary to maintain healthy functioning at more advanced ages. ... late fatherhood may serve as a sigh that mortality rates are low. ... If your father and grandfather were able to live and reproduce at a later age, this might predict that you yourself live in an environment that is somewhat similar - an environment with less accidental deaths or in which men are only able to find a partner at later ages. In such an environment, investing more in a body capable of reaching these late ages could be an adaptive strategy from an evolutionary perspective."

Link: http://www.medicaldaily.com/news/20120611/10251/reproduction-fatherhood-children-longevity.htm

An example of the sort of work presently taking place in the stem cell field: "scientists purified a subset of stem cells found in fat tissue and made from them bone that was formed faster and was of higher quality than bone grown using traditional methods, a finding that may one day eliminate the need for painful bone grafts that use material taken from the patient during invasive procedures. ... Traditionally, cells taken from fat had to be cultured for weeks to isolate the stem cells which could become bone, and their expansion increases risk of infection and genetic instability. ... [Researchers] used a cell sorting machine to isolate and purify human perivascular stem cells (hPSC) from adipose tissue and showed that those cells worked far better. They also showed that a growth factor called NELL-1 [enhanced] the bone formation in their animal model. ... People have shown that culture-derived cells could grow bone, but these are a fresh cell population and we didn't have to go through the culture process, which can take weeks. The best bone graft is still your own bone, but that is in limited supply and sometimes not of good quality. What we show here is a faster and better way to create bone that could have clinical applications. ... The purified human hPSCs formed significantly more bone [and] these cells are plentiful enough that patients with not much excess body fat can donate their own fat tissue. ... if everything goes well, patients may one day have rapid access to high quality bone graft material by which doctors get their fat tissue, purify that into hPSCs and replace their own stem cells with NELL-1 back into the area where bone is required. The hPSC with NELL-1 could grow into bone inside the patient, eliminating the need for painful bone graft harvestings. The goal is for the process to isolate the hPSCs and add the NELL-1 with a matrix or scaffold to aid cell adhesion to take less than an hour."

Link: http://www.newswise.com/articles/a-better-way-to-grow-bone-fresh-purified-fat-stem-cells-grow-bone-better-faster

Naked mole rats are in the press ever more often of late - their longevity and cancer resistance makes them an ideal subject of study for researchers who aim to tinker human metabolism into a better state. We're all mammals in this end of the biosphere, so perhaps some of the mechanisms used by exceptional species can be ported over to humans in the form of medicine - gene therapies or carefully designed protein treatments that replicate the effects of having a particular gene. That research has been taking place for some years, but it always takes the public a while to catch up with what is happening in the research community. Here is a good introductory article on naked mole rats:

Pitch dark, dank, and seething with saber-toothed, sausage-shaped creatures, the world of the African naked mole-rat is a hostile habitat. In the 1980s, scientists made the remarkable discovery that naked mole-rats live like termites with a single, dominant breeding queen and scores of nonbreeding adult helpers that never leave their natal colony. But the bizarreness doesn't stop there. Naked mole-rats, unlike other mammals, tolerate variable body temperatures, attributed to their lack of an insulatory layer of fur. Their pink skin is hairless except for sparse, whisker-like strands that crisscross the body to form a sensitive sensory array that helps them navigate in the dark. Both the naked mole-rat's skin and its upper respiratory tract are completely insensitive to chemical irritants such as acids and capsaicin, the spicy ingredient in chili peppers. Most surprisingly, they can survive periods of oxygen deprivation that would cause irreversible brain damage in other mammals, and they are also resistant to a broad spectrum of other stressors, such as the plant toxins and heavy metals found in the soils in which they live. Unlike other mammals, they never get cancer, and this maintenance of genomic integrity, even as elderly mole-rats, most likely contributes to their extraordinarily long life span. In contrast to similar-size mice that only live 2-4 years, naked mole-rats can survive and thrive, maintaining normal function and reproduction, into their 30s.

From my perspective, naked mole rat research is likely to be more important for the cancer research community than for longevity science; their cancer resistance might be largely a matter of different behavior in a single gene, which gives researchers a clear target for investigation. On the longevity front, at this point it looks probable that naked mole rats are walking confirmations of the pacemaker membrane hypothesis, showing that the resilience of mitochondria to damage is very influential in determining life span. That doesn't mean we should try to make our mitochondria look like those of the naked mole rat, however - that would be enormously challenging, a massive undertaking. Instead, we should prioritize presently ongoing research aimed at repairing mitochondria. We don't need better mitochondria if we can walk into a clinic and have all of their damage repaired every decade or two.

This is in fact an expression of the general argument against all attempts to slow aging by changing human metabolism or the make up of our biochemistry. It will be very hard, and it will bring little benefit. Working on ways to repair the biology we have is a far better strategy, a goal that will be less expensive to achieve, and will produce a far superior result.

