LongeCity has been around for a while, and is home to an energetic community interested in health and longevity. There is as much talk of supplements, frivolous stuff to my eyes, as there is of serious longevity science aimed at rejuvenation, such as the Strategies for Engineered Negligible Senescence, but over the years the folk there seem to have made that work in a sustainable way. The LongeCity crowd are more biased towards supporting rejuvenation research than any other health-focused community you're likely to find out there.

One of the other distinctions of LongeCity is that they have spent some years raising funds from the community for small research projects. They have been doing that for some time longer than the current crop of science crowdfunding startups have existed, for example. Making this work is a hard nut to crack, both from the point of view of practical administration and from convincing people to donate, but plenty of $20-40,000 sized projects exist in longevity-related life science research that are both useful and feasible to undertake. So the LongeCity administrators have established an ongoing grant scheme under which they solicit applications, raise funds, and monitor the progress of projects such as evaluating the effects of transplanting young microglia cells into old mice to see if such a procedure can slow or reverse neurodegeneration.

This ongoing set of initiatives and the efforts of crowdfunding startups like Microryza are just the opening notes in the near future symphony of community science funding. There will be a great deal more open fundraising and many more people helped to advance their own favored causes by careful funding of specific small research projects. Like medical tourism, this is still at the stage of shaking out an industry with standards, best practices, and approaches that work. Growth is yet to come: the foundation work is still underway.

On this topic I noticed a recent post that looks over the LongeCity crowdfunding activities and projects of past years:

Help Conquer Death with Grants & Research Funding from LongeCity!

LongeCity has been doing advocacy and research for indefinite life extension since 2002. With the Methuselah Foundation and the M-Prize's rise in prominence and public popularity over the past few years, it is sometimes easy to forget the smaller-scale research initiatives implemented by other organizations. Anyone can have a great idea, and there are many low-hanging fruits that can provide immense value and reward to the field of life extension without necessitating large-scale research initiatives, expensive and highly-trained staff or costly laboratory equipment.

In the past LongeCity has raised funding by matching donations made by the community to fund a research project that used lasers to ablate (i.e. remove) cellular lipofuscin. LongeCity raised $8,000 dollars by the community which was then matched by up to $16,000 by SENS Founation. LongeCity's second successfully funded research initiative was mitochondrial uncoupling. LongeCity's 3rd success was their project on Microglia Stem Cells in 2010. This project studied the benefits of transplanting microglia in the aging nervous system. LongeCity's fourth research-funding success was on Cryonics in 2012, specifically uncovering the mechanisms of cryoprotectant toxicity.

These are real projects with real benefits that LongeCity is funding. Even if you're not a research scientist, you can have an impact [by helping to fund a] small-scale research grant from LongeCity.

Something like a third of medical research funding comes from government sources. It is the most transparent and easily quantified source, so it is the one most often discussed. The incentives put upon researchers competing for these funds steer them towards largely mundane, low-risk, low-reward work, and greatly favor large institutions over smaller research groups. This is a proven way to edge out the sort of research that tends to occasionally produce meaningful or even spectacular results, in favor of research that is essentially make-work or pointless in comparison to what could be done. It's why you shouldn't expect much from massive public spending on research: the yield of meaningful work is very low.

The private funding world is mostly for-profit research, and that has its own issues that are driven by the enormous imposed costs of regulation and short time horizons. So as a general rule near all of the really interesting and potentially game-changing research programs in aging and the broader life sciences were started by and are still largely funded by philanthropists. Consider the SENS Research Foundation, for example, or the Glenn Laboratories, or the points made by Peter Thiel's radical philanthropy initiative: too much funding is biased towards the incremental and the meaningless, while ignoring the tremendous possibilities of the near future. So progress is far slower than it might be.

Here are a few comments on the public funding environment from a discussion on the Gerontology Research Group list:

One of the main reasons for a lack of serious anti-aging basic science [is] the current and recent funding climate of academia. As a scientist currently in the middle of the funding rat race, I can tell you why not a lot of scientists want to work on aging. The NIH/NIA/NCI want preliminary data. They want it on every single grant application. If you don't have it, they won't fund it, and this is a relatively new phenomenon (and the definition of "preliminary data" has become significantly more burdensome). Effectively, in order to get new work funded, it has to be partially (or in some cases nearly entirely) complete, meaning that you have to have some other funding source and a functional laboratory *before you get the grant*.

This shifts risk from the funding agency to the investigator, such that if you are using your current funding, left over from some already completed grant or tangentially related to a grant in progress on a new project, you want to be sure that the new project will work, because if it doesn't, you're out of funding and have exhausted the most precious resource you have in securing new funding - your old funding! You won't do things that are hard or risky unless you're a very rich lab (which tend to be entrenched in certain fields that aren't hard or risky, because that's how they got to be a rich lab), because hard and risky things can fail, and then your career is over. Aging research is hard and risky.

