I'll point out three recently published papers today, all of which are the fruits of the ongoing studies of long-lived people. There are a fair number of these efforts at the present time, a combination of decades-long longitudinal studies which now consist of a cohort of exceptionally old survivors, combined with new studies launched over the past decade as academic interest in the genetics of human longevity grew. As it turns out, long-lived human lineages differ from the rest of us in a number of identifiable ways - and given that it's really only been a handful of years that these sorts of study have been underway, I would imagine that many more characteristic genetic differences remain to be identified.

A genome-wide association study confirms APOE as the major gene influencing survival in long-lived individuals

We conducted a case-control genome-wide association study (GWAS) of human longevity, comparing 664,472 autosomal SNPs in 763 long-lived individuals (LLI; mean age: 99.7 years) and 1085 controls (mean age: 60.2 years) from Germany. ... Our GWAS failed to identify any additional autosomal susceptibility genes [beyond the APOE gene]. One explanation for this lack of success in our study would be that GWAS provide only limited statistical power ... A recent GWAS in Dutch LLI independently confirmed the APOE-longevity association, thus strengthening the conclusion that this locus is a very, if not the most, important genetic factor influencing longevity.

Mitochondrial Haplogroup X is associated with successful aging in the Amish

Mitochondrial lineages described by patterns of common genetic variants ("haplogroups") have been associated with increased longevity in different populations. We investigated the influence of mitochondrial haplogroups on [health in later life] in an Amish community sample. ... [Healthier old people] were more likely to carry Haplogroup X (OR = 7.56, p = 0.0015), and less likely to carry Haplogroup J (OR = 0.40, p = 0.0003). Our results [suggest] that variants in the mitochondrial genome may promote maintenance of both physical and cognitive function in older adults.

Relationship between plasma ghrelin, insulin, leptin, interleukin 6, adiponectin, testosterone and longevity in the Baltimore Longitudinal Study of Aging

Caloric restriction (CR) is the most robust and reproducible intervention for slowing aging, and maintaining health and vitality in animals. Previous studies found that CR is associated with changes in specific biomarkers in monkeys that were also associated with reduced risk of mortality in healthy men. In this study we examine the association between other potential biomarkers related to CR and extended lifespan in healthy humans. .... Based on the Baltimore Longitudinal Study of Aging, "long-lived" participants who survived to at least 90 years of age (n=41, cases) were compared with "short-lived" participants who died between 72-76 years of age (n=31, controls) in the nested case control study. Circulating levels of ghrelin, insulin, leptin, interleukin 6, adiponectin and testosterone were measured from samples collected between the ages 58 to 70 years. ... At the time of biomarkers evaluation (58-70 yrs), none of the single biomarker levels was significantly different between the two groups. However, after combining information from multiple biomarkers [the] global score differentiated the long- and short-lived participants.

While interesting, and probably the basis for what will eventually be a massive industry of drug development aimed at gently slowing down the aging process, this sort of work is still something of a sideshow. Understanding the contributions of metabolic differences to the pace of aging and resistance to frailty and degeneration will not lead to a true cure for aging. Repair and reversal of aging, the foreseeable biotechnologies that can make the old young once again, can only come from lines of research like those undertaken by the SENS Foundation.

RasGrf1 is the gene associated with longevity in engineered mice with two female parents, and a deficiency in the gene achieved through other means boosts life span as well. Here is more theorizing on what it all means: "Interestingly, RasGrf1 is one of parentally imprinted genes transcribed from paternally-derived chromosome. Erasure of its imprinting results in RasGrf1 downregulation and has been demonstrated in a population of pluripotent adult tissues-derived very small embryonic like stem cells (VSELs), stem cells involved in tissue organ rejuvenation. ... downregulation of RasGrf1 in VSELs [protects] from premature depletion from adult tissues. Thus, the studies in RasGrf1-/- mice indicate that some of the imprinted genes may play a role in ontogenetic longevity and suggest that there are sex differences in life span that originate at the genome level. All this in toto supports a concept that the sperm genome may have a detrimental effect on longevity in mammals." So in summary, one of the ways in which RasGrf1 extends life seems to involve improvement in the capacity of stem cells in the older organism, and a significant effect on longevity can emerge from the contributions of one parent through the epigenetic imprinting process.