From The Scientist: "After 20 years of high-profile failure, gene therapy is finally well on its way to clinical approval. The concept is simple: if a mutated gene is causing a problem, replace or supplement it with a new, accurate copy. In theory, such a strategy could not just treat, but cure countless human genetic diseases. In practice, however, developing safe and effective gene therapies has not been easy. Even when identifying a disorder's genetic basis is fairly straightforward, finding the appropriate delivery vector to target the diseased tissues in the body, while avoiding unintended consequences, has challenged would-be gene therapists for more than 20 years. But more and more researchers are convinced that the technique is on the brink of becoming a common medical practice. ... In the last year alone, he says, major breakthroughs have been published for the use of gene therapy in patients with hemophilia, solid tumors, and leukemia, not to mention the dozens of trials yielding positive results for gene therapies to treat various types of blindness. ... It's just remarkable. These decades of work are suddenly really paying off. ... The history of medicine says every new technology starts with a great idea and then requires hard work and optimization. And I think that's exactly what's happened with gene therapy. Hurdles were identified - and there's always hurdles once you get into a complex human disease situation - and they've been addressed. ... The concepts aren't that much different than they were early on, but the tools are much better. Now [gene therapy] is actually fulfilling the promise that people said it would have."

Link: http://the-scientist.com/2012/06/01/targeting-dna/

A clever way to target an infused therapy to particular regions in the body by using their physical properties: "Treatment options [for atherosclerosis] are currently available to people who suffer from the disease but no drug can target solely the diseased areas, often leading to generalized side effects. Intravenous injection of a vasodilator (a substance that dilates blood vessels), such as nitroglycerin, dilates both the diseased vessels and the rest of our arteries. Blood pressure can thus drop, which would limit the desired increased blood flow generated by vasodilatation of diseased vessels and needed for example during a heart attack. In order to increase the effectiveness of treatments against atherosclerosis and to reduce side effects, a team of researchers [have] developed nanocontainers having the ability to release their vasodilator content exclusively to diseased areas. ... Though no biomarker specific to atherosclerosis has been identified, there is a physical phenomenon inherent to stenosis (the narrowing of blood vessels) known as shear stress. This force results from fluctuations in blood flow induced by the narrowing of the artery and runs parallel to the flow of blood. It is by making use of this phenomenon that the team of researchers has developed a veritable 'time bomb', a nanocontainer which, under pressure from the shear stress in stenosed arteries, will release its vasodilator contents. By rearranging the structure of certain molecules (phospholipids) in classic nanocontainers such as liposome, scientists were able to give them a lenticular shape as opposed to the normal spherical shape. In the form of a lens, the nanocontainer then moves through the healthy arteries without breaking. This new nanocontainer is perfectly stable, except when subjected to the shear stress of stenosed arteries."

Link: http://www.eurekalert.org/pub_releases/2012-06/udg-rda060812.php

The liver is likely to be one of the earliest human organs grown to order from a patient's stem cells: liver tissue is already far more capable of regeneration than the tissues of other organs, and researchers have been making good progress in recent years in coaxing stem cells to form live tissue. As of today, a press report is doing the rounds to claim that a Japanese group have managed to grow a small functional mass of liver tissue - calling it a liver is no doubt considerably overstating the case, given the small size. Details are somewhat light on the ground, but we'll no doubt hear more soon.

Japanese researchers grow stem cell liver:

Japanese researchers have created a functioning human liver from stem cells, a report says. ... A team of scientists transplanted induced pluripotent stem (iPS) cells into the body of a mouse, where it grew into a small, but working, human liver, the Yomiuri Shimbun said.

A team led by professor Hideki Taniguchi at Yokohama City University developed human iPS cells into "precursor cells", which they then transplanted into a mouse's head to take advantage of increased blood flow. The cells grew into a human liver 5 millimetres (0.2 inches) in size that was capable of generating human proteins and breaking down drugs, the Yomiuri reported.

An abstract of Taniguchi's research was delivered to regenerative medicine researchers ahead of an academic conference next week, but Taniguchi declined to comment to AFP before the meeting.

The liver is a good example of an organ where the real challenges will lie in generating suitable blood vessels throughout the liver tissue and then integrating it with a patient's vascular system - being able to reliably build a mass of liver tissue from stem cells is but the first step on the path. Not that this is unknown; you might take a look at one of the more recent publications from Hideki Taniguchi's team, for example:

Generation of functional human vascular network:

One of the major obstacles in regenerating thick, complex tissues such as the liver is their need for vascularization, which is essential to maintain cell viability during tissue growth and to induce structural organization. Herein, we have described a method to engineer a functional human vascular network.

...

Vascularization is the key challenge to organ generation. We successfully generated human vascular networks inside a matrix. Integration of parenchymal cells using our engineering technique should facilitate future efforts to reconstitute vascularized human organ systems in vitro.

Andrew Weil, who is something of an apologist for aging, here holds forth on the merits of intermittent fasting (IF) - shown to improve health and extend life in laboratory animals through mechanisms that largely, but not entirely, overlap with those of calorie restriction: "An IF regime works, proponents say, because it aligns with our evolutionary history. Over the 250,000 years that Homo sapiens have been around, food supply has waxed and waned. We evolved to take advantage of this fact, building muscle and fatty tissue during times of abundance, then paring it back during lean ones. Fasting periods accelerate the clearing-out of waste left by dead and damaged cells, a process known as autophagy. A failure of autophagy to keep up with accumulated cellular debris is believed by many scientists to be one of the major causes of the chronic diseases associated with aging. Occasional fasting also seems to boost activity and growth of certain types of cells, especially neurons. This may seem odd, but consider it from an evolutionary perspective - when food is scarce, natural selection would favor those whose memories ("Where have we found food before?") and cognition ("How can we get it again?") became sharper. Research indicates that the benefits of IF may be similar to those of caloric restriction (CR) in which there are regular meals, but portions are smaller than normal. ... The positive effects of IF have been chronicled in a variety of animal and human studies, starting with a seminal experiment in 1946, when University of Chicago researchers discovered that denying food every third day boosted rats' lifespans by 20 percent in males, 15 percent in females. A 2007 review by University of California, Berkeley, researchers concluded that alternate-day fasting may: 1) Decrease cardiovascular disease risk. 2) Decrease cancer risk. 3) Lower diabetes risk (at least in animals, data on humans were less clear, possibly because the trial periods in the studies were not long enough to show an effect). 4) Improve cognitive function. 5) Protect against some effects of Alzheimer's and Parkinson's diseases."

