Why do cold-blooded species live longer in colder environments? Researchers have a prospective mechanism that is shared by mammals:

Scientists have known for nearly a century that cold-blooded animals, such as worms, flies and fish all live longer in cold environments, but have not known exactly why. Researchers [have] identified a genetic program that promotes longevity of roundworms in cold environments - and this genetic program also exists in warm-blooded animals, including humans. "This raises the intriguing possibility that exposure to cold air - or pharmacological stimulation of the cold-sensitive genetic program - may promote longevity in mammals."

Scientists had long assumed that animals live longer in cold environments because of a passive thermodynamic process, reasoning that low temperatures reduce the rate of chemical reactions and thereby slow the rate of aging. "But now, at least in roundworms, the extended lifespan observed at low temperature cannot be simply explained by a reduced rate of chemical reactions. It's, in fact, an active process that is regulated by genes."

[Researchers] found that cold air activates a receptor known as the TRPA1 channel, found in nerve and fat cells in nematodes, and TRPA1 then passes calcium into cells. The resulting chain of signaling ultimately reaches DAF-16/FOXO, a gene associated with longevity. Mutant worms that lacked TRPA1 had shorter life spans at lower temperatures.

Because the mechanisms [also] exist in a range of other organisms, including humans, the research suggests that a similar effect might be possible. The study also links calcium signaling to longevity for the first time and makes a novel connection between fat tissue and temperature response. Researchers have known that lowering the core body temperature of warm-blooded animals, such as mice, by 0.9 degrees Fahrenheit can extend lifespan by 20 percent, but it hasn't been practical for humans to attempt to lower the core body temperature.

It's worth noting that past research has shown that not all methods of lowering core body temperature in mammals will extend life. It matters how it's done, which suggests that it isn't so much temperature as the particular mechanisms that are running that is driving the effect. For example, calorie restriction is associated with a lower core body temperature.

Link: http://www.eurekalert.org/pub_releases/2013-02/uom-sca021413.php

Source:
http://www.fightaging.org/archives/2013/02/on-greater-longevity-in-colder-environments.php

Nitric oxide shows up in many places in the the biochemistry of longevity, the processes by which differences in the operation of metabolism influence the pace of aging. In this example, however, it isn't particularly clear that it has any great relevance to human biology:

Although humans and many other organisms have the enzyme needed to produce nitric oxide, C. elegans does not. Instead, [the] worm can "hijack" the compound from the soil-dwelling Bacillus subtilis bacterium that is not only a favored food but also a common colonist within its gut. This resourcefulness [partially] explains why worms fed B. subtilis live roughly 50 percent longer than counterparts fed Escherichia coli, which does not produce the compound.

In the new study, the average C. elegans lifespan increased by nearly 15 percent, to about two weeks, when researchers fed the worms nitric oxide-producing B. subtilis bacteria, compared to worms fed mutant B. subtilis with a deleted nitric oxide production gene. The research group also used fluorescent sensors to show that C. elegans does not make its own nitric oxide gas. When the worms were fed normal B. subtilis bacteria, however, the fluorescent signal appeared in their guts.

Fluorescent labeling and other tests also demonstrated that B. subtilis-derived nitric oxide penetrated the worms' tissues, where it activated a set of 65 genes. Some had been previously implicated in stress resistance, immune response, and increased lifespan, though others have unknown functions. Importantly, the researchers showed that two well-known regulatory proteins were essential for activating all of the genes.

"What we found is that nitric oxide gas produced in bacteria inside the worms diffuses into the worm tissue and activates a very specific set of genes acting through two master regulators, hsf-1 and daf-16, resulting in a high resistance to stress and a longer life. It's striking that a small molecule produced by one organism can dramatically affect the physiology and even lifespan of another organism through direct cell signaling."

Link: http://www.eurekalert.org/pub_releases/2013-02/jhm-jhr021213.php

Source:
http://www.fightaging.org/archives/2013/02/nitric-oxide-and-longevity-in-nematodes.php

Alpha-synuclein is associated with Parkinson's disease (PD), and is believed to play a central role in the mechanisms that cause the destruction of dopamine-generating neurons, and thus the pathology of the condition. Here, researchers dig deeper into the processes involved:

Overexpression of a protein called alpha-synuclein appears to disrupt vital recycling processes in neurons, starting with the terminal extensions of neurons and working its way back to the cells' center, with the potential consequence of progressive degeneration and eventual cell death. "This is an important new insight. I don't think anybody realized just how big a role alpha-synuclein played in managing the retrieval of worn-out proteins from synapses and the role of alterations in this process in development of PD."

Using a variety of leading-edge imaging technologies, including a new fluorescent tagging technique developed for electron microscopy, [the] scientists created three-dimensional maps of alpha-synuclein distribution both in cultured neurons and in the neurons of mice engineered to over-express the human protein. They found that excess levels of alpha-synuclein accumulated in the presynaptic terminal - part of the junction where axons and dendrites of brain cells meet to exchange chemical signals.

"The over-expression of alpha-synuclein caused hypertrophy in these terminals. The terminals were enlarged, filled with structures we normally don't see." [As] alpha-synuclein accumulates in the terminals, it appears to hinder normal degradation and recycling processes in neurons. This would progressively impair the release of neurotransmitters. In time, the neurons might simply stop functioning and die.