Link: http://impactaging.com/papers/v3/n7/full/100354.html

From the Technology Review: "In a bid to harness the potential of embryonic stem cells, surgeons in California have implanted lab-grown retinal cells into the eyes of two patients going blind from macular degeneration. ... The two patients, whose names weren't released, are among the first volunteers ever to receive a treatment created using embryonic stem cells. ... We are excited about this treatment, because we think this has the potential to slow the disease progression. This company has had their ups and downs, and I am really happy to see they got into the clinic. We've had our fingers crossed. ... During a recent visit to Advanced Cell's laboratories, a research technician adjusted a microscope to show off the company's lead product: cube-shaped retinal pigment epithelial cells growing in a petri dish. Some were translucent, while others already had the brownish coloring of a mature cell. (The pigment absorbs stray light in the eye, acting as a kind of glare shield.) These retinal cells are the type that are killed off in macular degeneration, eventually leading to the death of photoreceptors, and the gradual loss of central vision. Advanced Cell believes that injecting new, lab-grown cells into the eye may cure the condition. ... It's no accident [that] both early studies of embryonic stem-cell therapies - those of Geron and Advanced Cell - involved cells of the nervous system. The reason is that embryonic stem cells naturally want to make neuroectoderm, a cell lineage in the embryo that forms the nervous system. ... Embryonic stem cells have a mind of their own, and they want to do certain things ... Efforts to produce other cell types, such as liver cells, have proved far more difficult."

Link: http://www.technologyreview.com/biomedicine/38030/

Open Cures is an initiative aimed at speeding up progress along the best and most logical path for commercial development of demonstrated longevity-enhancing biotechnologies. Which is to say that they should be developed overseas, outside the reach of the FDA, and then accessed via medical tourism - just like all the cutting edge medical technologies that are available only outside the US, thanks to massive regulatory overkill.

Open Cures kicked off in earnest in May 2011, so this is still very much the stage of telling people about the idea and letting the community of potential supporters know that the initiative even exists. One part of that effort is a series of essays, the latest of which was published at h+ Magazine today under the title "Longevity Science Needs Documentation". Open Cures is a phased initiative, and the article is a deeper look at why Phase 1 of Open Cures involves the production of documentation - pulling out the best and most promising of present biotechnologies of longevity buried in research papers, and producing textbook quality how-to documents that are comprehensible to people who are not cutting edge researchers:

One of the challenging attitudes I've encountered of late is the idea that documentation of longevity science in this manner is largely worthless - that time and funds spent trying to make science clear to developers and laypeople should go towards other, more direct activities like further research. This sort of criticism is, I think, symptomatic of a failure to understand the necessary role of documentation in the broader scope of technological progress. This article, then, is an answer of sorts: what is the role of documentation, and why is it important enough to need dedicated organizations that do it well?

Read the whole thing, as the answer to that question isn't easily summarized in a single sentence - and that in and of itself is actually a part of the challenge. Complex ideas are hard to convey, and that fact places constraints on support for new technologies.

On the topic of producing documentation, you can see some of the early work in the Open Cures Wiki, such as a protocol outline for DIYbio participation in LysoSENS, and a similar protocol outline for mitochondrial protofection. For reference, a protocol is the name given to the step by step directions followed by a researcher or technician when carrying out a procedure in the laboratory. Both of these sketch outlines provide only the technical bare bones of their respective protocols, but are presently being expanded into full protocol documents, with the aim of producing textbook-quality publications.

Over the past few weeks, I've been working through oDesk to contract with biologists and biochemists around the world to work on these and other documents. It's an interesting business, and the global competition largely keeps the rates at an appropriate level for a volunteer initiative, even for writing that is fairly technical. My goal for the next few months is to acquire a reliable stable of writers this way, though this and similar services, and produce the first few high-quality protocols documents in full.

This involves a fair degree of learning and working through the pitfalls - but it should settle the questions of price and feasibility. So far it looks like there are a sufficient number of life scientists out there on these global contracting sites, some of whom can write decently well in addition to knowing their field. Also so far it looks like my initial guesses at the cost of producing documentation is not a million miles away from the reality - we'll see if that still holds once I'm into the next stage of finding artists to produce the necessary diagrams where openly available versions cannot be found.