There's too much focus on low hanging fruits because of the pressure to publish and get grants. My lab is no exception on this, but the fact is that all my high-risk, high-reward grant applications have been rejected (my more conservative grants also often get rejected, but at least sometimes they are funded). Some years ago I asked a well-known biogerontologist why his lab was doing a certain series of experiments that, while getting results and papers, seemed to beat around the bush of understanding aging. His answer was: "Because I've got a mortgage to pay."

Link: http://postbiota.org/pipermail/tt/2013-June/013563.html

Ten years from now blood donation might be a thing of the past in wealthier regions of the world:

Researchers based at the Scottish Centre for Regenerative Medicine (SCRM) in Edinburgh hope to use stem cells to manufacture blood on an industrial scale to help end shortages and prevent infections being passed on in donations. The UK's Medicines and Healthcare products Regulatory Agency (MHRA) has now granted a licence so scientists can make blood from stem cells which can be tested in humans - the first step towards large-scale clinical trials, which will hopefully lead to the routine use of blood created in this way.

As well as the blood research, the licences will also allow scientists in the coming years to create stem-cell products to treat patients who have suffered a stroke and people with Parkinson's disease, diabetes and cancer. But much of the attention has focused on how stem cells could be harnessed to create blood products - seen by many as the "holy grail" of blood research.

A key difference in their work going forward would be the use of stem cells derived from adult tissue - known as induced pluripotent stem cells. "In the first part of the project we used human embryonic stem cell lines and one of the problems with using those lines is you can't choose what the blood group is going to be. Over the last few years there has been a lot of work on induced pluripotent stem cells and with those an adult can donate a small piece of skin or a blood sample and the technology allows for stem-cell lines to be derived from that sample. This makes our life a lot easier in some ways because that means we can identify a person with the specific blood type we want and get them to donate a sample from which we could manufacture the cell lines."

Link: http://www.scotsman.com/the-scotsman/health/scots-scientists-to-trial-synthetic-human-blood-1-2948081

Calorie restriction is definitely good for you, provided that you maintain an optimal intake of micronutrients in your smaller diet. There is a tremendous weight of evidence for the benefits of calorie restriction in animals and a large weight of evidence for benefits in humans: it improves near all short term measures of health, slows down the progression of near every measure of degenerative aging, and extends healthy life in most species. Research publications are usually more understated in their evaluation of calorie restriction, of course. See this, for example:

Caloric Restriction: Implications for Human Cadiometabolic Health

Evidence from animal studies and a limited number of human trials indicates that calorie restriction has the potential to both delay cardiac aging and help prevent atherosclerotic cardiovascular disease via beneficial effects on blood pressure, lipids, inflammatory processes, and potentially other mechanisms.

The candidate list of mechanisms by which calorie restriction likely delivers its benefits include reduced visceral fat, increased levels of autophagy, altered mitochondrial function, and metabolic changes caused by reduced levels of methionine in the body. All of these on their own have been shown to extend life and improve measures of health in animal studies. Many other measurable changes result from calorie restriction, but identifying which of them are definitively primary and which are definitively secondary is still a work in progress.

Methionine is one of the essential amino acids that your metabolism doesn't manufacture. You have to obtain it in the diet, and it's an essential component for the cellular manufacture of new protein machinery. There are all sorts of studies in mice and rats showing that if you keep the same dietary calorie level but strip out much of the methionine then the animals involved live longer, and exhibit many of the same changes in metabolism as occur from reduced calorie levels. Here is a recent example:

Methionine restriction affects oxidative stress and glutathione-related redox pathways in the rat

Lifelong dietary methionine restriction (MR) is associated with increased longevity and decreased incidence of age-related disorders and diseases in rats and mice. A reduction in the levels of oxidative stress may be a contributing mechanistic factor for the beneficial effects of MR. To examine this, we determined the effects of an 80% dietary restriction of Met on different biomarkers of oxidative stress and antioxidant pathways in blood, liver, kidney and brain in the rat.

Male F-344 rats were fed control (0.86% methionine) or MR (0.17% methionine) diets for up to six months. Blood and tissues were analyzed for [levels of the natural antioxidant] glutathione (GSH). related enzyme activities and biomarkers of oxidative stress. MR was associated with reductions in oxidative stress biomarkers [and] erythrocyte protein-bound glutathione after one month with levels remaining low for at least six months.

Levels of free GSH in blood were increased after 1-6 months of MR feeding whereas liver GSH levels were reduced over this time. In MR rats, GSH peroxidase activity was decreased in liver and increased in kidney compared with controls. No changes in the activities of GSH reductase in liver and kidney and superoxide dismutase in liver were observed as a result of MR feeding. Altogether, these findings indicate that oxidative stress is reduced by MR feeding in rats, but this effect cannot be explained by changes in the activity of antioxidant enzymes.