Link: http://www.sciencedaily.com/releases/2013/02/130207141402.htm

Source:
http://www.fightaging.org/archives/2013/02/parkinsons-disease-as-localized-garbage-catastrophe.php

The broad variety and rapid change in mechanisms within cancerous cells is one of the reasons that cancer is hard to tackle - every cancer is different and evolving. Circumventing this to find truly effective cancer therapies will require the discovery of some mechanistic commonality that can be targeted, some biological process that all cancers depend on and which distinguishes their cells from non-cancerous cells. The proposed SENS approach, for example, is to go right to the root and remove all ability to lengthen telomeres in the body, as all cancers depend on that. The mainstream research community aims to find markers for cancer stem cells, or low-level mechanisms shared between cancers to some degree and which can be sabotaged to slow down or reverse progression of the disease. Not all shared mechanisms are sufficient to build a true cure, unfortunately.

Here is an example of one such lesser mechanism in the early stages of research and development:

Epithelial to mesenchymal transition is important to embryonic development, turning stationary epithelial cells into mobile mesenchymal cells to move them within the embryo. For example, a cell might be converted and then gather with other cells forming, for example, the kidney. Once there, it transitions back to an epithelial cell again and stays put. Research has shown that carcinomas, tumors that form in the epithelium (lining) of organs are able to reactivate EMT. About 85 percent of all solid tumors are carcinomas.

"We found that FOXC2 lies at the crossroads of the cellular properties of cancer stem cells and cells that have undergone epithelial to mesenchymal transition (EMT), a process of cellular change associated with generating cancer stem cells. There are multiple molecular pathways that activate EMT. We found many of these pathways also activate FOXC2 expression to launch this transition, making FOXC2 a potentially efficient check point to block EMT from occurring."

[Researchers believe] that targeting FOXC2 pathway [will] be an effective therapeutic strategy for inhibiting EMT and consequently reducing EMT/cancer stem cell-associated metastasis, relapse and therapy resistance.

Link: http://www.sciencedaily.com/releases/2013/02/130213131940.htm

Source:
http://www.fightaging.org/archives/2013/02/searching-for-commonalities-in-cancer.php

Decellularization involves taking a donor organ and stripping its cells, leaving just the shaped extracellular matrix behind. When new cells of the right types are seeded into the matrix, they will inhabit it, grow, and follow its cues to rebuild the tissue as it was. This might prove to be a shortcut to the future of organs grown to order - you can't use it to produce an organ such as the heart from scratch, but you can take animal organs and make it possible to transplant them into humans with minimal risk of rejection.

This, at least, is the goal. So far decellularization has worked for some human donor tissues, such as veins, replacing the donor's cells with those of the recipient to remove immune rejection issues. This suggests that it will work just fine for animal organs too. Researchers are working on opening the doors to widespread xenotransplantation of pig organs, for example, by turning porcine tissues into those of the organ recipient.

Saving lives with help from pigs and cells

One recent morning, a pig heart hung suspended in a clear homemade tank in the lab built for Taylor and her team. Filled with detergent, the heart had expanded to the size of a large man's fist, excess liquid dripping slowly out its sides.

Once the heart is thoroughly cleaned, hard-working human stem cells - immature cells found in our organs and tissues that help repair damage on a daily basis - will bring it to life. "We can take stems cells from bone marrow, blood or fat and place them onto a heart, liver or lung scaffold," Taylor explains. "My motto for a long time has been 'Give nature the tools and get out of the way.'?"

Taylor and her team will add stem cells to the heart one of two ways: by inserting a tube in the aorta and letting the cells drip inside, or by injecting the cells with a syringe through the wall of the heart. A heartbeat is perceptible after just a few days. Within a few weeks, the heart is strong enough to pump blood.

Taylor predicts that in the next two years, she and her team will approach the U.S. Food and Drug Administration and ask to do a first-in-human study with the bio-artificial hearts. "Will it be a whole heart? Probably not," Taylor says. "But it could be a cardiac patch or a valve. We might start with a piece to show the safety and efficacy of the technology."

Source:
http://www.fightaging.org/archives/2013/02/working-on-the-use-decellularization-to-make-pig-hearts-suitable-for-human-transplantation.php

Here is another small step on the way towards the creation of artificial cells as medical devices. If you can wrap nanoparticles in cell membranes, then its not hard to see that disguising any arbitrary nanomachinery that way is on the agenda - such as those that can dispense or create proteins, or perform other tasks inside our tissues.

By cloaking nanoparticles in the membranes of white blood cells, [scientists] may have found a way to prevent the body from recognizing and destroying them before they deliver their drug payloads. "Our goal was to make a particle that is camouflaged within our bodies and escapes the surveillance of the immune system to reach its target undiscovered. We accomplished this with the lipids and proteins present on the membrane of the very same cells of the immune system. We transferred the cell membranes to the surfaces of the particles and the result is that the body now recognizes these particles as its own and does not readily remove them."

Nanoparticles can deliver different types of drugs to specific cell types, for example, chemotherapy to cancer cells. But for all the benefits they offer and to get to where they need to go and deliver the needed drug, nanoparticles must somehow evade the body's immune system that recognizes them as intruders. The ability of the body's defenses to destroy nanoparticles is a major barrier to the use of nanotechnology in medicine. Systemically administered nanoparticles are captured and removed from the body within few minutes. With the membrane coating, they can survive for hours unharmed.

"Being able to use synthetic membranes or artificially-created membrane is definitely something we are planning for the future. But for now, using our white blood cells is the most effective approach because they provide a finished product. The proteins that give us the greatest advantages are already within the membrane and we can use it as-is."