In working with biologists scattered around the world, I've been greatly aided by those Open Cures volunteers willing to review and comment on works in progress. Many hands make light work, and while I've followed biotechnology for a number of years, I'm far from qualified to judge the contents of a protocol as accurate or not. I should also note that along the way, some other folk are also looking into producing informational documents on the state of medical tourism by country, and an early example of that sort of thing can also be found in the wiki.

Once this first stage of the first stage of the way and the Open Cures group has a set of completed protocols and writers ready to go, then it will be time to open things up to run a little faster: make the big list of documentation we'd like to have done in Phase 1, and push it into the sausage-making process of technical writing just as fast as it will go. That's about when I'll probably start soliciting funds and doing the rounds with cap in hand, but we'll see how that turns out.

The ability to use funding in and of itself requires some organization to set up: there's the legal side of the house, management and paperwork, and getting into the process to become a formally registered 501c3 charity. Fortunately some of the folk in the community are willing to help out on that front - it's "just" a matter of more time and energy put in that direction. Postponing it while the first stage of documentation is underway doesn't hurt, and in many ways it's better to put off the legal formalization of an initiative until you're sure that there's something there and that it's working the way you want it to.

So that's where things stand at the moment. Very early days yet, and lot yet to be accomplished.

At the Wall Street Journal: "At his lab in the Bronx, geneticist Nir Barzilai has spent more than a decade trying to unlock the biology of aging. His secret weapon: some of the New York area's oldest Jews. One of his major studies analyzes the genetic make-up and life habits of the oldest of the old: 500 physically and cognitively healthy individuals living well past the century mark. ... Research that began with some of the oldest New Yorkers is now set to spread throughout the U.S. Barzilai's work is the template for a ambitious national study to create a full sequencing of the genomes of 100 ethnically and geographically diverse centenarians. ... Barzilai's work seeks to improve the quality of life for the elderly. His research has found, to his surprise, that the 100-plus crowd has less than sterling health habits. As a group, they were more obese, more sedentary and exercised less than other, younger cohorts. ... Biologically speaking, what has allowed the centenarians in his study to live so long, even with life habits that often lead to disease and death in others? ... Barzilai and his team at Einstein's Institute for Aging Research have so far discovered three uncommon genotype similarities among the centenarians: one gene that causes HDL, good cholesterol, to be at levels two- to three-fold higher than average; another gene that results in a mildly underactive thyroid, which slows metabolism; and a functional mutation in the human growth hormone axis that may be a safeguard from age-related diseases, like cancer. He suspects there may be additional genotypes that scientists have yet to locate."

Link: http://blogs.wsj.com/metropolis/2011/07/13/in-the-science-of-aging-oldest-new-yorkers-hold-the-key/

Organovo is the bioprinting startup whose investors include the Methuselah Foundation: "Organovo has been generating enough revenue from a series of new partnerships that [the company] put off an expected Series A venture round. ... the company has raised just over $2 million from private investors to develop 'bio-printing' technology that operates much like an inkjet printer. Instead of laying down ink, however, Organovo's bio-printer lays down a pattern of cultured cells and a jello-like hydrogel that supports the cells in a 3-D structure. In this way, Organovo already has been able to grow bio-engineered blood vessels, and to lay more ambitious plans to create kidneys, livers, and other vital organs in the same way. ... the work is still highly experimental, so getting regulatory approval to graft a bio-engineered blood vessel in a living patient will take years. In the meantime, [Organovo] found a burgeoning market among pharmaceutical companies by [creating] 3-dimensional 'constructs' of diseased or dysfunctional human cells that can be used as models for testing new drugs. Creating a 3-D matrix of cells enables each cell to interact with adjoining cells, so they react to drug compounds much as they would in the body. ... one of the pharmaceutical partnerships is with Pfizer to create 3-D constructs for drug discovery in two therapeutic areas. Organovo also is in talks with several additional partners ... One of the things that's been good about the past six months is that the promise of our technology is holding true. The constructs we're creating robustly build [blood vessels] with collagen, so the blood vessel grows stronger over time. The next challenge is getting to greater and greater vascularization of the construct. The emerging story is going to be, 'Who can make thicker tissues with more blood vessels inside?'"