Link: http://www.huffingtonpost.com/andrew-weil-md/fasting-health_b_1557043.html

This interview, machine-translated from the Russian, will be of interest to those who look into the history of transhumanist thought on the defeat of aging and radical life extension. It has deep roots back into the early 20th century, and one thread of these ideas was evolving through the ongoing disaster that was Russia of that century - the Russian cosmists are thought of as important predecessors to modern transhumanism, for example. These are some thoughts and recollections of someone who was publishing and thinking on the topic in the 1960s and later; note that the Russian end of the longevity science community are far from shy when it comes to talking about physical immortality as the end goal of medicine: "Meanwhile, today, in the [21st] century, when we talk about the necessity of victory over death, of making real the possibility of personal immortality and resurrection [of cryopreserved] people - people often do not even bother to think about it, but with some, or even masochistic pleasure begin to look for rebuttal. One would think, what to look for them? Why create additional obstacles? Chance of dying there at all. So there is nothing to lose. Is not it better to try to work together and find ways to avoid it? ... But, oddly enough, and sadly, no modern humanity, nor any single country (maybe with the exception of Japan, as far as I know), even such a purpose not intended. It's still pretty amazing! After all, people continue to die today, but no action is [taken]. How so? ... And yet ... There is no doubt the science over the past half century has leaped forward. Scientific and technological progress has radically changed many things in our lives. And the inspirational process is irreversible. You ask ... where the source of my optimism. He is in me and outside me. This is my inner conviction, supported by all the progressive tradition of Russian philosophical thought and [unstoppable] scientific thought."

Link: http://translate.google.com/translate?hl=en&sl=ru&tl=en&u=http%3A%2F%2Fm-batin.livejournal.com%2F144701.html

Researchers interested in finding genetic contributions to longevity generally start with some form of correlation study: trying to find commonalities between the genomes and epigenomes of long-lived individuals. So far, this has produced a great deal of data, much of which is unique to particular study populations - which suggests that there are many, many contributions to longevity buried in human genetic variations, and most are not all that important when considered in isolation. The odds of finding anything resembling a master switch for additional life span look remote at this point.

So the situation is complex, quite aside from the fact that it would still be a troublesome field of research even if the hunt was for one or more master switches. Researchers face an uphill struggle, as noted in a recent open access commentary, and thus have to be more inventive in their research:

It is a stroke of irony that lifespan - the principal phenotype used to search for aging genes - is a terrible phenotype for genetic analysis. Lifespan has relatively low heritability under most conditions, and it is affected by chronic, age-related diseases that confound its use as a biomarker of aging.

If the majority of aging genes are pleiotropic, as proposed by the evolutionary theory of aging, an opportunity is provided to identify these genes through the "back door," using phenotypes that are more amenable to genetic analysis.

To choose the pleiotropic phenotype for our studies, we went back more than 50 years to Williams, who, in his seminal paper, specified four "physiological expectations that follow from the theory," two of which we applied: "Rapid individual development should be correlated with rapid senescence," and, to specify a particular developmental phenotype, "The time of reproductive maturation should mark the onset of senescence." Therefore, to search for genes that regulate lifespan, we looked in the other direction - for genes that govern reproductive maturation.

The researchers then outline some of their investigations; when it produces candidate genetic variants, those variants still have to be confirmed in the same old standard, slow, and laborious way - animal studies of life span. In general the work of building a catalog of aging-related gene variants is slow going, and in the end will have far less practical application than other approaches to longevity science. This isn't to say that it shouldn't be done; all life science knowledge has value. But if the goal is to do something about the terrible cost of human aging, and do it as soon as possible, then approaches other than genetic investigation must have priority in the field.

Via EurekAlert!: "For the first time, we are showing evidence that vascular diseases are actually a kind of stem cell disease. ... It is generally accepted that the buildup of artery-blocking plaque stems from the body's immune response to vessel damage caused by low-density lipoproteins ... Such damage attracts legions of white blood cells and can spur the formation of fibrous scar tissue ... The scar tissue, known as neointima, has certain characteristics of smooth muscle, the dominant type of tissue in the blood vessel wall. Because mature smooth muscle cells no longer multiply and grow, it was theorized that in the course of the inflammatory response, they revert, or de-differentiate, into an earlier state where they can proliferate ... However, no experiments published have directly demonstrated this de-differentiation process ... researchers turned to transgenic mice with a gene that caused their mature smooth muscle cells to glow green under a microscope. In analyzing the cells from cross sections of the blood vessels, they found that more than 90 percent of the cells in the blood vessels were mature smooth muscle cells. They then isolated and cultured the cells taken from the middle layer of the mouse blood vessels. ... Notably, none of the new, proliferating cells glowed green, which meant that their lineage could not be traced back to the mature smooth muscle cells originally isolated from the blood vessels. ... We did further tests and detected proteins and transcriptional factors that are only found in stem cells. No one knew that these cells existed in the blood vessel walls because no one looked for them before. ... In the later stages of vascular disease, the soft vessels become hardened and more brittle. Previously, there was controversy about how soft tissue would become hard. The ability of stem cells to form bone or cartilage could explain this calcification of the blood vessels. ... Other tests in the study showed that the multipotent stem cells were dormant under normal physiological conditions. When the blood vessel walls were damaged, the stem cells rather than the mature smooth muscle cells became activated and started to multiply." Though if you want to consider root causes, look at mechanisms like accumulated damage to mitochondria that leads to a greater level of oxidized low-density lipoproteins in the blood.

