Fight Aging! Newsletter, February 22nd 2016

February 22nd 2016

Fight Aging! provides a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress towards the medical control of aging in order to prevent age-related frailty, suffering, and disease, as well as improvements in the present understanding of what works and what doesn't work when it comes to extending healthy life. Expect to see summaries of recent advances in medical research, news from the scientific community, advocacy and fundraising initiatives to help speed work on the repair and reversal of aging, links to online resources, and much more.

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  • An Interview with Gary Hudson of Oisin Biotechnologies, Senescent Cell Clearance Startup
  • Fight Aging! Invests in Oisin Biotechnologies
  • Oregon Cryonics, a New US Cryonics Provider
  • Engineering Arteries in Hours Rather than Weeks
  • An Interview with Researcher David Spiegel on the Development of Glucosepane Cross-Link Breakers
  • Latest Headlines from Fight Aging!
    • The Slow Upward Trend in Life Expectancy at 65 Continues
    • We Create Technology to Remove Suffering and Death
    • Anti-Myostatin Antibody Treatment Increases Muscle Mass and Strength in Mice
    • A Look at the Laron Syndrome Population
    • An Example of the Present State of Tissue Printing
    • Links Between Mammalian Hibernation and Longevity
    • DNA Methylation Changes with Aging in Younger Individuals
    • Older Measures of Age via DNA Methylation Correlate with Increased Risk of Cancer
    • A Stem Cell Treatment for Optic Neuritis
    • Cancer Found in Naked Mole-Rats


As an approach to treating aging, senescent cell clearance has come of age. Rapid progress in a number of strategies has taken place in the past couple of years, UNITY Biotechnology made their big splash announcement of intent a few weeks ago, and life extension has been robustly demonstrated in mice through the removal of senescent cells. It is a great time for SENS, the Strategies for Engineered Negligible Senescence, as this one important strand of rejuvenation research - supported and advocated for more than a decade - is now energetically moving into clinical development. This pulls in previously unavailable funding from the venture community and at the same time expands public awareness of the plausibility of treating aging as a medical condition.

Today's topic is another young senescent cell clearance company that I've been enthused about since early last year: the company is Oisin Biotechnologies, founded and initially self-funded by Gary Hudson and Matthew Scholz. The Oisin researchers have what is arguably the best of current approaches to senescent cell removal and are to my eyes closer to implementation in humans than is UNITY. The early Oisin prototype work was known to the SENS Research Foundation folk soon after they started - this is a small community - but the path to getting the company seed funding in 2014 from first the Methuselah Foundation and then a few months later by the SENS Research Foundation was driven by David Gobel of the Methuselah Foundation. That funding paid for a successful proof of concept demonstration in mice, and earlier this year a new round of fundraising took place to set in motion the next stage of clinical development. I'm pleased to say that Fight Aging! participated in that round, a small helping hand for this important development project. More on that tomorrow, but for now let me turn you over to Gary Hudson of Oisin Biotechnologies to explain how they are approaching the challenge of senescent cell clearance to produce a rejuvenation therapy:

Who is Oisin Biotechnologies, how did you meet and decide that this was going to be your next venture?

Oisin was founded by two individuals, Matthew Scholz, who came up with the basic scientific approach for our first technology, and myself, who provided the initial angel funds along with the Methuselah Foundation and later, the SENS Research Foundation. I'm serving as Acting CEO while the company is in virtual mode.

Matt and I met a few years ago at one of the Bay Area Health Extension Salon evening programs (created by Joe Betts-Lacroix of Mousera). Interestingly, the primary speaker that evening was an old friend of mine, Judy Campisi of the Buck Institute. Matthew was a kick-off speaker introducing his then-new gene therapy company Immusoft. Judy was talking about exciting work that had just been published out of the Mayo Clinic that showed profound benefits of removing senescent cells in transgenic mice. Coincidentally, a follow up to this original work just published in Nature last week showing that clearing senescent cells could substantially extend life in naturally aged mice.

After the talks, Matthew and I were musing about potential ways to kill senescent cells that could be viable in humans. (By this time Matthew had spent a great deal of time researching vectors for gene therapy and was working with a non-viral suicide gene developed at Baylor and already used in humans). Matthew said he thought we could use a particular liposomal vector he'd come across in the past with the suicide gene to kill senescent cells in humans. He said he was too busy with and committed to Immusoft to take on another project, and it was so different from Immusoft's technology that it would likely be a detrimental distraction to their work if he tried to pursue it there. But the more we talked about it, the more compelling it sounded. Finally, I just said, "This has to happen. If you write this up, I'll fund it myself. I'll be the CEO and raise the rest of the money we need to see if it works." So, we licensed the liposomal vector, filed the first patent and built our prototype.

You are clearing senescent cells; what is the approach you are using, and how far along is it?

Our approach is quite different from most other attempts to clear these cells. We have two components to our potential therapy. First, there is a gene sequence consisting of a promoter that is active in the cells we want to kill and a suicide gene that encodes a protein that triggers apoptosis. This gene sequence can be simple, like the one in the Baker paper that kills p16-expressing cells, or more complicated, for example, incorporating logic to make it more cell type specific. The second component is a unique liposomal vector that is capable of transporting our gene sequence into virtually any cell in the body. This vector is unique in that it both very efficient, and appears to be very safe even at extremely high doses.

There's a subtle but profound distinction between our approach and others. The targeting of the cells is done with the gene sequence, not the vector. The liposomal vector doesn't have any preference for senescent cells. It delivers the gene sequence to healthy and senescent cells. We don't target based on surface markers or other external phenotypic features. As Matthew likes to say "we kill cells based on what they are thinking, not based on surface markers." So if the promoter used in our gene sequence (say, p16) is active in any given cell at the time of treatment, the next part of our gene sequence - the suicide gene - will be transcribed and drive the cell to apoptosis. However, if p16 isn't active in a given cell, then nothing happens, and shortly afterwards the gene sequence we delivered would simply be degraded by the body. This behavior allows our therapy to be highly specific and importantly, transient. Since we don't use a virus to deliver our gene sequence, and our liposomal vector isn't immunogenic, our hope is that we should be able to use it multiple times in the same patient.

So far we have demonstrated that our vector and gene sequence can efficiently and selectively kill senescent human cells in culture, and that we can target senescent cells in vivo in mice treated with chemotherapy. The next step is to show that our approach can achieve senescent cell clearance along the lines of the work done at the Mayo Clinic, but in a translatable model - without the use of their transgenic INK-ATTAC mice. After all, we aren't transgenic mice. As exciting as their work is, the data in those papers is purely an academic exercise; the treatment they gave the mice would be of limited value in humans. Our hope is that we will have our first data from our next studies this year.

How does your approach differ from that of UNITY Biotechnology?

I don't have any first-hand knowledge of the activities underway at UNITY; you and I have probably read the same coverage of their efforts. It appears that they are focused primarily developing small molecule drugs to kill senescent cells. As I was describing earlier, we are taking a transient gene therapy approach. Put another - less conventional - way, we're effectively killing senescent cells with a genetic computer program that we upload with our liposomal vector.

The beauty of our approach compared against a small molecule is that, if we want or need to, we can very rapidly tailor our treatment to kill a specific kind of cell under a specific circumstance, or tailor it to avoid a specific kind of cell - all by just changing the gene sequence we deliver. What we really have is a platform that allows us to selectively kill cells based on very specific and customizable genetic criteria. That kind of flexibility just isn't possible with a small molecule drug.

You just raised a funding round, what is the plan for the next year or so?

As I mentioned, all of the elements of our approach are working well, so now it is time to combine the pieces and do the work required to turn a promising candidate into a life-changing therapeutic. We hope to conduct several in vivo studies in the near future to assess the impact of the treatment on senescence induced by various means. If time and money permit, we'll also begin to try to understand what dose ranges are optimal, how many treatments might be required to dramatically diminish senescent cell body burden, and so on. We'd also like to set up for a large lifespan study in mice and maybe other animals as well. We'll be looking to make alliances with pharma partners that are focused on particular FDA indications, such as COPD, BPH, and so on.