You might compare the comments above with the two calorie restriction research papers I pointed out earlier today - you'll quickly see the similarities, such as the fact that the behavior of antioxidants and oxidants in metabolism is complex and hard to tie to the observed benefits in health and longevity. All in all it is convincing to argue that methionine sensing is at the heart of the metabolic changes that produce the benefits of calorie restriction:

• Calorie Restriction Versus Resveratrol Treatment
• Reviewing the Literature on Calorie Restriction and Oxidative Stress

From the practical standpoint of day to day effort and willpower, I'd say that that there isn't much difference between eating a calorie restricted diet and a methionine restricted diet. The latter is harder by far to organize, I think. You certainly couldn't do it without a lot of research, extra food preparation, and meal planning, and there are few resources out there to help you short-cut the process. Calorie restriction, on the other hand, just requires you to keep count and be sensible, plus of course to have a willingness to be hungry for some time every day. It's that latter item that most people find a challenge, in this age of ubiquitous, cheap, tasty food. Calorie restriction also has a far greater weight of supporting evidence for benefits to health in humans, which is probably the most important factor of those mentioned here, but every choice you make has trade-offs.

Researchers here compare the effects of calorie restriction and dietary resveratrol on the pace of sarcopenia, the age-related loss of muscle mass and strength. What I take away from this is that calorie restriction produces meaningful results on this front, albeit modest in comparison to what we'd like to see, and resveratrol doesn't.

Aging is associated with a loss in muscle known as sarcopenia that is partially attributed to apoptosis. In aging rodents, caloric restriction (CR) increases health and longevity by improving mitochondrial function and the polyphenol resveratrol (RSV) has been reported to have similar benefits. In the present study, we investigated the potential efficacy of using short-term (6 weeks) CR (20%), RSV (50 mg/kg/day), or combined CR+RSV (20% CR and 50 mg/kg/day RSV), initiated at late-life (27 months) to protect muscle against sarcopenia by altering mitochondrial function, biogenesis, content, and apoptotic signaling in both glycolytic white and oxidative red gastrocnemius muscle (WG and RG, respectively) of male Fischer 344 x Brown Norway rats.

CR but not RSV attenuated the age-associated loss of muscle mass in both mixed gastrocnemius and soleus muscle, while combined treatment (CR+RSV) paradigms showed a protective effect in the soleus and plantaris muscle. Sirt1 protein content was increased by 2.6-fold in WG but not RG muscle with RSV treatment, while CR or CR+RSV had no effect. PGC-1α levels were higher (2-fold) in the WG from CR-treated animals when compared to ad-libitum (AL) animals but no differences were observed in the RG with any treatment.

These data suggest that short-term moderate CR, RSV, or CR+RSV tended to modestly alter key mitochondrial regulatory and apoptotic signaling pathways in glycolytic muscle and this might contribute to the moderate protective effects against aging-induced muscle loss observed in this study.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23747682

Oxidative theories of aging place the blame for the damage of aging on reactive oxidizing molecules, generated most notably in the mitochondria of your cells, and which tend to break the protein machinery they react with. Oxidative stress is the term given to ongoing damage (and efforts to repair it) caused by the presence of oxidative molecules in and around cells. Levels of oxidative stress can alter as a result of heat, exposure to ionizing radiation, the details of diet, and all sorts of other environmental influences.

The relationship between oxidative stress and the pace of aging is far from straightforward, however. There is more oxidative stress with age, but this is an expected result of carrying a high level of cellular and molecular damage. Some very long-lived species, such as naked mole rats, show very high levels of oxidative stress but don't appear to be particularly harmed by it. Mild oxidative stress can be beneficial, triggering increased cellular maintenance for a time to produce a net benefit. Oxidative compounds are also widely used in our biochemistry for necessary signaling purposes.

You can see the nature of this complex relationship between oxidative stress and aging by looking at what happens in interventions that reliably slow aging and extend life, such as calorie restriction in rodents:

Oxidative stress is observed during aging and in numerous age-related diseases. Dietary restriction (DR) is a regimen that protects against disease and extends lifespan in multiple species. However, it is unknown how DR mediates its protective effects. One prominent and consistent effect of DR in a number of systems is the ability to reduce oxidative stress and damage. The purpose of this review is to comprehensively examine the hypothesis that dietary restriction reduces oxidative stress in rodents by decreasing reactive oxygen species (ROS) production and increasing antioxidant enzyme activity, leading to an overall reduction of oxidative damage to macromolecules.

The literature reveals that the effects of DR on oxidative stress are complex and likely influenced by a variety of factors, including sex, species, tissue examined, types of ROS and antioxidant enzymes examined, and duration of DR. [In] a majority of studies, dietary restriction had little effect on mitochondrial ROS production or antioxidant activity. On the other hand, DR decreased oxidative damage in the majority of cases. Although the effects of DR on endogenous antioxidants are mixed, we find that glutathione levels are the most likely antioxidant to be increased by dietary restriction, which supports the emerging redox-stress hypothesis of aging.