Link: http://www.sciencedaily.com/releases/2013/01/130131144114.htm

Source:
http://www.fightaging.org/archives/2013/02/wrapping-nanoparticles-in-cell-membranes.php

From a few weeks back, an audio interview with Aubrey de Grey of the SENS Research Foundation:

Anti-aging scientist and biogerontologist Aubrey de Grey told [the host] about his work with the SENS Foundation, an organization he founded with the purpose of defeating aging. According to him, aging is treated as a disease that should be defeated by targeting the 7 cellular activities that cause us to age. Dr. de Grey discussed the science that researchers at SENS are studying to back up the claim that we could live to 1000 years some day soon. "The problem is the funding," de Grey said. "We've been trying to fight what we've described as the pro-aging trance." The pro-aging trance, according to Dr. de Grey, is the social conception we have that death is inevitable. "No one wants to keep cancer, no one wants to keep heart disease, so what would we want to keep aging?" de Grey asks. Part of Aubrey de Grey's work is marketing his ideas and helping to diminish the acceptance society has of death. Citing his long beard which [the interviewer] said looked "like Rasputin's," de Grey said, "This is something my team and I have discussed. It's something that helps me stick in people's minds."

[The interviewers] briefly talked about the social, economic, and cultural consequences of a longer life extension. When [the interviewers] pressed de Grey on these issues, Aubrey reiterated that his work is not a "longevity issue, but a health care issue, so stop thinking of it that way please." Aubrey pressed that the key for his scientific success lies in his publicity: getting more exposure and raising money through his foundation.

Link: http://glucksolutions.podomatic.com/entry/index/2013-01-18T12_39_16-08_00

Source:
http://www.fightaging.org/archives/2013/02/a-podcast-interview-with-aubrey-de-grey.php

Vegetarianism is associated with health benefits such as reduced risk of age-related disease. It is also associated with carrying less of the visceral fat shown to cause harm to long-term health - which on balance probably means a lower calorie intake. As we all know by now, calorie intake has a disproportionate effect on measures of health. So that would seem to be a more plausible mechanism than, say, reduced dietary intake of AGEs or lower levels of methionine.

Here, however, researchers are claiming that differences in body mass index - a not-so-great proxy measure for the amount of body fat - between vegetarians and non-vegetarians are not terribly important in comparison to blood pressure and cholesterol measures. That is not a particularly intuitive result:

The risk of hospitalisation or death from heart disease is 32% lower in vegetarians than people who eat meat and fish, according to a new study. "Most of the difference in risk is probably caused by effects on cholesterol and blood pressure, and shows the important role of diet in the prevention of heart disease."

This is the largest study ever conducted in the UK comparing rates of heart disease between vegetarians and non-vegetarians. The analysis looked at almost 45,000 volunteers from England and Scotland enrolled in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Oxford study, of whom 34% were vegetarian. Such a significant representation of vegetarians is rare in studies of this type, and allowed researchers to make more precise estimates of the relative risks between the two groups.

The Oxford researchers arrived at the figure of 32% risk reduction after accounting for factors such as age, smoking, alcohol intake, physical activity, educational level and socioeconomic background.

Participants were recruited to the study throughout the 1990s, and completed questionnaires regarding their health and lifestyle when they joined. These included detailed questions on diet and exercise as well as other factors affecting health such as smoking and alcohol consumption. Almost 20,000 participants also had their blood pressures recorded, and gave blood samples for cholesterol testing. The volunteers were tracked until 2009, during which time researchers identified 1235 cases of heart disease. This comprised 169 deaths and 1066 hospital diagnoses, identified through linkage with hospital records and death certificates.

The researchers found that vegetarians had lower blood pressures and cholesterol levels than non-vegetarians, which is thought to be the main reason behind their reduced risk of heart disease. Vegetarians typically had lower body mass indices (BMI) and fewer cases of diabetes as a result of their diets, although these were not found to significantly affect the results. If the results are adjusted to exclude the effects of BMI, vegetarians remain 28% less likely to develop heart disease.

Link: http://www.eurekalert.org/pub_releases/2013-01/uoo-vcr012913.php

Source:
http://www.fightaging.org/archives/2013/01/vegetarianism-associated-with-lower-risk-of-heart-disease.php

One of the side-effects resulting from members of the research community now being far more willing to talk openly about engineering human longevity or building therapies for aging is that university publicity offices are now far more willing to write materials that sound like something the "anti-aging" market would come up with. That's not great, but it is what it is - as for the mass media and marketing, the primary incentives for these folk have nothing to do with truth, accuracy, or helping the public understand the actual relevance of a particular research result. If any of those things happen, it's either by accident or because they help achieve the real goals of the publicity group. Bear that in mind while reading the release materials linked below.

Sirtuins have been a hot topic in aging research - largely undeservedly as it turned out - for some years, the large sums of money flowing into that field of research helping to drive enthusiasm for the slow, expensive road of slowing aging by metabolic manipulation. Most of the relevant research community, those who might be working on SENS or other rejuvenation biotechnologies if the money was there, work towards similar goals. They are producing knowledge rather than applications that can influence human lifespan, and have little expectation of producing anything more than knowledge for decades to come. Knowledge is never useless, but this path is not likely to deliver meaningful extension of human life in time to matter to us, nor is it likely to produce technologies that will help people who are already aged.

There are a number of different sirtuins, and while research initially focused on SIRT1, it is SIRT3 and SIRT6 that have generated the more interesting results in the past couple of years. SIRT3 is the topic for today, a mitochondrial protein - it is noteworthy to see just how many longevity-related genes and proteins are connected to the mitochondria in some way. Calorie restriction is noted to boost levels of SIRT3, and SIRT3 is thought to promote antioxidant activity in cells, reducing damage in the places where oxidants are produced as a side-effect of the operation of metabolism - something that you can't achieve by ingesting antioxidants, I should add.