What is your take on the bigger picture of SENS and the goal of ending aging?

I've been interested in this topic since I was a teenager, right at the time we were doing real moonshots (not the Google equivalent). When people asked me what I wanted to do with my life, I routinely and only half jokingly replied - "fly to the stars and live forever" - borrowing a theme from the science-fiction writer James Blish. But I found that it was hopeless to expect progress on the aging front in 1969, so I turned my attention to space, and became one of the first commercial space entrepreneurs. After 45 years in that "space" I'm now ready to spend some time focusing on engineering a solution to the problems of aging.

I was also the first major contributor to the SENS project. I helped fund the first SENS conferences and also the Methuselah Mouse Prize. I believe in the basic SENS notion of treating aging as an engineering problem - repair, replace, and restore function and you will both increase healthspan and move towards escape velocity.

What do you see as the best approach to getting nascent SENS technologies like this one out into the clinic?

This is a complex question. Personally, I'm not too interested in the normal "pharma" path to the clinic. That's not to say that we (or more likely some future pharma partners) won't pursue this route, but the costs have to be weighed against the need to move therapies into public view, soon. So it's necessary to examine alternative routes to the clinic. One area that is slightly orthogonal to the traditional path is to work on veterinary and companion animal treatments before a human product. Working out our strategy is a significant part of my near-term job, with the other focus being the next major raise of funds in our Series A, sometime in 2016.

If this works stupendously well and everyone involved becomes wealthy, what next?

Essentially all of my ownership stake in Oisin will go into my nonprofit (to be announced shortly) and will be used to advance cutting edge translational medicine. But while I hope we make a profit for our investors' sake, my ambition in helping found Oisin has been to move the needle on true anti-senescence therapies. If we're successful, yes, we have a good chance to make money. But money is only important to me in that it'd allow us to move quickly onto the next aging-related problem, and that's what we'll do.

To the degree that Oisin succeeds, that success will channel funds into the Methuselah Foundation and SENS Research Foundation, as well as to a number of individuals who are already strong supporters of the longevity science cause. These are people who, like myself, are well aware that the only rational use for excess money is to fund the development of radical life extension technologies. What use is wealth to the sick and the dead? The true power of wealth in our day and age is that it can now be spent to build the technologies needed to defeat aging and illness. If only it was the case that more people realized this, we might be so much further ahead.


As I mentioned in yesterday's interview with Gary Hudson of Oisin Biotechnologies, I'm pleased to be able to say that Fight Aging! participated in the recent funding round for this senescent cell clearance startup. It was an unexpected opportunity to support this important line of SENS rejuvenation research, and will be my principle material contribution to the cause this year. From the point of view of where the money goes, there is actually little to no difference between investing in an early stage startup and making charitable donations to a laboratory group. In both cases the money buys research: lab time, reagents, mice, and the efforts of scientists. There is no rule that says a particular study has to be carried out before or after the point at which non-profit labwork transitions to for-profit labwork; where the work happens in the typical chronology of clinical translation is very much a matter of circumstance and the character of those involved. The closer things come to a working prototype, the more likely that someone will launch a company.

I consider it to be just as important to support the development of nascent SENS companies in their early stages as it is to fund the foundational work required prior to the point at which founding a startup becomes practical. An important part of the future of the rejuvenation biotechnology field is to create a virtuous cycle in which which an ecosystem of growing companies feeds new funding back into fundamental research. The ideal situation for such a company is the one for Oisin Biotechnologies, in which the people and organizations with the largest ownership stakes and the earliest investment are all SENS insiders who are going to pour any realized gains back into research in one way or another. As for all startups in biotechnology, these are long bets, and there must be many of them in order to catch the few that spark into lasting flame. Most will fail, leaving only their research results, and the ones that succeed may take five years or so to get to the point at which funds can meaningfully flow back to research.

Ah, but ... all it takes is one SENS startup to do well enough, and, provided it is run by the right people, it will sweep up and carry forward all of the rest of the SENS agenda. One thing to remember about SENS rejuvenation biotechnology is that it is very cheap in comparison to, say, traditional drug development. At this point finishing the SENS agenda to produce first generation therapies in mice capable of repairing all of the primary forms of cell and tissue damage that cause aging, say half a billion to a billion at this point, is much less than the cost of developing a single small molecule drug in the big pharma world, say two billion or so. A startup company in this field that made the transition to look something like a mid-sized pharmaceutical entity, with a market capitalization of billions, could probably finish up prototyping SENS on its own over a decade. It wouldn't be on its own, of course. If nothing else, the current clinical development of senescent cell clearance therapies, coupled with lifespan studies in mice, is going to wake up the world on the topic of rejuvenation. That is another good reason to support Oisin Biotechnologies.

At this point let me take a brief diversion into the evils of the US Securities and Exchange Commission (SEC). How is it that I knew about and had the chance to invest in Oisin Biotechnology and you didn't? Simply because I'm close enough to being an insider in this community to get an invite. The rules put in place on early stage investment essentially act to forbid what is called general solicitation: an early stage startup company can't simply advertise for investors. The founders can't reach out to the community at large. Raising a round cannot be public. The only only people normally allowed to invest in startups are those in the upper 5-10% of income or net worth, and the exceptions to that rule needed for seed and friends and family rounds, consisting of people of modest means like myself, to exist at all again require refraining from general solicitation. This is a great example of regulatory capture at work. The rules, ostensibly to protect people from themselves, as heaven forbid anyone actually be trusted to make their own assessments of risk in this world, are absolutely and definitely shaped over the years for far less altruistic reasons. The goal is to restrict the opportunity to invest in high-risk, high-reward early stage companies to established networks of professionals, to build barriers and keep out anyone not on the inside.

This is changing, however. The advent of Kickstarter and its competitors has meant that suddenly a whole range of companies could bypass the whole idea of early stage investment in favor of mass preordering as a source of early funding. That works really well for manufacturing and creative efforts with a fairly short time frame. It is obviously much less useful for biotechnology and medical development. The SEC, for reasons that may have to do with the basic bureaucratic urge to control everything, or the interest of various parties in building new opportunities for regulatory capture, has altered their rules on early stage funding to permit general solicitation in a crowdfunding like manner. Though of course, this being the SEC, it is legalistic, top-heavy, and people are still quite restricted in what they can invest. However, the basic point is that the investment process can be open and public, and in such a case anyone can invest. The new rules go into effect in the middle of 2016, and it remains to be seen how much of a mess or an opportunity it will be.

Mess or not, there is the potential to do something with this in our community. We are, modesty aside, pretty good at putting together and supporting modestly sized fundraisers for SENS research. If we can raise a quarter of a million in charitable donations for research, as happened last year, then I don't see it as beyond the pale that we could raise that much to crowdfund the founding of a future rejuvenation biotechnology company. Perhaps a glucosepane clearance venture, when that research gets to the point of a drug candidate, for example. Will this or something similar come to pass? Perhaps. It is at least possible, and as I pointed out above the funds still go to carrying out research. It is all a question of where that research is in the line of development from first spark through to clinical prototype.

So to finish up, what does this all mean for SENS charitable fundraising this year? Well, 2016 certainly promises to be as active as 2015 based on what I know is coming up already. The Major Mouse Testing Program will be running a crowdfunding effort in the months ahead, and I think at least one other SENS-relevant group may do the same. When it comes to this year's main SENS fundraising in the last quarter of the year, however, I can't lead in the same way as I've done in past years by putting money on the table and telling the world to match it - what might have been those funds went to Oisin Biotechnology and senescent cell research this year, an opportunity I could scarce turn down. Nonetheless, I believe we have plenty of time left in which to organize something interesting and useful, and I will still be the cheerleader to match the SENS Research Foundation's leadership when it comes to running the fundraiser. But let me put it to this audience: here is a bit of a gap, and all assistance in filling it will be greatly appreciated.