While thinking about antioxidants and their effect on aging, it's important to remember that location matters immensely. Ingested antioxidants of the sort you can buy in the store are convincingly demonstrated to do nothing for your health, and there is evidence to suggest that they are actually mildly harmful - for example by blocking some of the oxidant-based signaling mechanisms the body uses to dial up cellular housekeeping and muscle growth responses after exercise. Meanwhile researchers are demonstrating benefits in mice by targeting designed antioxidant compounds to the mitochondria in cells, the place that most oxidants are generated. Those antioxidants are not yet available for the rest of us, however. The antioxidant pills from the store don't deliver their contents to your mitochondria, and are thus not terribly helpful.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23743291

It is usually the case that the first knee-jerk reaction in opposition to increased human longevity is based on the mistaken belief that life extension technologies would lead to people being ever more frail and decrepit for a very long time. This is far from the case, and it's probably not even possible to cost-effectively engineer a society of long-lived frail people - even if that was the goal to hand. If you are frail and decrepit then you have a high mortality rate due to the level of age-related cellular and molecular damage that is causing the failure and degeneration of your body and its organs. You won't be around for long. No, the only way to engineer longer healthy life is extend the period of youth and vitality, a time in which you have little age-related damage and your mortality rate is very low. Most present strategies are aimed to prolong that period of life, either by slowing the rate at which damage occurs (not so good) or finding ways to periodically repair the damage and thus rejuvenate the patient (much better).

Once people grasp that longevity science is the effort to make people younger for far longer, then the second knee-jerk objection arises. This is the belief that a very long-lived individual would become overwhelmed by boredom: they would run out of interest and novelty. This is by far the sillier objection, and there is absolutely no rational basis for it. Even a few moments of thought should convince you that there is far more to do and learn that you could achieve in a thousand life spans - and it's a little early in the game to be objecting to enhanced longevity on the basis that you can't think of what to do with life span number number 1001.

Considering boredom, futility, meaningless, and related matters, I noticed what appears to be an argument by induction in the article below. Mathemetical induction is a tool used in formal proofs wherein if you can prove that something is generally true for n and n+1 (where n is a natural number), and then show that it is true for 1, then you can conclude it must be true for all natural numbers. If it is true for 1, then it must be true for 1+1 = 2, and true for 2+1 = 3, and so on.

Life Extension Leads to Meaningless Days? NO!

Person X lives a fulfilling and meaningful life for X number of years before that life is terminated by a sudden, massive heart attack.Now, imagine another person whom we shall label (not too creatively) 'Person 2′. Person 2′s life follows the same general path as person 1 with one exception: It is one day longer than person 1′s was. Now ask yourself: Is there any reason to suppose that this day, let us assume it is aTuesday, strikes person 2 as being meaningless despite the fact that all Tuesdays (and indeed every other day in person 2′s past) seemed worth living?

OK, so now imagine yet another person who goes by the label of... yes, you guessed it, Person 3. You can probably also guess that Person 3 lives one day longer than person 2. Once again, I can think of no reason why, where we have two people who live meaningful lives but one lives one day longer, that extra day would not seem worth experiencing. Put another way: If possible would persons 2 and 1 rather not be dead on Wednesday (the last day for person 3) when Monday and all preceding days were worth experiencing? So far as I can see, the answer to that question is, 'yes'. There seems to be no reason why this argument should not hold for any number of hypothetical people, each one of which lives one day longer than the last.

Unfortunately you can't prove conjectures about aspects of human nature with induction (or not yet, at least). What you can do is use it, as above, to mount a more convincing argument. This one is somewhat akin to one of the standard lines in any debate between a person who is in favor of greatly extending healthy life versus someone who isn't.

Advocate: So you are fine with aging and dying?

Deathist: Yes.

Advocate: So you are fine with dying right now, done and finished?

Deathist: Well, no.

Advocate: Why would you think any differently ten days, or a hundred days, or decades from now, if you still had your health and vigor?

Deathist: Um...

There seems to be a strange disconnect in many people's minds, in which they are vigorously in favor of being alive right this instant or next week, but they nonetheless believe that their future self of years ahead will be of a different opinion and want to die. Now if you're on the downhill slope of aging, in great pain, and your body is falling apart, desiring a stopping point is not unreasonable. (With the best of present options for those in that position being cryonics). But in a world of rejuvenation therapies, in which older life is just as healthy, low-risk, and full of possibility as younger life, what mysterious thing is going make people want to die?

Young mammals, and occasionally adults, can regenerate lost fingertips. This seems like a good place to learn more about the mechanisms of regeneration, gaining insight into why it is that mammals cannot replicate the feats of limb and organ regeneration exhibited by species such as salamanders and zebrafish. More importantly, researchers hope to find that it is practical to adjust human biology to allow this sort of exceptional regeneration:

If a salamander loses its leg, it can grow a new one. Humans and other mammals are not so fortunate, but we can regenerate the tips of our digits, as long as enough of the nail remains. This was first shown some 40 years ago; today researchers finally reveal why it is that nails are necessary. Working with mice, [researchers] have identified a population of stem cells lying beneath the base of the nail that can orchestrate the restoration of a partially amputated digit. However, the cells can do so only if sufficient nail epithelium - the tissue that lies immediately below the nail - remains.