Here, researchers demonstrate a modest reversal of one small aspect of the breadth of aging biology by boosting levels of SIRT3 in old mice:

Discovery opens the door to a potential 'molecular fountain of youth'

The researchers first observed the blood system of mice that had the gene for SIRT3 disabled. Surprisingly, among young mice, the absence of SIRT3 made no difference. It was only when time crept up on the mice that things changed. By the ripe old age of two, the SIRT3-deficient mice had significantly fewer blood stem cells and decreased ability to regenerate new blood cells compared with regular mice of the same age.

What is behind the age gap? It appears that in young cells, the blood stem cells are functioning well and have relatively low levels of oxidative stress, which is the burden on the body that results from the harmful byproducts of metabolism. At this youthful stage, the body's normal anti-oxidant defenses can easily deal with the low stress levels, so differences in SIRT3 are less important.

"When we get older, our system doesn't work as well, and we either generate more oxidative stress or we can't remove it as well, so levels build up. Under this condition, our normal anti-oxidative system can't take care of us, so that's when we need SIRT3 to kick in to boost the anti-oxidant system. However, SIRT3 levels also drop with age, so over time, the system is overwhelmed."

To see if boosting SIRT3 levels could make a difference, the researchers increased the levels of SIRT3 in the blood stem cells of aged mice. That experiment rejuvenated the aged blood stem cells, leading to improved production of blood cells.

Source:
http://www.fightaging.org/archives/2013/01/learning-more-about-the-role-of-sirt3-in-aging.php

If the 2045 initiative continues onwards as the founder intends, we're all going to be hearing more about what here is called "cybernetic immortality" - copying the data of the mind to run in machinery that is much more robust and longer-lasting than its biological equivalent. I consider the popularity of this goal (as put forward by Ray Kurzweil, for example) something of an existential threat, insofar as it may drain enthusiasm and allies from work on rejuvenation biotechnology now, and in future decades it may become cheaper to build mind-copies than to finalize the means to reverse and prevent aging in our biological bodies. You don't need to fully understand the brain to copy it given powerful enough computers and scanning tools, and you don't need to understand aging much better than we do today to create rejuvenation biotechnology.

There are more than enough people in the world who consider a copy of themselves a suitable continuation to support this sort of technology in preference over medicine for rejuvenation. Today a person can choose to support programs like SENS research on the rejuvenation side or the 2045 group on the mind copying side - it's not just talk, it's a rather important choice between aiming for continued survival of the self or aiming for death while a copy of you survives.

Cybernetic immortality - fantasy or scientific problem? I can answer that right away. It is a scientific problem - of approximately the same type as the problem of people going into outer space, which was proposed by Tsiolkovsky at the turn of the 20th century. Why, despite the support of important scientists (such as V. Turchin, C. Joslyn, R. Kurzweil, A. Bolonkin, B. Bainbridge and others), is this idea rejected by many, or at best treated with skepticism?

There are many reasons for this. Firstly: the scale of this super-project, which really does verge on fantasy, is too "overwhelming", for the "average" scientific mindset, which is mundane and cautious, and too dependent on the opinion of the scientific management. Anything is proposed nowadays if financing can be secured for it. I'm not even talking about the colossal growth of false science - charlatans, mages, "miracle-workers". All of this throws a shadow on the idea of cybernetic immortality.

Furthermore, we are now only at the approach stage of a solution to this problem, specific steps for its development are in many ways only at discussion level, and creative solutions are required. The eternal idea of immortality has been expressed in myths, legends and religious beliefs. Hence the prejudice that it is not compatible with science.

What is the basis for the conviction that the problem of cybernetic immortality is a real scientific problem? It does not contradict the principles of science. In fact, it finds a theoretical basis in them - above all, in the fundamental principle of the iso-functionalism of systems, which essentially heralded the beginning of the computer era. The idea of this principle is that the same complex of functions may be reproduced on substrates with different physical properties. Hence the fundamental possibility to reproduce the functions of a living system and the brain on non-biological substrates, which also fully applies to mental functions.

Link: http://hplusmagazine.com/2013/01/21/d-i-dubrovsky-cybernetic-immortality-fantasy-or-scientific-problem/

Source:
http://www.fightaging.org/archives/2013/01/considering-cybernetic-immortality.php

From the Russian end of the longevity advocacy community:

A man strives for justice, but the most unjust thing in life is the inevitability of death. Here's a small child, then an adult, he learns, grows up, falls in love, gets married - divorce, have children, he is happy and suffering, dreaming and disappointed, laughing and crying, running, resting, but for all that the fate is death, imminent death due to aging. Monstrous injustice! A man with his life does not deserve death. People put up with this situation, they talk about natural dying, saying that a person must make room. These excuses have the sound of death due to frustration, due to a lack of knowledge about the theoretical possibilities of science, not a desire to act rationally. A person finds it easier to accept death and aging than to begin to act.

So the struggle with death and aging: a complex internal decision, the decision to confront the established foundations, the victory of reason over faith and the desire for psychological comfort, the victory over short-term interest. In 20 years it will not matter exactly what you ate today, what color your wallpaper, and where you go to relax - only one thing will be important, how you confronted death in our day. And in a hundred years, nothing that you are or do now will be important if aging is not defeated.