Cryonics is the low-temperature preservation of the recently deceased, with the aim of preserving the fine structure of the brain, and thus the data of the mind, for a future in which advanced technology will allow for a return to active life. The odds of success are unknown, but certainly infinitely greater than the zero odds offered by all of the present alternatives. Billions will die from old age before the earliest possible date on which the first complete set of robust rejuvenation therapies will become widespread. Are we really to write them off? I would like to think that we can do better than that - and hence the one viable chance offered by cryonics.

The non-profit cryonics industry, as opposed to the hobbyist endeavors that immediately preceded it, has existed for more than 40 years. Yet it has struggled to grow; over that time, only a few hundred people at most have been preserved. Only in recent years has the subject been treated with greater respect by the media and public, and bridges built with the cryobiology research community, who have long treated cryonics as an assault upon the integrity of their field. Now that reversible vitrification of organs is clearly plausible, and numerous groups are working towards that goal to improve the logistics of organ donation, transplantation, and tissue engineering, it is no longer possible to abitrarily declare that preserving the brain through the same methods is somehow fringe and outlandish.

Still, there are very few cryonics providers in the world, and only one outside the US, although this tiny, still largely non-profit industry also includes a surrounding halo of service and research companies such as Suspended Animation and 21st Century Medicine. These are as much involved in working towards the use of cryonics technologies in other areas of medicine as they are in improving the methodologies used to preserve patients at the end of life. The actual cryonics providers are simply listed: the long-standing US duopoly of the Alcor Life Extension Foundation and Cryonics Institute, and comparatively recent addition of KrioRus in Russia.

Given this, it is encouraging to see that a new group is launching another small US cryonics provider capable of long-term cryopreservation: Oregon Cryonics based in Salem. Their intent is clearly to compete on price with the established US non-profits, as their materials focus on preservation of the brain alone at a comparatively low price point. Assuming they have the technical resources to back up their efforts, and it is always important to carry out due diligence when paying for these sorts of services, then this strikes me as a positive evolution in the industry. More well-founded efforts, and a greater diversity of focus in those efforts, is very welcome. It is a little early for any meaningful public discussion in the cryonics community on the recent press for Oregon Cryonics, and the evolving contents of their web site, but it should be interesting to see what is thought of this approach.

As is usually the case, note that the local press coverage is terrible on the science and specific details. In particular, it is important to note that people are not frozen when cryopreserved, they are vitrified. There is a very big difference between these two things. After 40 years of practice, the operations and methodologies involved in carrying out a cryopreservation have become quite refined. It is also interesting to note that the Oregon Cryonics founder is another individual in the industry who favors the end goal of scanning and emulation of the mind in software rather than restoration of the original tissue, which will always seem to me to be a matter of engineering self-defeat at the final hurdle. A copy is not the self, and survival means survival of the specific package of matter that expresses the self, which means the brain must be restored.

Oregon Cryonics: 'The ultimate lottery ticket'

A Salem non-profit, Oregon Cryonics, is one of only four facilities around the world. The Salem location is run by Dr. Jordan Sparks. Cryonics is considered controversial, but Sparks says the hope is there. He envisions a future human or digital self in the next hundred years. "We can see a clear pathway from here to how somebody might be revived. If we don't do preservation, there's zero chance for survival," says Sparks. "We have electron micro-graphs showing good structured preservation and scientists around the world are currently mapping out neuroconnectors." He knows people are skeptical. "For some it's radical but so were the Wright brothers hanging out in the garage trying to invent flight. So until it happens, until people see it demonstrated, then it probably will remain controversial."

Frozen in time: Oregon firm preservex brains in hopes that science catches up

Until recently, there were only two cryonics facilities in the country freezing people or their brains, the Cryonics Institute in Detroit and Alcor Life Extension in Scottsdale, Ariz. Oregon Cryonics has signed up 10 clients to have either their bodies or their brains preserved and frozen after they die. Its operating model also has promised no small bit of controversy. The industry appears to be gradually gaining adherents, especially among young men who embrace technology. Sparks is a successful dentist and entrepreneur who says his startup is filling an industry niche -- lower-cost cryo for people willing to have just their brains preserved. He's banking on technology -- the idea that brain scanning will someday become sophisticated enough to map an entire brain and all its neural circuits. Then the brains that have been cryopreserved can be thawed, mapped and digitally downloaded. The people who once lived with those brains might live again, as software.

Phaedra and Aschwin de Wolf have opened a Northeast Portland lab called Advanced Neural Biosciences. There, among other things, they research the best methods for delivering cryoprotectant chemicals prior to freezing. Before moving to Portland, de Wolf worked for a Florida firm called Suspended Animation that provides services to cryonics companies. De Wolf also has signed up for full-body cryopreservation. He guesses that in 75 years technology will have reached a point where he can be brought back, with techniques to repair molecular damage that took place while he was frozen.

Fledgling Oregon Cryonics in Salem would seem to be a natural choice for the eventual preservation of Phaedra and de Wolf, since every minute counts in preserving the body after death if cellular decay is to be minimized. But both say they currently are committed to being preserved at Alcor in Arizona, and leaving open the possibility of switching over to Oregon Cryonics at some point. Both say they are concerned with the less than state-of-the-art preservation methods Oregon Cryonics has been willing to employ. In addition, de Wolf points out that in the past, cryo labs have shut down their operations and abandoned clients who were in cryo storage. The lesson there, de Wolf says, is that cryonics labs need to be well-established and accept only clients who can fully fund their treatment and preservation up front. "Some people say something is better than nothing, but I think that's not a good principle for cryonics," de Wolf says.

De Wolf's is not an uncommon position to take. Young companies are inherently risky, and in the case of cryonics the risk isn't just that you have to switch to use another product, but that you may indeed wind up in the grave and oblivion if the company goes out of business and can't negotiate a rescue with the rest of the industry. This is a challenge, but it is a challenge that every new entry in the field of medical services has to deal with. The way forward is to offer robust, reliable products and services, and to make use of independent certification agencies who can verify the claims made by the company and so offer customers peace of mind and assurance.


Today I'll point out a good example of a new and improved methodology in tissue engineering: model arteries created in hours rather than the previous standard of weeks. There is a lot going in in this field, and the ability to create tissues from the starting point of cells and raw biomaterials is improving in leaps and bounds from year to year. From the point of view of speeding up research, many of the most important advances in the life sciences relate to logistics, and thus go largely unheralded because they have no direct connection to clinical translation of research into therapies. Yet any new technique that dramatically reduces time or cost in materials means that all of the research groups using it can get more done at a given level of funding. Moreover, reductions in cost usually also mean that researchers who were previously stuck on the sidelines can now get involved, adding their efforts to moving the state of the art that much faster. At the large scale, and over the long term, science is built on a foundation of ever-better infrastructure, not leaps of ideation.

At the present time a lot of the most important advances in tissue engineering are logistical, somewhat distant from clinical applications. The first engineered tissues very similar to those in living individuals are not destined for therapies, but rather to be used to speed up testing and research. Living tissue sections can replace a lot of the use of animal models, and at a much lower cost. At some stages small amounts of engineered human tissue can be far better tools for research than animal models, especially where tissue can be produced from the cells of patients with specific diseases or genetic conditions.

Another reason for this focus on small tissue sections for research is that generating blood vessel networks sufficient to support larger solid tissue masses, such as whole organs, is not yet a robustly solved problem. Researchers are definitely making progress, especially with the use of bioprinters capable of generating scaffolds incorporating small-scale structures, but the practical upper size limit on engineered tissue is still too small to be building organs in their entirety. This is one of the reasons why a great deal of effort is going into decellulization as a transitional technology, the use of donor organs cleared of cells to create a scaffold with blood vessels already in place that can be repopulated with a recipient's cells.