The process is limited compared with the regenerative powers of amphibians, but the two share many features, from the molecules that are involved to the fact that nerves are necessary. "I was amazed by the similarities. It suggests that we partly retain the regeneration mechanisms that operate in amphibians."

The nail base contains a small population of self-renewing stem cells, which sustain the nail's continuous growth. This ongoing growth depends on signals carried by the Wnt family of proteins - if this signalling pathway is disrupted, mouse nails cannot form. The team found that the same pathway is involved in the regeneration of lost mouse toe tips. After amputation, the Wnt pathway is activated in the epithelium underlying the remaining nail and attracts nerves to the area. Through a protein called FGF2, the nerves drive the growth of mesenchymal cells, which restore tissues such as bone, tendons and muscle. Within five weeks, the digit is good as new.

However, none of this can happen if the digit is amputated too far back, and too much nail epithelium is lost. In such cases, the Wnt pathway is never activated, the nerves do not extend and the other tissues cannot regenerate.

Link: http://www.nature.com/news/how-nails-regenerate-lost-fingertips-1.13192

Researchers have produced an improvement in methods of gene therapy used to treat some rare forms of blindness, and which may allow the use of gene therapy in the treatment of more common forms of degenerative blindness that occur in old age:

Three groups of researchers have successfully restored some sight to more than a dozen people with a rare disease called Leber's congenital amaurosis. [They] achieved this by inserting a corrective gene into adeno-associated viruses (AAV), a common but benign respiratory virus, and injecting the viruses directly into the retina. The photoreceptor cells take up the virus and incorporate the functional gene into their chromosomes to make a critical protein that the defective gene could not, rescuing the photoreceptors and restoring sight.

Unfortunately, the technique cannot be applied to most blinding diseases because the needle often causes retinal detachment, making the situation worse. Yet the standard AAV used in eye and other types of gene therapy cannot penetrate into tissue to reach the photoreceptors and other cells, such as retinal pigment epithelium, that need to be fixed.

[Researchers] set out to find a way to "evolve" AAV to penetrate tissues, including eye and liver, as a way to deliver genes to specific cells. [They have] generated 100 million variants of AAV - each carrying slightly different proteins on its coat - [and] selected five that were effective in penetrating the retina. "Building upon 14 years of research, we have now created a virus that you just inject into the liquid vitreous humor inside the eye and it delivers genes to a very difficult-to-reach population of delicate cells in a way that is surgically non-invasive and safe. It's a 15-minute procedure, and you can likely go home that day."

The engineered virus works far better than current therapies in rodent models of two human degenerative eye diseases, and can penetrate photoreceptor cells in the eyes of monkeys, which are like those of humans. [This] could greatly expand gene therapy to help restore sight to patients with blinding diseases ranging from inherited defects like retinitis pigmentosa to degenerative illnesses of old age, such as macular degeneration.

Link: http://www.eurekalert.org/pub_releases/2013-06/uoc--rde061213.php

Cryonics is the industry and technologies that can provide long-term low-temperature storage of your body and mind following death. The balance of evidence presently favors the supposition that vitrification of cryoprotectant-infused tissue, avoiding ice-crystal formation, preserves the fine structure of neural cells in which the data of the mind is stored. That is the core of the matter: whether cryonics preserves the mind well enough to allow future technologies to repair and revive suspended people. If you are going to die prior to the advent of rejuvenation biotechnology, and this is a significant risk for most of us, then cryonics and its uncertainties are the only shot at a longer life in the future. It's a very reasonable wager, all told: a bet that the future of technological progress will continue, versus the certainty of oblivion found in the grave.

Cryopreservation is modestly expensive if you pay in a lump sum: usually more than $100,000, depending on which provider you go with and the details of your arrangements. Most people fund this service via life insurance, however. If you obtain a policy early enough in life the monthly payments are very cheap. It's not a terribly large amount of money even if you start in mid life.

Cryonics should be far more popular than it is. The cost is reasonable, any number of other businesses with multi-decade customer lifetimes prosper, and the potential upside is considerable. Four decades after its emergence from amateur practice into professional practice it remains a niche industry, while billions have gone to the grave over that same span of time. You might compare this with the same puzzling lack of interest in extending life through medical technology: at times one is forced to conclude that most people just don't care about living longer.

A generally favorable, well-researched, long article on the cryonics community recently emerged in the alternative online press. I think it's worth your time to read it all, and if you are presently trying to persuade anyone to see the merits of cryonics, then this would an excellent piece to pass along:

Are We Warming Up to Cryonics?