Link: http://www.xconomy.com/san-diego/2011/07/13/organovos-bio-printing-technology-yields-unanticipated-revenue-from-pharma-partners/?single_page=true

If you spend time following life science research, you'll see a fair amount of work in which scientists remove a piece of biological machinery in laboratory animals so as to try to figure out what it does - the changes that occur in the studied animals will hopefully allow researchers to piece together the surrounding biology and place the machinery in the full context of what is already known. In many cases this reduces life span or accelerates the pace of some form of damage that normally increases with aging - but that outcome doesn't necessarily mean that the machinery removed is connected to aging in any significant way, or that it has any relevance to ways to slow aging and extend healthy life.

I'm sure, if you put your mind to it, you could think of a dozen ways to slowly ruin the type of machine you are most familiar with (clog up the spark plugs, remove the oil, pull out the filter head, and so forth), and few of them can be extrapolated the other way into ways to make a perfectly maintained machine last much longer than it normally does.

So it is with the biochemical machinery of life. The only true test of relevance to aging is to demonstrate that you can use the mechanism in question to extend life beyond the normal limits for a healthy individual in that species, or reduce some form of biological damage to levels far below what is normally the case at a given age. If all you are showing is that you can increase damage and shorten life span, then there's no doubt interesting science involved, but it's too soon to be getting excited.

This is why I think that the title and summary of a recent news item is absolutely wrong:

Researchers from the Universities of Bonn and Mainz have discovered a previously unknown function of the cannabinoid-1 receptor (CB1): it can protect against aging processes. Cannabinoids, such as THC (the active agent in Cannabis sativa) and endocannabinoids, and those formed by the body bind to the CB1 receptors. ... The animals in which the CB1 receptor had been switched off genetically [showed] clearly diminished learning and were less successful in their search for the platform. In addition, they showed a clear loss of nerve cells in the hippocampus, the researchers said.

The original paper, which is a matter of increasing damage only, has nothing but inference on how this applies to aging while CB1 is active and normally operational, and it's speculative to say that anything could come from this to move the needle in the opposite direction.

The reason I noticed this work at all is because it's possible that endocannabinoids are involved in calorie restriction in some way, based on work in nematode worms:

Not only have we been able to identify some of these molecules for the first time in the worm, but we have also been able to show they act as a signal of nutrient availability and ultimately influence the worm's lifespan. What makes this important is that the same molecules are present in both humans and C. elegans, so these molecules may play similar roles in both organisms. ... The molecules identified in the new study are N-acylethanolamines (NAEs), a group of signaling molecules derived from lipids that help indicate nutrient availability in the environment and maintain an animal's internal energy balance. [Researchers showed that] NAE abundance in the worm is reduced during periods of dietary restriction, and that NAE deficiency in the presence of abundant food is sufficient to extend the animal's lifespan. ... Importantly, this particular NAE is similar to endocannabinoids in mammals, which regulate many different physiological processes including nutrient intake and energy balance, as well as inflammation and neuronal function.

The CB1 paper above adds nothing much in the way of weight to that conjecture, however, and so I'd say it remains a fairly tenuous connection at this time. You'd need a study that shows extended life in mice through something very similar to NAE deficiency in worms, but engineered using endocannabinoids. So further research is required - and there are a great many more important things that researchers could be doing with their time.

An introductory open access review paper looks briefly at some of the theories of aging: "Ageing and senescence are related words and are often used interchangeably as both processes are characterized by progressive changes in the tissue of the body, eventually leading to a decline in function and death of the organism. Senescence refers to a post-maturational process that leads to diminished homeostasis and increased vulnerability of the organism to death. Ageing, in contrast, refers to any time-related process and is a continuous process that starts at conception and continues until death. The mechanisms involved in ageing are partially intrinsic to the organism, like genetic and epigenetic factors, and partially to the external origin, such as nutrition, radiation, temperature and stress. ... Various theories have evolved to improve our understanding of the ageing process so as to formulate strategies that enhance extension of life. The theories of ageing are classified based on the level at which the ageing mechanism is targeted: 1. Evolutionary theories, 2. Systemic theories, 3. Molecular and cellular theories ... Evolutionary theories state that ageing results from a decline in the force of natural selection. As evolution acts primarily to maximize reproductive fitness in an individual, longevity is a trait to be selected only if it is beneficial for fitness. Life span is, therefore, the result of selective pressures and may have a large degree of plasticity within an individual species as well as among species. ... In systemic theories, the ageing process is related to the decline of organ systems essential for control and maintenance of other systems within the organism. ... [Molecular and cellular theories] theories attempt to discern the mechanisms of ageing process at the cellular and subcellular levels."