"But what about Pushkin? Everyone remembers him!" - Pushkin would love to change places with you, as he is dead while you are alive and can act. The memory of a man is not the man himself. The good works of Pushkin do not help him in any way nor are a compensation for his dying. Conversely, a victory over aging grants a continuation and the opportunity to do many things. Transhumanism is the desire for freedom. Freedom is possibility. Pain, suffering and aging limit our possibilities. Death reduces them to zero. Improving people via the new nano-, bio-, info-technology of the 21st century offers opportunities only dreamed of by philosophers of the past. It is important to take action.

Link: http://translate.google.com/translate?hl=en&sl=auto&tl=en&u=http://m-batin.livejournal.com/154691.html

Source:
http://www.fightaging.org/archives/2013/01/but-what-about-pushkin.php

Building scientific communities with strong ties to the broader public runs in just the same way as building any community in this day and age - which means very differently to the way things used to be. The internet, open data, and cheap global communication allow a whole new layer of activism and effort by small groups of researchers to stand beside the traditional conferences, funding sources, and institutional relationships. The successful research community of today will be a lot more in touch with the public who stand to benefit from its work, and with the advocates and activists who support progress in the field. You might look at calorie restriction research as an example of strong ties between researchers and advocates, leading to a greater number of human research programs and a greater visibility for calorie restriction as a lifestyle choice. Similarly for aging research: efforts like the Methuselah Foundation and SENS Research Foundation have emerged as much from visionaries and support outside the research community as from the work of those within.

It may be easier to build communities these days, but that doesn't mean it's easy. Effort is definitely involved, along with some measure of fortuitous happenstance, the upkeep of watering holes and initiatives, a need for strong personalities to make and maintain diverse connections, the creation of collaboration tools and outreach programs. The list goes on.

Some of the folk at the International Longevity Alliance are enthused by the idea of building more and better threads to link and strengthen the longevity science community. From their point of view there is much yet to be done in terms of opening up collaboration between research groups and between researchers and interested members of the public. For the moment their efforts center around the Denigma resource database:

When I started research 12 years ago, articles were on paper or from books borrowed at the library in whatever language, and contacting researchers was done through letters sent by mail - needless to say the pace of research was much slower then. The Internet and the area of computerized experimental data is changing everything. PubMed is the new bible and collaborations *can* go at the speed of emails. *Can*, because there is still much that can be done to go even faster:

Research labs generally remain local and closed places that do not interact much with other ones, even if it were beneficial for both. In many cases this a matter of distance and not knowing each other, which some summarize as follows:"science improves at the rate of congresses".

Citizen science is a burgeoning new revolution: Imagine what could happen if a large part of the longevity alliance (currently about 5,000 members) was attending lab meetings and helping in one way or another... For example statistics, experiment design, grant or paper writing, or basic administration (another break for research...)

Luckily we are not the first ones to try to optimise and systematize research, in biogerontology in particular: pioneers have created important bricks for the grand edifice. We have the ingredients and now we need to create a recipe to be adopted by aging research This was clearly highlighted at the Eurosymposium on Healthy Ageing (EHA2012, organised by Heales in Brussels, and where various members of the International Longevity Alliance met). The need for a centralized place for collaboration against aging was strongly raised and a few days later emails were springing on the matter, with names like "Collaborative Resource for Gerontology" (by Georg Fullen, who presented Denigma at EHA2012) or "inSilicoSENS" (by Aubrey de Grey, where SENS = Strategies to Engineer Negligible Senescence).

There is a fair amount of this sort of sentiment in the broader research community these days: towards open publishing, greater transparency, relationships established with philanthropists and supporters in the public. It is the mood of the times, enabled by the falling cost of communication and the increasing capacity of the internet. But mood of the times or not, it still takes people to do the work, bang the drum, build the tools.

Source:
http://www.fightaging.org/archives/2013/01/on-strengthening-the-longevity-research-community.php

An open access review paper looks at the rise of mole-rats in cancer and aging research:

Most rodents are small and short-lived, but several lineages have independently evolved long lifespans without a concomitant increase in body-mass. Most notable are the two subterranean species naked mole rat (NMR) and blind mole rat (BMR) which have maximum lifespans of 32 and 21 years, respectively. The longevity of these species has sparked interest in the tumor suppression strategies that may have also evolved, because for many rodent species (including mice, rats, guinea pigs, gerbils, and hamsters) tumors are a major source of late-life mortality.

Here, we review the recent literature on anti-cancer mechanisms in long-lived rodents. Both NMR and BMR seem to have developed tumor defenses that rely on extra-cellular signals. However, while the NMR relies on a form of contact inhibition to suppress growth, the BMR evolved a mechanism mediated by the release of interferon, and rapid necrotic cell death. Although both organisms ultimately rely on canonical downstream tumor suppressors (pRB and p53) the studies reveal species can evolve different strategies to achieve tumor-resistance. Importantly, studies of these cancer-resistant rodents may benefit human health if such mechanisms can be activated in human cells.