Looking at the results linked below, I think you'll agree that this is an impressive piece of work, though still removed a way from the desired end goals of firstly producing patient-matched replacement blood vessels to order for transplantation, and secondly finding a way to create blood vessel networks to order inside engineered tissue as it grows.

Rapidly Building Arteries that Produce Biochemical Signals

Arterial walls have multiple layers of cells, including the endothelium and media. The endothelium is the innermost lining of all blood vessels that interacts with circulating blood. The media is made mostly of smooth muscle cells that help control the flow and pressure of the blood within. These two layers communicate through a suite of chemical signals that control how the vascular system reacts to stimuli such as drugs and exercise. In a new study, biomedical engineers successfully engineered artificial arteries containing both layers and demonstrated their ability to communicate and function normally. The blood vessels are also miniaturized to enable 3D microscale artificial organ platforms to test drugs for efficacy and side effects. The new technique may also enable researchers to conduct experiments on arterial replacements in record time.

"We wanted to focus on arteries because that's where most of the damage is caused in coronary diseases. Most previous studies had focused on the media cells but hadn't spent much time on the endothelial cells, and nobody had shown how the two would interact. Many of the techniques for creating artificial tissue also were rather lengthy, which was frustrating." The frustration came from the six-to-eight weeks it took to grow arteries in the laboratory. Turning to the literature, researchers found a paper detailing a much faster technique used to create a trachea. The method works by putting cells of the desired tissue inside collagen and compressing for a few minutes. This both squeezes out excess water and increases the mechanical strength of the resulting tissue. For the next six months, researchers worked to convert the technique so they could create arteries. And not just any arteries - arteries scaled down to one tenth the size of a typical human's, which made the translation even trickier. "With a smaller diameter, we could make a lot of these artificial vessels in a short amount of time. We can make these vessels and use them in only a few hours. To me that was the biggest advance, because spending several weeks on each set was driving me crazy. While our arteries are small and intended for testing, they're just as mechanically strong as those intended to be put inside of the body. So the technique could be beneficial to researchers trying to create artificial arteries to replace damaged ones in patients as well."

Human Vascular Microphysiological System for in vitro Drug Screening

In vitro human tissue engineered human blood vessels (TEBV) that exhibit vasoactivity can be used to test human toxicity of pharmaceutical drug candidates prior to pre-clinical animal studies. TEBVs were made by embedding human neonatal dermal fibroblasts (hNDFs) or human bone marrow-derived mesenchymal stem cells (hMSCs) in dense collagen gel. The TEBVs developed in this study had several novel features. They could be prepared with inner diameters of 500-800 μm and perfused in less than three hours. In contrast, other approaches to prepare TEBVs require 6-8 weeks in vitro culture before the mechanical strength is sufficient to enable perfusion.

After 1 week of perfusion, medial hNDFs or hMSCs expressed contractile proteins α-smooth muscle actin and calponin, indicating a switch to a contractile phenotype. TEBVs also produced the extracellular matrix proteins laminin, collagen IV, and fibronectin and exhibited burst pressures similar to human saphenous veins. Quantifiable and physiologically relevant reactions to vasoactive stimuli occurred after only 1 week. TEBVs released nitric oxide, elicited endothelium-independent vasoconstriction to phenylephrine and endothelium-dependent vasodilation in response to acetylcholine, and maintained these responses during 5 weeks of in vitro perfusion culture.


The Longecity community leadership runs a regular podcast series, interviewing notable advocates and researchers in the longevity science community. The latest podcast is a discussion with researcher David Spiegel at Yale on the topic of glucosepane cross-link breaking. His research group, funded in part by the SENS Research Foundation, is working towards the means to remove glucosepane cross-link accumulation as a contributing cause of aging. Loss of tissue elasticity lies at the root of arterial stiffening, hypertension, and cardiovascular disease, for example, but this is only one of many problems caused by the growing numbers of persistent cross-links in old tissues. You can look back in the Fight Aging! archives for a long post from earlier this year that outlines the present state of research in this field, so I won't cover the same ground here, but rather skip straight to the podcast transcript:

Justin Loew: Welcome back to Longecity Now. Some of you have been following the SENS theory of aging for over a decade now, and might be wondering if there is any progress. The answer is "yes", as we learned from a podcast with Aubrey de Grey late last year. In that interview Aubrey mentioned the artificial synthesis of glucosepane had recently been achieved. This is important because glucosepane is suspected be a significant culprit in aging tissues. In this edition we hear from the head of the lab that artificially created glucosepane. For those of you who are dying to hear more of the technical details of aging interventions, this interview with David Spiegel should satisfy your curiosity.

David Spiegel: Hello! Great to be here.

Justin Loew: As a little background, how did you come to be interested in synthetic chemistry? Was it mostly scientific curiosity, or was it a determination to cure human diseases?

David Spiegel: So, it's funny, I often get asked this question. I was probably a six-year-old kid, asked in second grade what I thought I would be doing in the year 2000, at the time still 21 years away. I still have the document in which I wrote that I wanted to be a chemist in a drug company. And so, I have stayed pretty true to that vision for my life. I have always been fascinated by molecules, and the fact that simple chemical matter has profound changes on human beings. So chemistry was a natural outgrowth of that interest, and in particular the idea that I could rationally design drugs to do things that nobody else had thought a drug could do. So that has led to research interests in my lab, one of which is in the area of immunotherapeutics, new kinds of molecules that can manipulate the immune system, to do interesting and cool things there. Also, the idea that drugs, small molecules, can be useful in reversal of the aging process.

Justin Loew: Your synthetic chemistry lab made headlines last year for synthesizing glucosepane. Many listeners are familiar with the theory that glucosepane is possibly a significant contributer to the aging process, being an extracellular cross-linking molecule that stiffens tissues, but most less familiar with the reasons why it is so difficult to do anything about it. Why has science been so stymied in regards to this molecule, even though it has been known for decades.

David Spiegel: Yes, it is a good question. So, it is a very difficult molecule to make. Well, two issues: first it is very difficult molecule to make, but also it is actually a difficult molecule to isolate. So even though it is found in all of us, it is found in our tissues, our bones, trying to isolate it in a pure form from the human body is incredibly difficult. Only very small quantities are obtained, and the compounds isolated are actually mixtures of very similar stereoisomers, a kind of different versions of glucosepane that simply can't be separated. So from my perspective I thought it would be quite valuable to take on this challenge, and that is really one of the main areas of focus for my laboratory, which is making very difficult molecules using techniques in organic chemistry. So in my mind, this is something that believed in for a long time. For glucosepane, it is a perfect marriage of interesting chemistry and incredibly interesting biology. The biology here is hard, and people have had a hard time, as you said, studying glucosepane, and of course making it has proven an incredibly difficult challenge because of its complex and intricate chemical structure. So we've been very interested in making it, and now we're in the phase of seeing what we can do with it, particularly with the goal of breaking glucosepane, or developing agents that can break glucosepane, that we think can actually reverse the pathology associated with aging.

Justin Loew: And on that, to add to the pathology aging, do you have any idea on how big of a role glucosepane plays in the aging process?

David Spiegel: You know, there is certainly a lot of evidence indicating that glucosepane levels correlate with organ damage and diseases like diabetes, and there is an argument that in diabetes one of the hallmark features is a kind of accelerated aging of the tissues. Also in people who are simply older, in people greater than 65 years of age, it turns out that there is more glucosepane found in collage than there are enzyme-catalyzed cross-links, the cross-links that are actually supposed to be there are outnumbered by glucosepane. It is these very tissues that are involved in the disease of old age. So collagen-containing tissues include blood vessels, bones, joints, and what do we see in old age? We see cardiovascular disease, we see joint disease, we see renal disease, often. So there is a lot of correlative evidence that is backed by with reasonable mechanistic speculation about a causative role that glucosepane can play, that I think really does implicate it as a key factor in what we term the pathophysiology, the damage, the disease, the element of old age that is a disease.