Link: http://www.eurekalert.org/pub_releases/2012-06/uoc--trc053112.php

One of the costs of being sedentary is fiscal: the cost of medical services you would otherwise not have needed due to your increased risk of age-related disease. Here is another researcher running the numbers: "Physical inactivity is a recognized public health issue in Canada and globally ... A common approach for assessing the public health impact of physical inactivity is to measure the prevalence of the population not meeting physical activity guidelines. Recent surveillance data based on objective measures indicate that 85% of Canadian adults do not meet Canada's physical activity guidelines of 150 min/week of moderate-to-vigorous physical activity ... A second approach for assessing the public health impact of physical inactivity is to estimate the proportion of a disease within the population that is directly attributable to physical inactivity. For instance, 19% of the coronary artery disease cases in Canadian men are due to physical inactivity ... A third approach for assessing the public health impact of physical inactivity is to estimate the financial burden it places on the health care system and economy. The most recent Canadian estimates, based on 2001 data, suggest that the annual economic burden of physical inactivity is $5.3 billion. ... Similar to the 2001 estimates, the health care cost of physical inactivity in this report was estimated using a prevalence-based approach, which required 3 pieces of information: (1) the risks of chronic conditions in physically inactive individuals, (2) the direct and indirect costs of these chronic diseases, and (3) the prevalence of physical inactivity in the population. ... The estimated direct, indirect, and total health care costs of physical inactivity in Canada in 2009 were $2.4 billion, $4.3 billion, and $6.8 billion, respectively. These values represented 3.8%, 3.6%, and 3.7% of the overall health care costs." It is interesting to compare these numbers with research on individual lifetime medical cost differences that stem from being out of shape, and with some other number crunching on the economics of health and longevity.

Link: http://www.nrcresearchpress.com/doi/full/10.1139/h2012-061

You might recall research published a couple of months ago on calorie restriction and heart function. It illustrated (again) that people who practice calorie restriction over the long term have physiologically younger cardiovascular systems - meaning notably less low-level cellular damage and better function than their peers of a similar chronological age.

Heart rate variability (HRV) is a marker for cardiac autonomic functioning. The progressive decline in HRV with aging and the association of higher HRV with better health outcomes are well established. [Researchers] compared 24-hr HRV in 22 CR individuals aged 35 - 82 yrs and 20 age-matched controls eating Western diets (WD). The CR group was significantly leaner than the WD group. Heart rate was significantly lower, and virtually all HRV significantly higher in the CR than in the WD group. HRV in the CR individuals was comparable to published norms for healthy individuals 20 years younger.

If there was a drug that did that, its financials would be staggering - and you'd never hear the end of it. It would be publicized and popularized in every corner of the world. But just ask someone to exercise a little willpower and planning in their diet to gain the same results ... and therein lies a lesson with regard to human nature.

I notice that the institutional publicity machine at Washington University in St.Louis has caught up with this research; if you'd like a little more commentary from the researchers involved, that's the place to look:

"This is really striking because in studying changes in heart rate variability, we are looking at a measurement that tells us a lot about the way the autonomic nervous system affects the heart," says Luigi Fontana, MD, PhD, the study's senior author. "And that system is involved not only in heart function, but in digestion, breathing rate and many other involuntary actions. We would hypothesize that better heart rate variability may be a sign that all these other functions are working better, too."

...

"Higher heart rate variability means the heart can adjust to changing needs more readily," says lead author Phyllis K. Stein, PhD. "Heart rate variability declines with age as our cardiovascular systems become less flexible, and poor heart rate variability is associated with a higher risk of cardiovascular death."

...

"The idea was to learn, first of all, whether humans on CR, like the calorie-restricted animals that have been studied, have a similar adaptation in heart rate variability," Fontana says. "The answer is yes. We also looked at normal levels of heart rate variability among people at different ages, and we found that those who practice CR have hearts that look and function like they are years younger."

...

"In many of our studies, we have found that a number of metabolic and physiologic changes that occur in calorie-restricted animals also occur in people who practice CR," Fontana says. And he says the finding that heart rate variability is better in people who practice CR means more than just that their cardiovascular systems are flexible. He says the better ratio suggests improved health in general.

"But we can't be absolutely positive that the practice of CR is solely responsible for the flexibility of the cardiovascular system," Stein says. "People who practice CR tend to be very healthy in other areas of life, too, so I'm pretty sure they don't say to themselves, 'Okay, I'll restrict my calorie intake to lengthen my life, but I'm still going to smoke two packs a day.' These people are very motivated, and they tend to engage in a large number of very healthy behaviors."

The point on calorie restriction practitioners practicing good health across the board is a fair one - peeling apart the beneficial effects of regular exercise from the beneficial effects of calorie restriction in humans, for example, is an interesting challenge. Still, it would be hard, I think, to find a population of humans who are exceptionally health-conscious without practicing calorie restriction and who nonetheless exhibit a youthful physiology to the degree seen in calorie restricted people. There are different classes of mechanism at work here.