Some things should not be left to the last minute. For instance, having yourself frozen. The act of being preserved in a giant thermos cooled by liquid nitrogen in the hopes that the scientists of the future will figure out how to revive you and repair whatever it was that drove you to require freezing in the first place is no small matter. There are insurance policies to settle upon. Legal documents to notarize. Relatives to appease. And all of this must be done far enough in advance that arrangements can be made for a field response team to reach you on your deathbed and stand by until a doctor declares you medically deceased, at which time they will leap into action and begin your cryopreservation.

Legally speaking, cryonics is okay because it's considered an extravagant funeral practice. Its few practitioners would not argue with the notion that the procedure would be more effective if started before the heart has taken its final beats, but to do so would be illegal, even if the soon-to-be-deceased is a willing participant. Thus, the process waits for death, and the longer after death it begins, the worse off you are. This is why the Alcor Life Extension Foundation really doesn't like to accept last-minute cases.

One thing to note is this news of funding and initiatives presently in the works. You might not be keeping up with this sort of behind the scenes progress if you're merely interested in cryonics rather than being an insider:

If ever a group is going to coalescence behind the idea of obviating death as we know it, it's the one currently ruling Silicon Valley, which came of age at a time when it really felt like the right combination of smart people and money could solve any problem. And the most intriguing name to sniff around cryonics publicly is Peter Thiel, the billionaire investor who co-founded [PayPal] and was the first outside investor in Facebook. Thiel, who has made no secret of his belief in experimental science, and of his interest in technologies that could suspend or eliminate aging, has a separate fund set up to invest in more outré scientific endeavors. And Breakout Labs, as it's known, has provided seed capital to two cryonics-related start-ups founded by former Alcor employees.

Thiel (who declined an interview request) was also part of the conversation that laid the groundwork for a cryonics X-Prize that is currently in development. The prize, as constructed, would challenge applicants to freeze and then thaw a human organ so that it returns to a viable state. This would enable organ banks, potentially solving a huge global problem - the shortage of organs for transplant - and would be the first proof-of-concept that large, complex collections of tissue could be stored indefinitely at low temperatures without damage. It's not a huge leap from there to imagine the same thing being done with a whole organism.

Here is a recent article from the local Los Angeles press, in which the author manages to touch on a broader range of the pro-human-longevity community than is usually the case:

What researchers do know is that there are limits to how far we can naturally extend the human life span. L. Stephen Coles, a UCLA lecturer and executive director of the Gerontology Research Group, documents and studies "supercentenarians" - people who live to 110 or longer. When he started tracking the longest-lived humans around 2000, "the oldest [known] person in history was a Frenchwoman named Jeanne Calment, who died in 1997 at the age of 122," Coles says. "I thought that because average life expectancy had increased significantly over the last hundred years, it meant someone would break her record." But that hasn't happened. "It's been more than 15 years, and no one has come close."

Even if scientists do find a way to create more supercentenarians, should they? Blogging for The Huffington Post last year, unofficial Hollywood Conscience Jamie Lee Curtis declared that any attempt to conquer aging was an affront to nature. "I am appalled that the term we use to talk about aging is 'anti,' " she wrote. "Aging is as natural as a baby's softness and scent. Aging is human evolution in its pure form. Death, taxes, and aging."

But she's missing the point, says Maria Entraigues, the L.A.-based outreach coordinator for the SENS Research Foundation, a Northern California nonprofit that focuses on longevity research. "I always tell people, Why is it not 'natural' to get sick?" Entraigues says. "Why do we go to the doctor? Aging is the same thing. If there's something we can do about it, we should."

Aubrey de Grey, a Cambridge University computer scientist turned antiaging theorist, launched SENS, short for Strategies for Engineered Negligible Senescence, in 2009. Fifty years old with a Rasputinesque beard, de Grey has gained fame through his appearances at TED talks and on The Colbert Report, among other venues, making the case that aging can be vanquished. He's proposed that seven specific types of damage cause human beings to deteriorate over time, including cellular mutations, an accumulation of "junk" inside and between cells, and a gradual loss of important cells in the brain and other organs. If it were possible to fix all or even some of these problems, he argues, the diseases and frailty that come with old age could be postponed or even reversed. And he believes it's possible that aging itself will be brought under medical control - via maintenance treatments of gene therapies, stem cell therapies, and immune stimulants - within our lifetimes.

Link: http://www.lamag.com/citythink/wellbeing/2013/06/10/forever-young

Mitochondria are the swarming powerplants of the cell, a bacteria-like herd of self-replicating machines that produce the chemical energy stores that power cellular processes. They bear their own DNA, and damage to this mitochondrial DNA (mtDNA) damage is important in aging. Per the mitochondrial free radical theory of aging, some types of mitochondrial DNA damage spread throughout the population of mitochondria in a cell, subverting the quality control mechanisms that normally destroy damaged mitochondria. This leads to harmfully altered mitochondrial function and malfunctioning cells that export damaging reactive compounds into the surrounding tissues.