Justin Loew: Now that you made the molecule, and are looking at breaking the molecule, do you have any estimate of how long it might be before there is an effective therapy that addresses glucosepane?

David Spiegel: That's a good question. I think that from the standpoint of basic research, we've already made some progress in identifying some potential strategies for breaking glucosepane. As you know, there is a significant regulatory challenge associated with bringing new therapeutics to market, and so if I had to estimate - well, this is a very high bar in terms of ... well it is an extraordinary challenge, just the idea of making therapeutics that can break a molecule is kind of an untested concept. But the progress we are making, and the surge of interest right now in protein and enzyme-based therapeutics in pharma, makes me speculate that it is possible we could have something that is therapeutically viable on the order of 10-20 years from now. That may not seem like a short time, but from a therapeutics perspective, I think it is within our kind of vision.

Justin Loew: Staying on that kind of thought there, that the breaking of glucosepane cross-links could be very important for aging research, some people think that cross-link breaking enzymes would be too big to reach the links that must be cut in collagen fibrils, and prefer small molecules. Other people think that small molecules would not be specific enough for the task, what do you think? What is your prefered strategy?

David Spiegel: That's another excellent question. I think that as a small molecule chemist, I would love nothing more than to develop a small molecule that could break glucosepane cross-links, and it is certainly something we've been thinking about for quite some time. I think it is actually a very difficult challenge for a small molecule to break a stable cross-link like glucosepane. Mechanistically speaking, in terms of the underlying chemistry, I think it's not clear how a small molecule would function. Now, on the enzyme side, or I should say on the protein side, I think it's possible to imagine low molecular weight enzymes that could be tissue-permeable to the extent that they actually do reach glucosepane cross-links. So my preferred strategy is a protein agent, but by all means I encourage anyone out there listening, and I'm also encouraging people in my own lab group, that small molecule strategies should not be abandoned. I think that both strategies are viable, but the one I see succeeding on the shortest time frame is probably an enzyme.

Justin Loew: Other work in your lab has revolved around using synthetic molecules to detect cancer, and encourage the immune system to attack. Do you think antibodies could be brought to bear against glucosepane?

David Spiegel: Absolutely, and I should say our lab is in the process, and we're making great strides towards identifying the first selective anti-glucosepane antibodies with just that goal in mind. One can imagine an antibody that can bind to glucosepane, and have attached to it some kind of catalyst that would enhance the breakdown of glucosepane. One could also imagine an antibody that is useful for the diagnosis, the detection of glucosepane cross-links in tissue, and so I think that antibody strategies are really high on the list.

Justin Loew: A lot people who would like to help out in this type of research but don't have the expertise use crowdsourced computing efforts such as folding@home. Could the search for a glucosepane breaker be helped by this type of work?

David Spiegel: Absolutely, and in fact we've certainly discussed those efforts. We have collaborators who have started work along those lines for computationally modelling the role of glucosepane in collagen cross-links, and with that information in hand, it really could be possible to develop a kind of hypothetical mechanistic strategy. When I say mechanistic I mean how would a molecule work, what would the chemistry have to look like for an antibody, a small molecule, some other kind of therapeutic modality, to break down glucosepane. It does have a very unique and suprisingly stable chemical structure. In fact, breaking down glucosepane is more than just causing it to degrade. One would also need to cleave the molecule in such a way as to separate the lysine and arginine strands that are being cross-linked by glucosepane, such as to restore the mobility and flexibility in the tissues that are being cross-linked.

Justin Loew: Then for the do-it-yourselfers who might be into synthetic chemistry, or for the other labs who might be listening in, is the molecule you synthesized patented? Is your university licensing the process or the molecule?

David Spiegel: Yes, so it is patented. We are in discussions surrounding licensing the molecule. We are also providing the molecule to the community for basically the cost it takes for us to make it. We want to encourage efforts of all kinds to find glucosepane breakers, so making it commercially available and developing collaborations with other laboratories are all very high on our priority list. For the do-it-yourselfers out there who are interested, feel free to contact me, and we can certainly make an arrangement where our lab will provide glucosepane for research purposes.

Justin Loew: They should just look online for the Spiegel Research Group at Yale University, and they'll be able to contact you or a member of your lab?

David Spiegel: Correct.

Justin Loew: Great! And lastly here, what other research is underway in your lab currently, something people should be keeping an eye out for?

David Spiegel: We have a number of research programs devoted to aging and age-related cross-links. I should also point out that we have been very grateful to the SENS Research Foundation for funding our work - Aubrey de Grey, William Bains, Michael Kope, and others at the organization have just been incredible in terms of the vision for funding this. This is fairly high risk research. We have antibodies, we are developing reagents for detecting a wide variety of advanced glycation end-products, all of which we believe are involved in the aging process. We also have a major effort, and as I mentioned before, in the development of new immunotherapies. So we're using small molecules that we designed to seek out various kinds disease-causing cells, organisms, proteins, for detection by the immune system. So we can actually make molecules that can alert the immune system to the presence of disease-causing factors that the immune system might have missed. So there is obvious therapeutic potential there, not only in aging, but also in cancer, infectious disease, autoimmune disease, and a whole range of other conditions as well.

Justin Loew: Well, that does sound very promising. We'll all look forward to future research publications from your lab. Dr. Spiegel, thank you for joining me.

David Spiegel: Thank you! Great to be a guest.

Justin Loew: It is refreshing to hear of the collaboration between SENS and the Spiegel research group. It seems that SENS has achieved good results from this investment. The problem is that the money is running out. Dr. Spiegel informed me that funding at his university is drying up, and Aubrey de Grey mentioned the same thing late last year in regard to SENS. This means that your support for rejuvenation research is even more crucial this year, as the world economy slows down. As a non-profit that advocates for life extension and provides funding for small-scale research, Longecity has the power to help out. Please consider joining us as a member, and watch for Longecity-approved fundraisers through 2016. Until next time.

As ever, progress in the field of rejuvenation research is constrained far more by lack of funding than by the difficulty of the challenges involved. The challenge in bootstrapping a movement is always the leap from funding source to funding source, the need to raise enough to get things done, and then build on that progress to attract the next source of revenue. Collectively we have achieved great success in the past fifteen years, going from no investment in SENS to tens of millions devoted to this field. That, of course, is just a set up for the latest leaps in search of more funding, enough to carry out the work that remains to be done. It is amazing the degree to which persuasion is required to get people to help in saving their own lives in the future, but that is the nature of the world we live in.


Monday, February 15, 2016

Remaining life expectancy for older people, such as at 65, has been increasing slowly for a long time. The smoothed rate is in the vicinity of one year of additional life expectancy gained for every passing decade, though as recent data shows the year to year changes in the statistical measure of life expectancy are more variable. This upward trend is most likely the result of some combination of increased wealth, which allows for greater use of medical technology among other things, and improvements in the quality of medical technology to treat age-related disease. Therapies and outcomes for heart disease have improved greatly over the past twenty years, for example.

It is still the case that all of this additional life is something of an incidental side-effect, however: the clinical community isn't yet deliberately targeting and treating the forms of cell and tissue damage that cause aging. Treatments are instead patching the consequences. While the patches are getting better, for so long as they fail to address the root causes of disease and degeneration, the benefits will always be limited. When efforts to repair the damage that causes aging start in earnest, when for example it is possible for the average person to buy a senescent cell clearance therapy a few years from now, then expect to see the life expectancy trend to leap upwards in comparison to the past.

Over the last 30 years there has been an upward trend in life expectancy at older ages in England. However, male life expectancy was lower in 2012 than 2011 at ages 85 and 95, and at ages 65 and 75 it was the same in both years. There were no further falls in 2013, and this flattening of the recent trend has not continued in 2014, which saw a rise in life expectancy once again.