Here is a study that points to amount of visceral fat as a dominant contribution to the risk of age-related type-2 diabetes - a condition rarely suffered by people who successfully avoid putting on weight over the years - something that doesn't just happen, but requires exercise and a sensible approach to diet and lifestyle. "A collaborative re-analysis of data from the InterAct case-control study [has] established that waist circumference is associated with risk of type 2 diabetes, independently of body mass index (BMI). Reporting in this week's PLoS Medicine, the researchers estimated the association of BMI and waist circumference with type 2 diabetes from measurements of weight, height and waist circumference, finding that both BMI and waist circumference were independently associated with type 2 diabetes risk but waist circumference was a stronger risk factor in women than in men. ... The prospective InterAct case-cohort study was conducted in 26 centres in eight European countries and consists of 12,403 incident [type 2 diabetes] cases and a stratified subcohort of 16,154 individuals from a total cohort of 340,234 participants with 3.99 million person-years of follow-up. ... These findings indicate that targeted measurement of waist circumference in overweight individuals (who now account for a third of the US and UK adult population) could be an effective strategy for the prevention of diabetes because it would allow the identification of a high-risk subgroup of people who might benefit from individualised lifestyle advice. ... Our results clearly show the value that measurement of [waist circumference] may have in identifying which people among the large population of overweight individuals are at highest risk of diabetes." A risk that is essentially yours to create, remove, or manage through the choices you make.

Link: http://www.eurekalert.org/pub_releases/2012-06/plos-wcl053112.php

The SENS Foundation Academic Initiative continues to grow, laying the foundation for the next generation of researchers working on rejuvenation biotechnology: "The Academic Initiative is likely to see another increased budget in 2013. We plan to offer at least as many scholarships and grants as we're offering this year, while we are nearly certain to expand our summer internship program, bringing in more interns overall and sending them to a greater number of labs. This year, some interns have been placed at the SENS Foundation Research Center, while others have gone to the Buck Institute for Research on Aging. We hope to place more interns at each location next year, and to add new locations. The Initiative's budget may not be the only thing that changes with the coming of the new year. SENS Foundation itself is still planning a revamp of its website, and the Academic Initiative won't miss that chance to have its own website enhanced further. Planning for our own next website has begun: long story short, it'll be simpler with less text and will offer very clear and immediate ways for students to get started. Some graphic design work that will go online with that new site is also underway. We'd like to finish by pointing out that we still have enough funding to continue to award materials grants throughout the summer and into the Fall 2012 semester. Since many students have extra time to put a proposal together over the summer, and since we're currently seeing a (likely summer-related) increase in interest in our grants, this is a particularly good time to apply."

Link: http://sens.org/node/2762

Microglia are immune cells that defend and clean up the brain and spinal cord. Like the rest of the immune system, they progressively fail in their work with age. Worse, like other immune system components, they begin to become actively harmful by causing chronic inflammation and other forms of damage instead of helping. Reversing that trend is one important line of research among many that, as they produce working medical technologies, will extend our healthy life spans.

Keeping the brain in good working shape is one of the most important goals of medical research. There is no short cut here by way of the comparatively advanced fields of stem cell medicine and tissue engineering - we can't look ahead to replacement brains in the next decade or two as we can for other organs. The brain has to be repaired in situ, completely and sufficiently for the long term: every form of age-related cellular damage either worked around or reversed. So microglia, as an important part of the existing maintenance systems in the brain, are of considerable interest. Can early successes be obtained by boosting their activity, or slowing or reversing their decline with age? The Longecity-funded research project on microglia transplants falls into this general area of research - something we'd like to see more of.

Following on from that topic, here is an open access review paper that provides an introduction to microglia in context of aging and neurodegeneration:

For many years, chronic neurodegenerative disorders of the central nervous system (CNS) were thought of in terms of primary neuronal dysfunction and loss with secondary glial and inflammatory responses. ... but of late this theory has required revision.

Microglia, which account for approximately 10% of the adult brain cell population, were first described by Pio Del Rio Hortega in 1919 ... However, it was not until the late 1980s that this field came of age when, using the new technique of immunohistochemistry, the McGeers showed that within the Alzheimer's disease (AD) brain there were large numbers of [activated] microglia. ... The pioneering work of the McGeers was to radically change how these diseases were seen as they went on to show that microglia were not only intimately bound to central inflammatory responses and antigen presentation, but in fact the whole innate immune system itself had a role to play in these CNS disorders.

Initial views on the role of microglia suggested that these cells were simply there to scavenge up debris and dead cells, while astrocytes fulfilled some supportive role in the CNS. However, microglia are now recognized to have a complex array of supportive and destructive roles in the CNS and that the balance between the two may be critical in driving some aspects of disease processes. Astrocytes are now seen as being fundamental in shaping and maintaining the developing and mature CNS, including a role in adult neurogenesis, axonal regeneration, and the [blood-brain barrier]. The dynamic interplay between all of these different CNS compartments is becoming more evident, such that some neurodegenerative disorders of the CNS may have a pathology as much in the glial cells as in the neurons themselves. This all means that understanding what happens in disease states is far more complex than originally conceived and that targeting each element of the interaction may be the route by which true disease modification can be achieved.