At this point the fastest way to confirm theories on aging and mitochondrial DNA damage is to implement one of the ways to replace or repair mitochondria DNA. There are a range of potential methods that might result in therapies. In the future, people will probably have their mitochondrial DNA globally refreshed every few decades, removing this contribution to degenerative aging.

Here researchers argue that the spread of mitochondrial DNA damage to all the mitochondria in a cell can't be just random, and thus has be driven by some advantage in selection - such as the ability to fool quality control mechanisms, as is proposed in mitochondrial theories of aging. If damaged mitochondria are culled by the cell less often, they will eventually out-compete undamaged mitochondria.

Mitochondrial DNA deletions accumulate over the life course in post-mitotic cells of many species and may contribute to aging. Often a single mutant expands clonally and finally replaces the wild-type population of a whole cell. One proposal to explain the driving force behind this accumulation states that random drift alone, without any selection advantage, is sufficient to explain the clonal accumulation of a single mutant.

Existing mathematical models show that such a process might indeed work for humans. However, to be a general explanation for the clonal accumulation of mtDNA mutants, it is important to know whether random drift could also explain the accumulation process in short-lived species like rodents. To clarify this issue, we modelled this process mathematically and performed extensive computer simulations to study how different mutation rates affect accumulation time and the resulting degree of heteroplasmy. We show that random drift works for lifespans of around 100 years, but for short-lived animals, the resulting degree of heteroplasmy is incompatible with experimental observations.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23742009

One of the emerging themes over the past few years of stem cell research is that various forms of pluripotent stem cell can be found in adult tissues. Pluripotency in a stem cell is the ability to differentiate to form lineages of any cell type in the body. The well known types of adult stem cell that researchers have cataloged over the past few decades are only multipotent, meaning that they are limited in the type of cell lineages they can create. A multipotent stem cell supports a particular tissue type made up of a few types of cell.

Why does this matter? It's all about the efficiency and cost of research and development of regenerative therapies based on the use of stem cells. If researchers must locate and understand specific multipotent cell populations in order to regenerate a specific type of tissue, then a great deal of work remains on the way to a comprehensive regenerative medicine toolkit. Every type of multipotent stem cell has its own distinct behaviors and mechanisms, and requires a different environment to grow in useful numbers outside the body. Discovering how to make use of any specific type of multipotent stem cell has proven to be a slow process of trial, error, and educated guesswork. On top of that, researchers haven't yet reliably identified multipotent stem cells in all types of tissue, and most of the known populations are far from well understood. There are hundreds of cell types in the human body, and much left to accomplish.

If researchers can obtain a reliable, low-cost source of pluripotent stem cells, however, then that single resource can be used to generate any type of cell you want, starting from the same shared baseline. It greatly cuts down the complexity and work required to move forward with regenerative medicine. This is why the research community is so focused on embryonic stem cells and the reprogramming of ordinary cells into induced pluripotent stem cells. Pluripotent cells obtained directly from an patient's tissues, especially those that are easily accessed such as skin and fat, may be even better than induced pluripotent stem cells in terms of cost-effectiveness. Such a resource cuts out yet another step in the process of obtaining broadly useful patient-matched cells for research and regenerative therapies.

In recent years a few research groups have claimed the identification of pluripotent stem cells in adult tissue. They have given the cells various different names, such as very small embryonic-like stem cells (VSELs), but they might all be talking about the same thing - or they might not. Biology is always more complex than you think it is. Why shouldn't there be all sorts of variously potent cell types hiding away in our bodies in larger or smaller numbers?

Here is an open access publication from another research group to have isolated pluripotent stem cells in adult tissue. From a long term perspective, the more of this that happens the better, I think. It suggests that over the next decade or two regenerative research will move more rapidly than would otherwise have been the case:

Awakened by Cellular Stress: Isolation and Characterization of a Novel Population of Pluripotent Stem Cells Derived from Human Adipose Tissue

Recently, a new stem cell population has been isolated from mesenchymal tissues such as human skin fibroblasts and bone marrow stromal cells under cellular stress conditions. These cells, termed Multilineage Differentiating Stress-Enduring (Muse) Cells, are of mesenchymal stem cell origin and comprise 1-3% of the entire cell population. Muse cells exhibit characteristics of both mesenchymal and pluripotent stem cells. They are double positive for CD105, a mesenchymal stem cell marker, and stage specific embryonic antigen-3 (SSEA3), well known for the characterization of undifferentiated human embryonic stem cells (ES) from bone marrow aspirates or from cultured mesenchymal cells such as bone marrow stromal cells and dermal fibroblasts. They express pluripotency markers including [those used to create induced pluripotent stem cells], differentiate into cells of ectodermal, endodermal, and mesodermal lineages both in vitro and in vivo, and have the ability to self-renew.