Link: http://www.frontiersin.org/Genetics_of_Aging/10.3389/fgene.2012.00319/full

Source:
http://www.fightaging.org/archives/2013/01/on-long-lived-cancer-resistant-rodents.php

Edge magazine recently ran their yearly question, which this year is "what should we be worried about?" There are more than a hundred and fifty responses from various authors and folk in the public eye, and I'll confess to not having read more than a handful - time is ever fleeting, and none of us have enough of it between dawn and dusk. Thus while I noticed Aubrey de Grey's response, I missed seeing this rather better one. You should definitely read the whole thing, not just the concluding except below:

What Should We Be Worried About: Natural Death

Even if the probability of quickly finding a technological method to delay or reverse senescence is low, we have been devoting far too little effort to it. After all, no matter what else we might achieve with our work in life, we soon won't be around to enjoy it. There are other problems on the planet to worry about, but none more personally important. And yet, despite this motivation, there is very little money being spent on longevity research. Because there is no history of success, and because of widely held religious beliefs, government won't fund it. And because achieving success will be difficult, and the marketplace is flooded with false claims, industry has little interest in solving the problem. Although the profit could be astronomical, there is no easy path to attain it, unlike for cosmetic improvements. Over a hundred times more money is spent on R&D for curing baldness than for curing aging. We may someday find ourselves with extended lifespans as an unintended side effect of taking a pill that gives us fuller hair.

This absurd situation is typical for high-risk, high-reward research in an area without an established record of success. Even with strong motivation, financial support is nearly nonexistent. Scientists working on life extension often lack for equipment or a livable salary, and risk their careers by conducting oddball research that repeatedly fails. The problems are hard. But even with limited resources, a handful of scientists are devoting their lives to the pursuit, because of what's at stake. Success will require research on a similar scale as the Manhattan Project, but government and industry won't be supporting it. The greatest hope is that private individuals will step forward and fund the research directly, or through organizations established for that purpose. Maybe an eccentric, farsighted billionaire will want a chance at not dying. Or maybe many people will contribute small amounts to make it happen. This is being done, to some extent, and it gives me hope.

Personally, I know I am not so different than other people. I also have a very difficult time accepting mortality. When I think about all who have and will be lost, and my own impending nonexistence, it makes me ill. It's entirely possible that the hope I have for a technological solution to aging and death is biased by my own aversion to the abyss. Being realistic, given our current rate of technological advance, although I'm hopeful that radical life extension will happen before I die, I think it's more likely that I'll just miss it. Either way, whether aging is cured within my lifetime or afterwards, it won't happen soon enough. Good people are suffering and dying, and that needs to change in a way that's never been done before.

The more people who set out to propagate this message with style and flair, the better all our chances become. Money is the root obstacle, a lack of funding for rejuvenation research based on the SENS vision that is well planned but moving slowly - but persuasion can move money to where it is needed. You just need enough of it.

Source:
http://www.fightaging.org/archives/2013/01/natural-death-we-should-be-worried-about-it.php

Over at In Search of Enlightenment you'll find an unpublished interview where the questions somewhat illustrate the point that most people don't look much beyond trivial matters when it comes to aging and longevity. Biotechnology like SENS and similar research projects are given no thought at all in most quarters, and even amongst advocates many favor the snail's pace path of trying to slow aging rather than working to repair its root causes to reverse it. This all means that there is much yet to accomplish in advocacy and education.

The field of research known as biogerontology, which studies the biology of aging, is a truly fascinating, though often misunderstood, area of scientific research. In 2011 the genome of the naked-mole rat was sequenced. This rodent is only the size of a mouse, and one might wonder what the significance of sequencing its genome could possibly be. But the naked-mole rate is the longest living rodent, it has a maximum lifespan exceeding 30 years and an exceptional resistance to cancer. Understanding the biology of this species could help unlock the mystery of healthy aging. A variety of experiments on fruit flies, mice and other species have demonstrated that the rate of aging can be manipulated, either by calorie restriction or by activating particular genes. Such research could eventually lead to the development of a drug that safely mimics the effects of caloric restriction (which delays the onset of disease) or actives the "longevity genes" that help protect against the diseases of late life.

The lion's share of funding for medical research is spent on disease research, such as research on cancer, heart disease or Alzheimer's disease. This approach, which I call "negative biology", assumes that the most important question to answer is "what causes disease?". Unfortunately this is a severely limited approach, especially for older populations. Even if you cured all 200+ forms of cancer (and we have not yet eliminated even just one cancer despite investing enormous sums of money for decades now), one of the other diseases of aging would quickly replace cancer as the leading cause of death because most people in late life are vulnerable to multiple diseases. So "positive biology" takes a different intellectual starting point. It assumes that the puzzles of exemplar health are just as important to understand as the development of disease. How can some (very rare) humans live over a century of disease-free life? Understanding these exemplar examples of health might prove to be more significant than trying to understand, treat and cure every specific disease of late life.

Link: http://colinfarrelly.blogspot.com/2012/12/readers-digest-interview-on-aging-and.html

Source:
http://www.fightaging.org/archives/2013/01/unpublished-readers-digest-interview-on-aging-and-longevity.php

Exercise correlates with all sorts of better measures of health, but there is some debate and conflicting evidence on whether more is better past the point of moderate regular exercise. This ties in to questions of causation - to what degree are endurance athletes drawn to their activities because they are already more robust than their peers, for example?

Telomeres are the molecular caps on chromosomes. They shorten with each successive cell division and are thus linked to aging. The shortening rate also varies among people. Shorter telomeres have been linked to increased disease risk as well as shortening of lifespan.

Chronic endurance training is at least modestly linked with long lifespan, though there are some controversies about whether it may increase the risk of some heart diseases. In the current study researchers sought to determine if chronic endurance training is associated with telomere length in older aged individuals. To perform the trial they measured the length of telomeres in four groups of individuals: young people and older people who did or did non engage in chronic endurance training. For the endurance training the researchers chose participation in a 58 km cross country ski competition.

They found that indeed the older people who were chronic endurance trainers had significantly longer telomeres than moderately active older controls. There was no difference in telomere length in the younger subjects whether they did endurance training or not. There was also an association in older people between VO2 max and telomere length.