Researchers dig deeper into the mechanisms of breast cancer risk: "Age-related physiological changes, including endocrine profiles and alterations of the microenvironments surrounding breast cells, have been associated with increased cancer risks, but the underlying cellular mechanisms behind these changes and their links to cancer have not been explained. ... Studying the aging process in any human tissue is a challenge primarily because of limited access to samples ... Human mammary epithelial cells (HMECs) are one of the few examples of an epithelial tissue that affords relatively good access because of mastectomies and cosmetic reduction surgeries. In both cases, surgical discards provide sample tissue for research [and researchers] were able to generate a large collection of normal HMEC strains derived from primary tissue in women aged 16 to 91 years. ... [The result was] a study in which it was determined that aging causes an increase in multipotent progenitors - a type of adult stem cell believed to be at the root of many breast cancers - and a decrease in the myoepithelial cells that line the breast's milk-producing luminal cells and are believed to serve as tumor suppressors. ... [Researchers] discovered that in finite-lifespan cultured and uncultured epithelial cells, the advancing years usher in a reduction of myoepithelial cells and an increase in luminal cells that express the proteins keratin 14 and integrin α6. In women under 30, these proteins are expressed almost exclusively in myoepithelial cells. ... The aging process therefore results in both a shift in the balance of luminal/myoepithelial lineages and to changes in the functional spectrum of multipotent progenitors that together appear to increase the potential for malignant transformation. We corroborated our culture data with parallel analyses of in vivo samples, but we still have dots to connect to demonstrate that these changes relate to an increased risk of malignancy. All the signs are there, though."

Link: http://newscenter.lbl.gov/news-releases/2012/06/04/aging-and-breast-cancer/

Via EurekAlert!: "When autologous (self-donated) lung-derived mensenchymal stem cells (LMSCs) were transplanted endoscopically into 13 adult female sheep modeled with emphysema, post-transplant evaluation showed evidence of tissue regeneration with increased blood perfusion and extra cellular matrix content. Researchers concluded that their approach could represent a practical alternative to conventional stem cell-based therapy for treating emphysema. ... previous transplantation studies, many of which used an intravenous delivery method, have shown that [bone marrow derived mensenchymal stem cells (BM-MSCs)] have been only marginally successful in treating lung diseases. Further, therapeutic responses in those studies have been limited to animal models of inflammatory lung diseases, such as asthma and acute lung injury. To try and answer the questions surrounding the utility of BM-MSCs for treating advanced emphysema, a disease characterized by tissue destruction and loss of lung structural integrity, for this study the researchers isolated highly proliferative, mensenchymal cells from adult lung parenchyma (functional tissue) (LMSCs) and used an endoscopic delivery system coupled with a scaffold comprised of natural extracellular matrix components. ... despite the use of autologous cells, only a fraction of the LMSCs delivered to the lungs alveolar compartment appeared to engraft. Cell death likely occurred because of the failure of LMSCs to home to and bind within their niche, perhaps because the niche was modified by inflammation or fibrosis. These cells are attachment-dependent and failure to attach results in cell death. Their findings did suggest, however, that LMSCs were capable of contributing to lung remodeling leading to documented functional improvement rather than scarring 28 days post transplantation."

Link: http://www.eurekalert.org/pub_releases/2012-06/ctco-cto060412.php

Buried in a recent post at Chronosphere, the blog of cryonics community luminary Mike Darwin, is this:

There are perhaps something on the order of 2,000 living cryonicists in the world, the majority of them in the English speaking/reading world. Of these, optimistically, perhaps 15% are technically/scientifically/philosophically oriented "activists" with an interest in the mechanics of cryonics, as opposed to people who have chosen cryonics as a service or product "as is," and are content to accept it without further improvement as a result of their own efforts.

As I understand Darwin's chief concerns with cryonics as a whole, they amount to (a) that he doesn't like the way business is undertaken at Alcor and the Cryonics Institute, and, more importantly, (b) he thinks that there is a real risk of cryonics failing as a human endeavor in the future due to its lack of growth and comparatively narrow base of community support.

Insofar as point (a) goes, I'm sure that everyone in the community has at some point offered a back-seat driver's vision for what should change at Alcor - easy enough when all you have to do is write about it or talk about it, and you're done. Sitting in the driver's seat is somewhat more challenging, I believe. For my money, I don't think that Darwin approaches point (a) in his writing in a way that's going to win friends and influence people - though he clearly feels strongly on the matter, which one might choose to believe stems from point (b). As noted in the past:

What I'll here call hyperactivism is a poisonous sort of dysfunction that you'll find in activist and advocate communities associated with struggling industries or long-standing initiatives that have failed to fulfill early visions of growth. It comes about because the early supporters in any new field tend to be passionate, driven, ornery, and focused: if they didn't have these characteristics, they wouldn't be up for the job of fighting over and again to persuade people to see things their way.

...

But when things don't go according to plan, and what was intended to be great fails to achieve its original promise, or moves too slowly, then the problems start. Some of the early activists, untempered by large numbers of new volunteers and supporters, become poisonous. Their hyperactivism manifests itself in perfectionism, attacks on members of the community, and other displays of frustration or bitterness: to their eyes, failure was avoidable, and the problem must be the other people involved.

My take on dissatisfaction with existing practices in cryonics is this: if you feel strongly enough and are motivated enough to be one of the few who actually gets things done, and write what amounts to a book on the topic, then the best response is to start your own organization and do things differently. Or start a complementary, more narrowly focused organization that can addresses specific issues of concern and can make itself useful in the ecosystem. If I were sufficiently fired up about the present state of cryonics, I'd probably try to do better on the service provision side of the house: a luxury line of services, better customer service, or running a better middle man service to ease organization of the methods of payment through life insurance. That sort of thing.