Advantageously, Muse cells do not appear to undergo tumorigenic proliferation, and therefore would not be prone to produce teratomas in vivo, nor do they induce immuno-rejection in the host upon autologous transplantation. In addition, Muse cells are shown to home into the damage site in vivo and spontaneously differentiate into tissue specific cells according to the microenvironment to contribute to tissue regeneration when infused into the blood stream. Therefore, they exhibit the potential to make critical contributions to tissue regeneration in the absence of restrictions attributed to the difficult extraction of bone marrow stromal cells and human skin fibroblasts, and time-consuming purification methods such as cell sorting. In order to increase the viability of Muse cells as a source of tissue regeneration, a more accessible supply must be utilized.

Harvesting human adipose tissue by lipoaspiration is a safe and non-invasive procedure, and hundreds of millions of cells can be isolated from 1-2 liters of lipoaspirate material. Therefore, adipose tissue could prove the ideal source for Muse cell isolation as opposed to bone marrow or dermis. Using lipoaspirate material, we developed a novel methodology for the isolation of a population of human Muse cells under severe cellular stress conditions (long term incubation with proteolytic enzyme, 4°C, serum deprivation, and hypoxia). Purification of human Muse cells derived from adipose tissue (Muse-ATs) does not require the use of cell sorting, magnetic beads or special devices.

Researchers are digging deeper into the mechanisms underlying the loss of bone that accompanies aging. A complete understanding of how imbalances occur between ongoing bone creation and destruction that takes place at the cellular level should eventually lead to ways to manipulate that process:

By analyzing biopsy specimens from patients with postmenopausal osteoporosis and primary hyperparathyroidism, investigators have begun to pay increasing attention to "reversal cells," which prepare for bone formation during bone remodeling. The hope is that these reversal cells will become critical therapeutic targets that may someday prevent osteoporosis and other bone disorders.

In adults, bones are maintained healthy by a constant remodeling of the bone matrix. This bone remodeling consists of bone resorption by osteoclasts and bone formation by osteoblasts. A failure in the delicate balance between these two processes leads to pathologies such as osteoporosis. How these two processes are coupled together is poorly understood. "Reversal cells may represent the missing link necessary to understand coupling between bone resorption and formation and to prevent osteoporosis."

Reversal cells actually cover more than 80% of the resorbed bone surfaces. Using histomorphometry and immunohistochemistry on human bone biopsies, researchers found that the reversal cells colonizing the resorbed bone surfaces are immature osteoblastic cells which gradually mature into bone forming osteoblasts during the reversal phase, and prepare the bone surface for bone formation. Researchers also found that some reversal cells display characteristics that suggest an "arrested" physiological status. These arrested reversal cells showed no physical connection with bone forming surfaces, a reduced cellular density, and a reduced expression of osteoblastic markers.

Biopsies from postmenopausal patients with osteoporosis showed a high proportion of arrested cells, but no such cells were found in biopsies from patients with primary hyperparathyroidism, in which the transition between bone resorption and formation is known to occur optimally. [Larger] arrested cell surfaces were associated with bone loss. "Our observations suggest that arrested reversal cells reflect aborted remodeling cycles which did not progress to the bone formation step. We therefore propose that bone loss in postmenopausal osteoporosis does not only result from a failure of bone formation as commonly believed, leading to incomplete filling of resorption cavities, but also from a failure at the reversal phase, uncoupling bone formation from resorption."

Link: http://www.eurekalert.org/pub_releases/2013-06/ehs-rcm060413.php

Long term administration of rapamycin has been demonstrated to slow aging in mice, and here one aspect of that outcome is examined in more detail:

Elderly mice suffering from age-related heart disease saw a significant improvement in cardiac function after being treated with the FDA-approved drug rapamycin for just three months. The research, led by a team of scientists at the Buck Institute for Research on Aging, shows how rapamycin impacts mammalian tissues, providing functional insights and possible benefits for a drug that has been shown to extend the lifespan of mice as much as 14 percent.

Researchers at the Mayo Clinic are currently recruiting seniors with cardiac artery disease for a clinical trial involving low dose treatment with rapamycin.

In this study, rapamycin was added to the diets of mice that were 24 months old - the human equivalent of 70 to 75 years of age. Similar to humans, the aged mice exhibited enlarged hearts, a general thickening of the heart wall and a reduced efficiency in the hearts ability to pump blood. The mice were examined with ultrasound echocardiography before and after the three-month treatment period - using metrics closely paralleling those used in humans. Buck Institute [researchers] said age-related cardiac dysfunction was either slowed or reversed in the treated mice.

"Rapamycin affected the expression of genes involved in calcium regulation, mitochondrial metabolism, hypertrophy and inflammation. We also carried out behavioral assessments which showed the treated mice spent more time on running wheels than the mice who aged without intervention."

It sounds a lot like increased exercise has as much to do with the outcome as direct effects of the drug. Exercise, like calorie restriction, has a powerful influence on all aspects of health.

Link: http://www.eurekalert.org/pub_releases/2013-06/bifa-ldg061013.php