Link: http://extremelongevity.net/2013/01/10/chronic-endurance-training-linked-to-longer-telomeres-in-older-adults/

Source:
http://www.fightaging.org/archives/2013/01/endurance-training-associated-with-longer-telomeres.php

Every few years research on the effects of deuterium on life span in lower animals surfaces, by way of exposing them to heavy water, D2O rather than H2O. The presence of deuterium rather than hydrogen results in an uptake of deuterium atoms into biological molecules, subtly and slightly changing their behavior. Too much of that and you fall over dead - the mechanisms of life do not have a high tolerance for such tinkering, and heavy water is effectively toxic. At lower levels, however, species such as flies and nematodes live longer as a result of exposure to deuterium. A few articles and papers were published back in 2007-2009, which together give a fair grounding as to where the science stands:

• Eat Isotopes to Live Longer
• Deuterium Again
• SENS4, Session 1, Combating Oxidation

Dr Shchepinov's theory is based on deuterium, a naturally-occurring isotope, or form of hydrogen, that strengthens the bonds in between and around the body's cells, making them less vulnerable to attack. He found that water enriched with deuterium, which is twice as heavy as normal hydrogen, extends the lifespan of worms by 10 per cent. And fruitflies fed the 'water of life' lived up to 30 per cent longer.

There is some skepticism and debate amongst various parties regarding the mechanisms by which deuterium uptake extends life span, but it's clear that exposure to heavy water at lower levels does in fact extend life in flies, worms, and so forth. Not too many people are working on this, so there is a lot of room for speculation and a lack of hard evidence that can rule out possibilities such as increased resistance to oxidative damage in important proteins. Given the evidence backing the membrane pacemaker theory of longevity, this is an attractive idea - there is plenty of support for the hypothesis that differences in the proteins that make up cell membranes are responsible for large differences in life span between various otherwise similar species. But robust evidence for the much smaller difference of a little extra deuterium substituted for hydrogen atoms - as opposed to completely different proteins - is lacking.

On this topic, I see that a new paper has arrived in the prepublication queue at Rejuvenation Research. It adds more data to the current thin stack on deuterium and fly life span:

Brief Early-Life Non-specific Incoporation of Deuterium Extends Mean Lifespan in Drosophila melanogaster Without Affecting Fecundity

We have investigated the effects of brief, non-specific deuteration of Drosophila melanogaster by including varying percentages of 2H (D) in the H2O used in the food mix consumed during initial development. Up to 22.5% D2O in H2O was administered, with the result that a low percentage of D2O in the water increased mean lifespan, while the highest percentage used (22.5%) reduced lifespan. After the one-time treatment period, adult flies were maintained ad libitum with food of normal isotopic distribution.

At low deuterium levels, where lifespan extension was observed, there was no observed change in fecundity. Dead flies were assayed for deuterium incorporation ... Isoleucine and leucine residues showed a small, linear dose-dependent incorporation of deuterium at non-exchangeable sites. Although high levels of D2O itself are toxic for other reasons, higher levels of deuterium incorporation, which can be achieved without toxicity by strategies that avoid direct use of D2O, are clearly worth exploring.

Hormesis is a possible (and disappointingly ordinary) explanation for this sort of result. Given the range of ways to make flies, worms, and rodents live longer by exposing them to adversity in early life, this almost seems like the first place to be looking. Perhaps lesser degrees of heavy water exposure, entirely separately from any deuterium uptake into proteins, have a hormetic effect, causing enough damage and disarray to spur repair mechanisms into greater efforts and leading to a net gain in life expectancy.

Well, either way, we shall hear more in future years. As the researchers point out above, you can conduct similar studies without the need for heavy water, and those should produce a more useful set of data.

Source:
http://www.fightaging.org/archives/2013/01/deuterium-and-lifespan-in-flies.php

Mitochondrial transcription factor A (TFAM) plays a number of important roles and shows up in connection with protofection research aimed at mitochondrial repair. Separately, researchers observe benefits by removing it from the fat tissue of mice:

Mutations in genes involved in the electron transport chain that cause mitochondrial dysfunction can sometimes paradoxically lead to improved health and/or enhanced longevity. One example is the situation in mice with conditional knockout of the mitochondrial transcription factor A (TFAM) specifically in fat. These F-TFKO mice exhibit mitochondrial dysfunction with increased energy expenditure, but are protected from age- and diet-induced obesity, insulin resistance and hepatosteatosis, despite increased food intake.

Mitochondrial DNA (mtDNA) is maternally inherited with multiple copies in each mitochondria. TFAM plays a critical role in maintenance and expression of mtDNA, and reductions of mtDNA copy number usually correlate with reduction of mitochondria content and function. So, how does a reduction in TFAM in fat have this beneficial effect?

Upon high fat diet, [the F-TFKO] mice develop a build-up of long chain acyl carnitines in both adipose tissue and the circulation. In addition, markers of oxidative stress are observed at the level of DNA and lipids in adipose tissue of F-TFKO mice on high fat diet, indicating overload of the ROS protection system. Despite this mitochondria stress, the mice remain lean and insulin sensitive even at 10 months of age. Although no formal aging studies have been conducted in these mice, we also noted that by 18 months of age, an age at which the control mice have started to die, the F-TFKO mice are still thriving, suggesting this knockout may be beneficial to aging mice as well.