For those aged 65, men can expect to live for another 19 years and women a further 21 years. Life expectancy among older age groups in England rose to its highest level in 2014 - with male life expectancy increasing by 0.3 years at age 65 and 0.2 years at ages 75, 85 and 95 since 2013. Female life expectancy increased by the same amounts at the same ages. In the past, statistics have tended to focus on life expectancy at birth but now that most deaths in England occur in people over the age of 80, patterns of mortality in older age groups are becoming more important.

In the EU as a whole there has been an overall upward trend in life expectancy at older ages. The charts show an upward trend for male and female life expectancy at ages 65, 75 and 85 for the EU as a whole and its largest countries, including the UK. There was a dip in life expectancy in 2012 for the EU and many of the largest EU countries. In the EU as a whole, male life expectancy at age 85 fell by 0.1 years between 2011 and 2012, and female life expectancy at age 85 fell by 0.2 years. In contrast, between 2012 and 2013, almost all countries in the EU had an increase in life expectancy. While some countries had particularly large increases in life expectancy at older ages between 2012 and 2013, the increases for the UK were small in comparison. The rise in the UK was smaller than the EU average rise in every age group except males aged 85, was smaller than similar sized countries such as France and Spain, but was greater than Germany.

Monday, February 15, 2016

Right from the outset, the spur for the creation of new technology was the desire to reduce the personal impact of suffering and death. In this I agree with author Stephen Cave that to a large degree the rise to civilization was driven by the day to day minutiae of the quest for immortality: don't starve, don't be cold, don't get injured, don't be conquered, cure sickness, heal wounds, preserve life and health in the moment so as to see another dawn. We're still building the medical aspects of that edifice one small brick at a time, most of the way through dealing with infectious disease, and now turning our view to aging. The agents of technological progress, the researchers and the developers, gnaw away at each of the myriad individual causes of pain and mortality, one at a time, sometimes getting rid of them entirely (smallpox, insufficient food production), sometimes merely reducing them a little (heart disease, cancer). The next group picks up the banner, and continues to try to further erode that cause of mortality and sickness.

Progress is accelerating. We can envisage numerous paths ahead that might lead to a defeat of degenerative aging before the end of this century. We may well begin the replacement of our evolved biology with much more efficient and resilient designed machinery, such as artificial immune systems and oxygen transport nanomachines. We may augment ourselves with new tissues, perhaps genetically improved, such as additional thymus organoids or extensions to the kidneys and liver. Alternatively we may remain in our present human form for a long time, and simply repair the damage that causes aging. All of these will be spurred by the desire to remove first mortality, then pain, and finally - when nothing else is left - inconvenience and frustrated desire. There is a hierarchy of needs, and we will follow it.

If death is inevitable, then all we can do is die and hope for the best. But perhaps we don't have to die. Many respectable scientists now believe that humans can overcome death and achieve immortality through the use of future technologies. But how will we do this? The first way we might achieve physical immortality is by conquering our biological limitations - we age, become diseased, and suffer trauma. Aging research, while woefully underfunded, has yielded positive results. In addition to biological strategies for eliminating death, there are a number of technological scenarios for immortality which utilize advanced brain scanning techniques, artificial intelligence, and robotics.

But why conquer death? Why is death bad? It is bad because it ends something which at its best is beautiful; bad because it puts an end to all our projects; bad because all the knowledge and wisdom of a person is lost at death; bad because of the harm it does to the living; bad because it causes people to be unconcerned about the future beyond their short lifespan; bad because it renders fully meaningful lives impossible; and bad because we know that if we had the choice, and if our lives were going well, we would choose to live on. That death is generally bad - especially for the physically, morally, and intellectually vigorous - is nearly self-evident.

Yes there are indeed fates worse than death and in some circumstances death may be welcomed. Nevertheless for most of us most of the time, death is one of the worst fates that can befall us. That is why we think that suicide and murder and starvation are tragic. That is why we cry at the funerals of those we love. Our lives are not our own if they can be taken from us without our consent. We are not truly free unless death is optional.

Tuesday, February 16, 2016

As an alternative to myostatin gene therapy, treatments that temporarily block the action of myostatin have potential as a therapy to build muscle mass and strength. This is of particular interest as a way to compensate for sarcopenia, the characteristic loss of muscle that accompanies aging, and the approach is already in human trials. It is quite likely that such alternatives to gene therapy will reach the clinic first in more regulated regions, if only because they are favored by researchers and regulators for translation of genetic studies into the clinic. There is a tendency to researchers to look for approaches that require ongoing treatment to maintain, a tendency for pharmaceutical companies to want treatments that require ongoing expenditure rather than a one-time payment, and a tendency for regulators to endlessly delay anything related to gene therapy. Given the relentless advance of CRISPR, however, reducing costs and spreading the capability for gene therapy to many new labs and clinics, this will be happening at the very same time that gene therapies are available via medical tourism, I'll wager.

Sarcopenia, or aging-associated muscle atrophy, increases the risk of falls and fractures and is associated with metabolic disease. Because skeletal muscle is a major contributor to glucose handling after a meal, sarcopenia has significant effects on whole-body glucose metabolism. Despite the high prevalence and potentially devastating consequences of sarcopenia, no effective therapies are available.

Here, we show that treatment of young and old mice with an anti-myostatin antibody (ATA 842) for 4 weeks increased muscle mass and muscle strength in both groups. Furthermore, ATA 842 treatment also increased insulin-stimulated whole body glucose metabolism in old mice, which could be attributed to increased insulin-stimulated skeletal muscle glucose uptake as measured by a hyperinsulinemic-euglycemic clamp. Taken together, these studies provide support for pharmacological inhibition of myostatin as a potential therapeutic approach for age-related sarcopenia and metabolic disease.

Tuesday, February 16, 2016

Laron syndrome is a form of dwarfism that occurs in a small human population all descended from a single mutant ancestor. It is of interest to aging researchers because the mutation is on the growth hormone receptor, analogous to that approach used to engineer the present record holder for mouse longevity, the growth hormone receptor knockout (GHRKO) lineage. These dwarf mice live 60-70% longer than their peers. However, as is the case for the differences in the long-term outcome of calorie restriction between mice and humans, there is no sign that Laron syndrome produces any meaningful lengthening of life. Human longevity has evolved to be much less plastic than that of short-lived mammals in response to circumstances and changes - such as those involving growth hormone - that affect insulin metabolism, and Laron syndrome is one of the illustrations of that point.

In the remote villages of Ecuador, 100 very small people may hold the key to a huge medical breakthrough. They all suffer from Laron Syndrome, an incredibly rare genetic disorder that stops them from growing taller than 4 feet but also seems to protect them against cancer and diabetes and maybe even heart disease and Alzheimer's. "There's only one patient that has died of cancer among all of the subjects. And that is fascinating," said Dr. Jaime Guevara-Aguirre, who has been studying the Laron population for 30 years.

The project has two goals: figuring out how to distill the anti-disease properties of Laron Syndrome into a medication that could be used to fight cancer, diabetes and other illnesses in the rest of the world, and getting treatment that could help young people with the syndrome grow to full size. "The complaint of these little people was, 'We're doing so much for you. What are science and the pharmaceutical companies, etc., doing for us?'" said Dr. Valter Longo, a longevity specialist.

Laron Syndrome was first identified in 1950 and there are only 350 people with it in the world, all descended from a single ancestor who introduced the mutated gene thousands of years ago. A third of them live in isolated communities in Ecuador, while others live in Spain. Unlike others with dwarfism, Laron patients don't lack growth hormone, but they have a defect in the receptor in the liver that is supposed to bind to the hormone and produce a substance called insulin-like growth factor 1. In Laron, there is no binding and no IGF-1 - and stunted growth as a result. But the absence of IGF-1 may also prevent the uncontrolled growth of cells that turn into cancer, and it creates extra sensitivity to insulin that serves as a shield against diabetes.