Clearly I'm not yet sufficiently fired up. Give it another decade and I'll be starting to weigh the balance of supporting cryonics versus supporting rejuvenation biotechnology a little more evenly. Time waits for no man.

But let us talk about point (b) instead, the existential threat of cryonics declining and ultimately evaporating as an endeavor. To my eyes there is a legitimate concern about the robustness of cryonics over the long term - by which I mean more than a few decades out from here. Nothing happens without putting in the work, and it's easy enough to point out any number of sports, hobbies, and semi-professional scientific study groups of the past two centuries that came, occupied a niche for some decades, and left. As Darwin points out in a number of posts on the history of cryonics over the past four decades, it was a mere handful of people who turned early cryonics from a noble failure to a more rigorous branch of speculative medicine that was set up to run for decades.

When it comes to robustness, you don't want to see things that succeed or fail based on a critical handful of people. You want to know that there are many parallel groups, all of whom will do just fine independently of one another, and who connect with one another to form a larger community. Nonetheless, based on the narrow history of cryonics we should expect the endeavor to last decades more simply by virtue of having lasted decades to date: there is a community, there are established centers and processes, there is a steady if slow pace of progress in improving the technology. Inertia works both ways. Certainly the present younger leadership will be going strong twenty years from now, and they were attracted to cryonics when it had a good deal less press and far more hostile press than is presently the case. I would be surprised if the next generation is any less capable.

The real concern is not the foreseeable twenty to forty years ahead, however. It arises when you consider that, by its very nature, in order to succeed cryonics has to have a good chance of continuing to provide solid and unbroken cold-storage service for a century or more. I think that we'd all feel much more comfortable if those estimated 2,000 supporters were an estimated 20,000 supporters or 200,000 supporters when looking at that sort of timescale. Over the long term, it is all about risk: what is the risk of catastrophic failure for a small group versus a large group versus many equal small groups? Robustness over time consists of a lower risk of extinction resulting from any given set of accidents and random occurrences.

What can you achieve with a community of two thousand people, most of whom are going to put in a good word or a few dollars here and there, but little more? For comparison, you might look at the SENS Foundation and Methuselah Foundation: their support base is probably quite similar in size. The funds raised there over the past eight years are largely a matter of record: something on the order of $12M to $14M by now. Neither of those ventures is going away any time soon.

But equally there is much improvement to be had; more people, more funds, and more publicity are all needed. Cryonics providers are still small concerns - far more vital than their size indicates, which is par for the course in anything to do with extending human life at the present time.

Researchers became interested in the Pink1 gene and its protein product because mutations in it are associated with a form of Parkinson's disease. Pink1 appears to be important in mitochondrial quality control: it is a part of the machinery that ensures damaged mitochondria can be effectively destroyed. Regular readers will know that an accumulation of damaged mitochondria is an important contribution to aging, so it should is perhaps not surprising that boosting levels of Pink1 extends life, here demonstrated in flies: "Overexpression of the gene coding for α-synuclein has been shown to be an inherited cause of Parkinson disease. Our laboratory has previously co-expressed the parkin and Pink1 genes to rescue α-synuclein-induced phenotypes within a Drosophila model. To further investigate the effect of Pink1 in this model, we performed longevity and behavioral studies using several drivers to express the α-synuclein and Pink1 genes. Our findings showed that overexpression of Pink1 and overexpression of Pink1 with α-synuclein resulted in an increased lifespan when driven with the TH-Gal4 transgene. This increase in longevity was accompanied by an increased healthspan, as measured by mobility over time, suggesting that this is an example of improved functional aging. Our results indicate that, in the dopaminergic cells targeted by TH-Gal4, increased expression of α-synuclein and Pink1 together have a synergistic effect, allowing for enhanced protection and increased survival of the organism."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22653599

Over at the IEET blog, a video interview: "Sonia Arrison is the author of "100 Plus: How the Coming Age of Longevity Will Change Everything, from Careers and Relationships to Family and Faith." In this video, Sonia discusses: how and why she got interested in technology in general and transhumanism and regenerative medicine in particular; how science and technology will allow us to live longer and healthier lives; the most common objections against increased longevity; the implications thereof on major religions; cryonics; her take on the technological singularity and our chances of surviving it; the fact that we cannot simply sit down and wait for longevity to happen." As noted, the future isn't a conveyor belt automatically bringing us better medicine and extended healthy life: every advance has to be advocated, funded, and built by someone. If too few people are working on longevity science, then rejuvenation biotechnology will not be developed in time.

Link: http://ieet.org/index.php/IEET/more/soniaarrison1on120120530

The second volume of the new open access journal Pathobiology of Aging and Age-related Disease is available online. I thought I'd point out one of the papers, which argues that the biology of long-lived mouse species should be considered evidence for the importance of chronic inflammation in determining life span.

Growth hormone, inflammation and aging

Mutant animals characterized by extended longevity provide valuable tools to study the mechanisms of aging. Growth hormone and insulin-like growth factor-1 (IGF-1) constitute one of the well-established pathways involved in the regulation of aging and lifespan. Ames and Snell dwarf mice characterized by GH deficiency as well as growth hormone receptor / growth hormone binding protein knockout (GHRKO) mice characterized by GH resistance live significantly longer than genetically normal animals.