Link: http://impactaging.com/papers/v4/n12/full/100518.html

Source:
http://www.fightaging.org/archives/2013/01/fat-tissue-knockout-of-mitochondrial-transcription-factor-a-is-beneficial-and-may-extend-life-in-mice.php

Regenerative medicine is not an all or nothing field of research. There are many useful waypoints on the road to being able to grow perfectly formed organs, blood vessels, muscle, and other tissues to order and from a patient's own cells. The partial results and half-way houses include a range of potential therapies and technologies that will be a great improvement over the present clinical state of the art.

Roadmaps in this sort of research tend to look like this:

• Gain knowledge of the underlying mechanisms: cell signaling, stem cell life cycles, and so forth.
• Use this new knowledge to better understand the workings of existing therapies, and perhaps optimize them a little.
• Produce new tools for diagnosis and testing procedures based on what is now known.
• Develop a helpful therapy that meets some fraction of the end goal: healing damage in an organ rather than growing a new organ; growing cells to populate a bioartificial system that carries out some of an organ's function, for use in dialysis for example; and so forth.
• Build poor versions of the end goal and find uses for them. The ability to grow small masses of tissue that can carry out some of the functions of a liver or a kidney may be very helpful as implants for those suffering organ failure, for example.
• Finally, the end goal: organs grown from a patient's cells that are good enough for transplant.

Below is an example of one type of waypoint in tissue engineering that is presently under widespread development: the use of cell transplants to spur regeneration and regrowth that would otherwise not have happened. This is a logical application of some of the knowledge gained regarding organ formation and growth; which cells are important, how they work together, and how they signal one another.

Stem cells found to heal damaged artery in lab study

[Scientists] have for the first time demonstrated that baboon embryonic stem cells can be programmed to completely restore a severely damaged artery. These early results show promise for eventually developing stem cell therapies to restore human tissues or organs damaged by age or disease.

Researchers completely removed the cells that line the inside surface from a segment of artery, and then put cells that had been derived from embryonic stem cells inside the artery. They then connected both ends of the arterial segment to plastic tubing inside a device called a bioreactor which is designed to grow cells and tissues. The scientists then pumped fluid through the artery under pressure as if blood were flowing through it. The outside of the artery was bathed in another fluid to sustain the cells located there.

Three days later, the complex structure of the inner surface was beginning to regenerate, and by 14 days, the inside of the artery had been perfectly restored to its complex natural state. It went from a non-functional tube to a complex fully functional artery. "Just think of what this kind of treatment would mean to a patient who had just suffered a heart attack as a consequence of a damaged coronary artery. And this is the real potential of stem cell regenerative medicine - that is, a treatment with stem cells that regenerates a damaged or destroyed tissue or organ."

Source:
http://www.fightaging.org/archives/2013/01/cells-derived-from-embryonic-stem-cells-rebuild-an-artery.php

I'd wager that the future of cell therapy probably won't involve much in the way of cell transplants, not even those created from the patient's own tissues. Instead it will be based on instructing existing cell populations in the body to take specific actions - progress here will proceed at a pace determined by how well researchers can catalog and understand the enormously complex networks of cell signaling that exists in every tissue type.

Even though there is a long way to go yet in creating that catalog, a range of possible therapies are already under investigation based on what is presently understood of controlling cell behavior. There is certainly no shortage of methods for changing the cell and its environment - only a shortage in knowing which of the million levers to pull and dials to set in order to achieve the desired result with minimal side-effects. Consider that a cell is a collection of machines built out of proteins, and the controlling mechanisms are driven by the presence and levels of yet more proteins: any technique that manipulates the level of a certain protein can be used to potentially good effect. So there is plain old gene therapy to make cells produce more of a protein encoded by a specific gene. There is RNA interference to block a specific protein. There are all sorts of other ways to tinker with how much of a specific protein is produced from the blueprint of a specific gene at a given time: gene expression is a process of many intricate stages, and the research community can presently accurately target most of them, provided the time is put in.

So all this said, we see technology demonstrations like the one noted below: no transplants, just instructing cells to do something different.

Gene therapy reprograms scar tissue in damaged hearts into healthy heart muscle

A cocktail of three specific genes can reprogram cells in the scars caused by heart attacks into functioning muscle cells, and the addition of a gene that stimulates the growth of blood vessels enhances that effect. "The idea of reprogramming scar tissue in the heart into functioning heart muscle was exciting. The theory is that if you have a big heart attack, your doctor can just inject these three genes into the scar tissue during surgery and change it back into heart muscle."

During a heart attack, blood supply is cut off to the heart, resulting in the death of heart muscle. The damage leaves behind a scar and a much weakened heart. Eventually, most people who have had serious heart attacks will develop heart failure.

Changing the scar into heart muscle would strengthen the heart. To accomplish this, during surgery, [researchers] transferred three forms of the vascular endothelial growth factor (VEGF) gene that enhances blood vessel growth or an inactive material (both attached to a gene vector) into the hearts of rats. Three weeks later, the rats received either Gata4, Mef 2c and Tbx5 (the cocktail of transcription factor genes called GMT) or an inactive material.

The GMT genes alone reduced the amount of scar tissue by half compared to animals that did not receive the genes, and there were more heart muscle cells in the animals that were treated with GMT. The hearts of animals that received GMT alone also worked better as defined by ejection fraction than those who had not received genes. [The] hearts of the animals that had received both the GMT and the VEGF gene transfers had an ejection fraction four times greater than that of the animals that had received only the GMT transfer.

There will be a lot more of this sort of thing going on in the years ahead.

Source:
http://www.fightaging.org/archives/2013/01/instructing-scar-tissue-to-change-itself-into-healthy-tissue.php