Longo duplicated Laron in lab rats. "The mice actually lived 50 percent longer and get a lot less diseases. It's very clear in the mice. Can it be true for people?'" His lab is testing drugs that would block IGF-1 in people, but the question is whether medicine will work as well as an actual mutation in humans. Longo said it will be at least a decade before they know the answer. Meanwhile, his team is also investigating its theory that Laron may be a defense against heart disease and Alzheimer's. Preliminary results show that at the very least, the little people don't have any higher risk of those conditions. The researchers say Laron patients tend to live just as long as their average-sized siblings.

Wednesday, February 17, 2016

Researchers here demonstrate the ability to print simpler tissues such as muscle and bone, using a novel approach to somewhat increase the size of the tissue that can be constructed and transplanted. Size is limited by the need to supply oxygen and nutrients to cells via a blood vessel network, and reliably producing that blood vessel network in printed tissue is still an open problem:

Scientists have printed ear, bone and muscle structures. When implanted in animals, the structures matured into functional tissue and developed a system of blood vessels. Most importantly, these early results indicate that the structures have the right size, strength and function for use in humans. "This novel tissue and organ printer is an important advance in our quest to make replacement tissue for patients. It can fabricate stable, human-scale tissue of any shape. With further development, this technology could potentially be used to print living tissue and organ structures for surgical implantation."

The system deposits both bio-degradable, plastic-like materials to form the tissue "shape" and water-based gels that contain the cells. In addition, a strong, temporary outer structure is formed. The printing process does not harm the cells. A major challenge of tissue engineering is ensuring that implanted structures live long enough to integrate with the body. The scientists addressed this in two ways. They optimized the water-based "ink" that holds the cells so that it promotes cell health and growth and they printed a lattice of micro-channels throughout the structures. These channels allow nutrients and oxygen from the body to diffuse into the structures and keep them live while they develop a system of blood vessels.

It has been previously shown that tissue structures without ready-made blood vessels must be smaller than 200 microns (0.007 inches) for cells to survive. In these studies, a baby-sized ear structure (1.5 inches) survived and showed signs of vascularization at one and two months after implantation. "Our results indicate that the bio-ink combination we used, combined with the micro-channels, provides the right environment to keep the cells alive and to support cell and tissue growth." Another advantage of the system is its ability to use data from CT and MRI scans to "tailor-make" tissue for patients. For a patient missing an ear, for example, the system could print a matching structure.

Wednesday, February 17, 2016

In this open access paper, researchers review what is known of the commonalities between the biochemistry of hibernation and variations in longevity between mammalian species:

Many mammals employ strategies of metabolic rate depression - entry into winter hibernation, summer aestivation, or daily torpor - to allow them to extend their survival chances under extreme environmental conditions. Hibernation is perhaps the best known phenomenon and has been observed in eight different groups of mammal. Prior to hibernation, metabolic re-programming is initiated that includes hyperphagia in the late summer /early autumn, which results in massive weight gain due to increased fat storage in white adipose tissue. Animals then typically go through a number of "test drop" events of short torpor bouts at reduced body temperatures that appear to induce metabolic re-programming. Subsequently animals can initiate prolonged periods of torpor (days to weeks) with up to 95-99% reduction of basal metabolic rate as compared to the nonhibernating state, body temperatures that can fall to near 0°C, and metabolism switched over to a main reliance on lipid as the primary metabolic fuel for all organs. In addition to regulating metabolic fuel storage to support hypometabolism, hibernators are also faced with increased cellular stress during their torpor bouts. The decrease in respiration and heart rate during torpor creates an environment that is vulnerable to hypoxia/ischemia damage, whereas animals are also susceptible to oxidative stress during interbout arousals when metabolic rate and oxygen consumption increases massively to rewarm the animal back to euthermic conditions. As such, hibernators are incredible models to study the mammalian metabolic plasticity and stress resistance.

While metabolic rate depression and stress resistance have been shown to be the fundamental mechanisms that are required to support hibernation, they are also two of the most common cellular processes that have been shown to directly influence aging. While research in the aging field to date has utilized impressive genetic models that have uncovered many fundamental mechanisms that regulate aging and longevity in a conserved manner, research in non-traditional models such as hibernators can provide new insights into how environmentally-induced metabolic adaptations could influence aging and longevity. Hibernators may provide an advantage over traditional aging models as they naturally induce a hypometabolic state that triggers regulatory responses in a number of cellular signaling pathways which produce a significant increase in maximum lifespan when genetically altered.

Understanding the mechanisms of the hibernation response is important from a comparative point of view, since the molecular mechanisms that regulate torpor-mediated metabolic depression are likely conserved across other similar adaptive stress responses such as anoxia and hypoxia tolerance. However, the uniqueness of hibernation as an adaptation in mammals provides potential applications for biomedicine. In addition to its potential importance in aging and longevity, hibernators are great research models for (1) natural organ preservation, as they experience minimal tissue damage while maintained at body temperature just above freezing, and (2) insulin resistance, as they undergo reversible periods of insulin resistance and obesity without the detrimental effects seen in diabetic patients.

Thursday, February 18, 2016

The measurement of changing patterns of DNA methylation is developing into a promising biomarker of aging. The study linked below provides confirming evidence to show that this approach works for a wide range of ages in humans, but can still be discerning over a fairly narrow age range, even at younger ages, those at which people are likely to first start using future rejuvenation treatments. DNA methylation is a form of epigenetic marker that alters protein production: decorations attached to DNA that change constantly in response to circumstances. Some of those circumstances involve the accumulating cell and tissue damage that causes aging, processes that are the same in every individual, and so we should expect to find characteristic changes in DNA methylation patterns that reflect the state of aging.

Biomarkers of aging of this sort are important as an independent measure of the degree to which a putative rejuvenation therapy is actually working, a test that can be carried out much more rapidly and cheaply than the only currently viable approach of life span studies. By "actually working" I mean not just clearing senescent cells, or breaking cross-links, or replacing stem cells, all of which are simple enough to verify in and of themselves given the technology to build the treatment in the first place, but that a successful implementation of such as therapy also has an impact on global measures that are (a) strongly associated with aging, and (b) sensitive enough to pick up a change in biological age corresponding to a few years of normal aging.

Chronological aging-associated changes in the human DNA methylome have been studied by multiple epigenome-wide association studies (EWASs). Certain CpG sites have been identified as aging-associated in multiple studies, and the majority of the sites identified in various studies show common features regarding location and direction of the methylation change. However, as a whole, the sets of aging-associated CpGs identified in different studies, even with similar tissues and age ranges, show only limited overlap. In this study, we further explore and characterize CpG sites that show close relationship between their DNA methylation level and chronological age during adulthood and which bear the relationship regardless of blood cell type heterogeneity.

In this study, with a multivariable regression model adjusted for cell type heterogeneity, we identified 1202 aging-associated CpG sites in whole blood in a population with an especially narrow age range (40 - 49 years). Repeatedly reported CpGs located in genes ELOVL2, FHL2, PENK and KLF14 were also identified. Regions with aging-associated hypermethylation were enriched regarding several gene ontology (GO) terms (especially in the cluster of developmental processes), whereas hypomethylated sites showed no enrichment. The genes with higher numbers of CpG hits were more often hypermethylated with advancing age. The comparison analysis revealed that of the 1202 CpGs identified in the present study, 987 were identified as differentially methylated also between nonagenarians and young adults in a previous study (the Vitality 90+ study), and importantly, the directions of changes were identical in the previous and in the present study.