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3125059/

Another good reason for researchers to better understand the biochemical roots of regeneration in lower animals such as newts and salamanders: "Goro Eguchi has shown that a newt's healing powers don't diminish with age. As long as they live, they retain the ability to efficiently regrow their body parts (or at least, the lenses of their eyes), even if they have to do so over and over again. We've known about the abilities of newts and other salamanders for over 200 years, thanks initially to Lazzarro Spallanzini, an Italian biologist and Catholic priest. But the limits of this ability have been unclear. Spallanzani once amputated limbs from a salamander six times over three months, and watched them grow back. ... The salamanders could repeatedly regrow their limbs, but eventually, abnormalities crept in. For example, the animals would occasionally develop missing bone structures. Both Spallanzani and Bonnet (and, indeed, Charles Darwin after them) held that newts regenerate their body parts less efficiently as they get older, especially if they accrue repeated injuries. But Eguchi thinks that these experiments, while historically important, were also flawed. The exposed stumps of the severed legs would have been exposed to the messy environment, which might have scuppered a clean regeneration. To truly test the extent of these animals' powers, Eguchi set up a 16-year-long experiment. In 1994, he collected several Japanese fire-bellied newts (Cynops pyrrhogaster) and successfully kept them in captivity. During that time, Eguchi periodically anaesthetised the animals and carefully removed the lens from their eyes. The surgeries involve a small nick to the cornea that quickly sealed, creating a protected environment where the lens could regenerate without any influence from the outside world. This happened 18 times in total. Eguchi found that the 17th and 18th lenses were exactly the same as the original ones, and those from untouched newts of the same age."

Link: http://blogs.discovermagazine.com/notrocketscience/2011/07/12/newt-healing-factors-unaffected-by-age-and-injury/

Dental tissue engineering is one of the most advanced areas in the broader field, as illustrated by work on growing teeth from stem cells. Several groups over the past five years have successfully implanted stem cells that led to the growth of replacement teeth in mice, and other forms of procedure such as the reattachment of teeth via engineered ligaments have also been demonstrated in laboratory animals.

In a more recent project, researchers grew mouse teeth outside the body, implanted them, and produced a very satisfactory end result as the teeth grew in and became functional:

In this proof of concept study [a] bioengineered tooth unit comprising mature tooth, periodontal ligament and alveolar bone, was successfully transplanted into a properly-sized bony hole in the alveolar bone ... Partial bone integration was observed at 14 days after transplantation, and full bone integration around a bioengineered tooth root was seen at 30 days after transplantation ... [The] engrafted bioengineered tooth displayed physiological tooth functions such as mastication, periodontal ligament function for bone remodeling and responsiveness to noxious stimulations.

...

These findings indicate that whole tooth regenerative therapy is feasible through the transplantation of a bioengineered mature tooth unit. This study also provides the first reported evidence of entire organ regeneration through the transplantation of a bioengineered tooth.

The age of bad teeth, old teeth, and artificial teeth will soon enough be coming to a close, I think. For my money, the most interesting parts of the paper relate to the challenges inherent in coaxing suitable dental stem cells into growing into teeth that have the right shape. The methodology that the researchers found worked was as follows:

To generate the shape- and length-controlled bioengineered tooth unit so that a suitable size was obtained, [the] tooth germ was inserted into a ring-shaped size-control device and then transplanted into a subrenal capsule.

Width was controlled by placing a barrier around the growing material, and the length controlled by how long the tooth was grown for - though the researchers also touched on other potential means of fine-tuning tooth shape and size. I look forward to seeing how well this methodology works when they move on to human teeth.