During normal aging of rodents and humans there is increased insulin resistance, disruption of metabolic activities and decline of the function of the immune system. All of these age related processes promote inflammatory activity, causing long term tissue damage and systemic chronic inflammation. However, studies of long living mutants and calorie restricted animals show decreased pro-inflammatory activity with increased levels of anti-inflammatory adipokines such as adiponectin. At the same time, these animals have improved insulin signaling and carbohydrate homeostasis that relate to alterations in the secretory profile of adipose tissue including increased production and release of anti-inflammatory adipokines.

This suggests that reduced inflammation promoting healthy metabolism may represent one of the major mechanisms of extended longevity in long-lived mutant mice and likely also in the human.

Regular readers will recall that there is a mountain of evidence to link aging and chronic inflammation. If you have higher levels of inflammation, you will have a worse - and usually shorter - time ahead. It causes damage, and that damage adds up; the easiest way in younger life to raise inflammation levels is to become fat, as visceral fat tissue works a number on your metabolism. But everyone's immune system runs off the rails given time, falling into a state wherein it is constantly roused but increasingly ineffective in its designated jobs. Many of the aspects of aging are clearly connected to immune system decline: raised levels of inflammation, increased numbers of senescent cells, increased risk of cancer, and more.

This all argues for some form of safer, more mature version of the immune system reboot therapies that can presently be accomplished, but are not available outside of trials at this time. A large fraction of the immune system's failure with age stems from structural issues: it has evolved to be very, very good at its job in early life, but at the cost of inevitably and predictably failing as it runs out of capacity later on.

Throughout our lives, we have a very diverse population of T cells in our bodies. However, late in life this T cell population becomes less diverse ... [one type of cell] can grow to become more than 80 percent of the total [T-cell] population. The accumulation of this one type of cell takes away valuable space from other cells, resulting in an immune system that is less diverse and thus less capable in effectively locating and eliminating pathogens.

But if the slate could be wiped clean (achieved by chemotherapy at the present time, which is far from ideal) and the immune system repopulated (using stem cells to generate a population of patient-matching immune cells), then this issue vanishes, and people could benefit from a strong immune system for decades longer than is presently the case. That would likely make a significant difference to the course of later life, even in the absence of other advances in medical technology.

Researchers make paralyzed rats walk through a mix of chemical stimulation and structured physical therapy; only a little regrowth in the spine occurs, but the lower spinal column can take over some of the lost functionality under the right circumstances: "a severed section of the spinal cord can make a comeback when its own innate intelligence and regenerative capacity is awakened. ... After a couple of weeks of neurorehabilitation with a combination of a robotic harness and electrical-chemical stimulation, our rats are not only voluntarily initiating a walking gait, but they are soon sprinting, climbing up stairs and avoiding obstacles when stimulated. ... until now the spinal cord expressed so little plasticity after severe injury that recovery was impossible. ... under certain conditions, plasticity and recovery can take place in these severe cases - but only if the dormant spinal column is first woken up. To do this, [researchers] injected a chemical solution of monoamine agonists into the rats. These chemicals trigger cell responses by binding to specific dopamine, adrenaline, and serotonin receptors located on the spinal neurons. This cocktail replaces neurotransmitters released by brainstem pathways in healthy subjects and acts to excite neurons and ready them to coordinate lower body movement when the time is right. ... Five to 10 minutes after the injection, the scientists electrically stimulated the spinal cord with electrodes implanted in the outermost layer of the spinal canal, called the epidural space. ... a stimulated rat spinal column - physically isolated from the brain from the lesion down - developed in a surprising way: It started taking over the task of modulating leg movement, allowing previously paralyzed animals to walk over treadmills. These experiments revealed that the movement of the treadmill created sensory feedback that initiated walking - the innate intelligence of the spinal column took over, and walking essentially occurred without any input from the rat's actual brain. This surprised the researchers and led them to believe that only a very weak signal from the brain was needed for the animals to initiate movement of their own volition. ... newly formed fibers bypassed the original spinal lesion and allowed signals from the brain to reach the electrochemically-awakened spine. And the signal was sufficiently strong to initiate movement over ground."

Link: http://www.sciencedaily.com/releases/2012/05/120531145714.htm

There is death and then there is information theoretic death - a person who is cryopreserved is a good deal less dead than someone who went to the grave. The fine structure and data of the mind still exist, in a cold-stored stasis, and thus might be restored through foreseeable future technology. Here are some notes on the legal situation with respect to cryopreserved people: "This article series seeks to compare the legal protection of cryonics patients under their present legal status to the legal protection which would be afforded them if they were recognized as persons under the law, thinking ahead to such future time as it becomes reasonably possible to put legal and political pressure towards enhanced legal recognition of cryonics patients. The previous article examined laws that directly affect what happens to a person's body after legal death, both in the period immediately after declaration of legal death, and indefinitely thereafter. We saw that the amount of prospective autonomy a person is permitted in this regard can vary significantly from jurisdiction to jurisdiction, with more or less consideration afforded to the wishes of the person's next of kin, religious beliefs, societal norms and other public interests. Two other legal structures which can and are used by cryonicists to promote the success and timeliness of cryopreservation, maintenance, and resuscitation are wills and trusts."

Link: http://www.evidencebasedcryonics.org/2012/05/05/legal-protection-of-cryonics-patients-part-2/