Here we report that aging-associated DNA methylation changes can be identified in a middle-aged population with a narrow age range of 9 years. A great majority of these sites have been previously reported as aging-associated in a population aged 19 to 90 years. Aging-associated DNA methylation changes are not uniform, but occur due to different reasons, at different rates and directions in different parts of the genome and are not alike in all cell types. Thus, due to this diverse nature of aging-associated DNA methylation changes, all confounding factors should be accounted for in the analysis, in order to obtain comparable results. Our results support the notion that cell type heterogeneity should be adjusted for when analyzing tissues consisting of mixed cell types. Moreover, our results imply that considerable proportion of DNA methylation changes show clock-like behavior throughout adulthood.

Thursday, February 18, 2016

Patterns of DNA methylation, a type of epigenetic marker that regulates protein production, have been shown to change with age in fairly well defined ways. This provides the basis for a biomarker of aging, a way to quickly measure how physically aged an individual is, meaning how much age-related cell and tissue damage he or she has accumulated in comparison to peers of the same chronological age. A part of the process of validating this approach to measuring biological rather than chronological age is to compare age-related disease incidence over time in people with higher and lower measures of biological age:

Epigenetic age is a new way to measure your biological age. When your biological (epigenetic) age is older than your chronological age, you are at increased risk for getting and dying of cancer, reports a new study. And the bigger the difference between the two ages, the higher your risk of dying of cancer. "This could become a new early warning sign of cancer. The discrepancy between the two ages appears to be a promising tool that could be used to develop an early detection blood test for cancer. People who are healthy have a very small difference between their epigenetic/biological age and chronological age. People who develop cancer have a large difference and people who die from cancer have a difference even larger than that. Our evidence showed a clear trend."

A person's epigenetic age is calculated based on an algorithm measuring 71 blood DNA methylation markers that could be modified by a person's environment, including environmental chemicals, obesity, exercise and diet. This test is not commercially available but is currently being studied by academic researchers. In DNA methylation, a cluster of molecules attaches to a gene and makes the gene more or less receptive to biochemical signals from the body. The gene itself - your DNA code - does not change. This is the first study to link the discrepancy between epigenetic age and chronological age with both cancer development and cancer death using multiple blood samples collected over time. The multiple samples, which showed changing epigenetic age, allowed for more precise measurements of epigenetic age and its relationship to cancer risk. Other studies have looked at blood samples collected only at a single time point.

The study was a longitudinal design with multiple blood samples collected from 1999 to 2013. Scientists used 834 blood samples collected from 442 participants who were free of cancer at the time of the blood draw. For each one-year increase in the discrepancy between chronological and epigenetic ages, there was a 6 percent increased risk of getting cancer within three years and a 17 percent increased risk of cancer death within five years. Those who will develop cancer have an epigenetic age about six months older than their chronological age; those who will die of cancer are about 2.2 years older, the study found.

Friday, February 19, 2016

Some classes of first generation stem cell transplants are known to reduce inflammation, though the signaling mechanisms involved are still poorly understood. Nonetheless, this means that a range of conditions thought to have a strong inflammatory component to their pathology are potential targets for treatment. Here for example, a clinician has found that stem cell transplants produce benefits in some patients suffering from the blindness produced by optic neuritis, chronic inflammation of the optic nerve that can occur for reasons that are unclear in many cases:

Vanna Belton was in Washington in 2009 when, while stuck in traffic one day, she noticed the streetlights were blurry. Weeks later she had almost no vision and no explanation for why everything seemingly went dark. She was diagnosed with a sudden and perplexing case of optic neuritis, a general term meaning optic nerve inflammation. As Belton searched for alternatives, she found Dr. Jeffrey N. Weiss, who was enrolling blind patients in an unorthodox stem cell study. He wasn't affiliated with a university or government institute, but he was taking on all those who could afford the roughly 20,000 to pay for the study and injecting stems cells into their eyes in one of three ways -- around the retina, in the retina and directly into the optic nerve -- in hopes of restoring some people's sight. He made no promises.

In early 2014, she had the surgery. During the four-hour procedure, Weiss and a medical team extracted bone marrow from Belton's hip, separated her stem cells in a machine and then injected the cells in and around her right eye's retina and directly into her left eye's optic nerve. Weiss is not following the usual steps of clinical studies. Among other things, he didn't test his treatment theories first on lab animals or using computer models, or randomize his trials by using either stem cells or placebos in study participants. He didn't test the procedure for safety on a small group before moving to a larger trial. Weiss, who is board-certified in ophthalmology, said he didn't have the patience for academic research, which is strictly governed by internal review boards and requires fundraising. Without a long history of stem cell research and a current academic appointment, he said, he sought legitimacy for his work by registering the trial with NIH, which scientific journals require to publish promising results.

The NIH also requires researchers to gain approval and oversight from an ethics review panel. Universities and government agencies have their own panels; Weiss tapped the International Cellular Medicine Society, an independent group that promotes stem cell therapies. Weiss said that 60 percent of his 278 patients with macular degeneration, glaucoma and other diseases have regained some sight. While he can't explain how it works, he believes that will become clear eventually. "We didn't know how penicillin worked for many years, but it saved many lives in the meantime. It is hubris to think that something can't work until you understand how it does. ... It is more important what the patient sees, not what I see." Sitting on the front steps of her home a year and a half ago, Vanna Belton was startled and thrilled when her eyes focused on a car's license plate. Essentially blind for more than five years, she could read the numbers and letters. No one disputes that Belton now sees well enough to, for example, read the menus in a restaurant. She can navigate the streets without the white cane she once used.

Friday, February 19, 2016

Naked mole-rats are very long-lived in comparison to near relative species, and have a great resistance to cancer - to the point at which researchers have not characterized and reported on any incidence of cancer in their laboratory colonies, now numbering thousands of individuals, and not for lack of searching. This is a far cry from similarly-sized rodent species, all of which have a very high rate of cancer. There has been considerable interest in the research community in recent years in identifying the underlying mechanisms of cancer resistance in naked mole-rats, with an eye to seeing whether or not they can form the basis for human therapies or enhancements.

Here researchers finally manage to find unambiguous incidence of cancer in naked mole-rats, which will hopefully go some way towards better understanding the mechanisms involved in the suppression of cancer in this species. Reading between the lines, I suspect that these researchers think that cancer incidence in naked mole-rats is very low but not as low as is presently implied in the literature, and there is perhaps a lack of rigor in this area of reporting. In any case, "highly resistant" is not the same thing as "immune":

In recent years, the use of naked mole-rats (NMRs) as animal models in aging and cancer research has increased as a result of their demonstrated extreme longevity and apparent resistance to cancer. We previously surveyed spontaneous histologic lesions in a zoo-housed NMR colony over a 10-year period, which revealed several age-related diseases and uncommon pre-cancerous lesions, consistent with their reported cancer resistance. However, overt cancer has not been formally documented in NMRs from either zoos or biomedical research facilities. Herein, we describe cancer in 2 NMRs and relate this to our previous findings of proliferative and pre-cancerous lesions found in additional zoo-housed NMRs with a brief discussion of diagnostic criteria of rodent neoplasia in a laboratory setting.

In Case No. 1, we observed a subcutaneous mass in the axillary region of a 22-year-old male NMR, with histologic, immunohistochemical (pancytokeratin positive, rare p63 immunolabeling, and smooth muscle actin negative), and ultrastructural characteristics of an adenocarcinoma possibly of mammary or salivary origin. In Case No. 2, we observed a densely cellular, poorly demarcated gastric mass of polygonal cells arranged in nests with positive immunolabeling for synaptophysin and chromogranin indicative of a neuroendocrine carcinoma in an approximately 20-year-old male NMR. We also include a brief discussion of other proliferative growths and pre-cancerous lesions diagnosed in a zoo colony. Although these case reports do not alter the longstanding observation of cancer resistance, they do raise questions about the scope of cancer resistance and the interpretation of biomedical studies in this model. These reports also highlight the benefit of long-term disease investigations in zoo-housed populations to better understand naturally occurring disease processes in species used as models in biomedical research.


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