Fight Aging! Newsletter, September 19th 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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  • Aubrey de Grey and Matthew O'Connor of the SENS Research Foundation Answer Questions on Mitochondrial Research at /r/futurology
  • The Inevitability of the Transhumanist Vision
  • Methuselah Foundation on Organovo's Progress in Kidney Tissue Models
  • A Visual Introduction to SENS Rejuvenation Research
  • Stroke Patients Tend to be Biologically Older, as Measured by DNA Methylation
  • Latest Headlines from Fight Aging!
    • A Profile of Kelsey Moody and Ichor Therapeutics
    • Mitochondrial DNA and the Longevity of Birds
    • More Evidence of a Role for Transposons in Aging
    • Signs that Earlier Physical Prowess has a Longevity Cost in Humans
    • The War on Aging
    • Working to Characterize the Epigenetics of Cellular Senescence
    • Surveying Views on Enhancement Technologies, such as Longevity Therapies
    • Lower Protein Synthesis Rates in Long-Lived Nematode Worms
    • Cold Plasma Claimed to Spur Wound Healing
    • A Measure of Just How Beneficial Clearing Cross-Links Might be for the Old

Aubrey de Grey and Matthew O'Connor of the SENS Research Foundation Answer Questions on Mitochondrial Research at /r/futurology

Aubrey de Grey, who should need little introduction here, is cofounder of the SENS Research Foundation, while Matthew O'Connor leads the foundation's in-house research efforts. O'Connor's focus is on the allotopic expression of mitochondrial genes, the complicated form of gene therapy needed to copy versions of these genes from the vulnerable mitochondrial genome into the much more secure nuclear genome, but altered in such a way that the resulting proteins can find their way back to the mitochondria where they are needed. Earlier today de Grey and O'Connor stopped by /r/futurology at Reddit to answer questions on this and other SENS rejuvenation research initiatives. One of the many benefits brought by this modern age of near zero cost communication is the way in which the barrier between researchers, supporters, and the public at large has faded to the point of non-existence. Any interested party can in a few minutes find out who is working in any specific areas of interest and reach out with questions or offers of support. Any researcher can find out where the interested parties congregate to talk about their research and join in. That was science fiction just a few decades ago. The world moves at a fast pace.

Once allotopic expression of the thirteen crucial mitochondrial genes involved in oxidative phosphorylation is realized, undergoing this gene therapy will ensure that the accumulation of mitochondrial DNA damage that occurs over the years no longer contributes to degenerative aging as it does today. It will be an actual, working narrowly focused rejuvenation therapy. As an incidental benefit, this technology will also provide cures for a range of inherited mitochondrial diseases. This work has been underway both at the SENS Research Foundation and in allied labs for some years now, and the biotech company Gensight has been founded on success in allotopic expression of the gene ND4. The SENS Research Foundation in-house team recently achieved success for the mitochondrial genes ATP6 and ATP8, and had a paper accepted by a noted journal, which all in all is a great step forward in a field that has proven to be quite challenging. I've pulled out some of the questions and answers from the AMA for posterity:

Aubrey de Grey and Matthew O'Connor AMA!

What is the updated timeline for when a MitoSENS-based therapy could be available for humans, and what would be its impact?

I think we're still several years away, which means any prediction of a timeline is pure speculation - but it's definitely accelerating.

For those that want to be alive when SENS 1.0 is here, what else can we do besides caloric restriction? Brisk walking?

Raise money for SENS Research Foundation! Seriously. The difference you can make to your own chances by hastening the arrival of SENS far exceeds what you can do with lifestyle etc. The less wealthy you are, the more people you probably know who are wealthier than you are. So, sure, it'll be the money of the people you persuade, rather than your own money, but that doesn't change what I said. Everyone can make a difference if they put real effort into advocacy.

Could you please tell what will be the next stage of the MitoSENS project, are you going to try to reproduce mitochondrial gene relocation in animals?

Yes we want to take this into animals next and yes we are starting now. I don't have any results to share yet but we are in the very earliest stages of pre-mouse work now. We are working in mouse cells to make sure that we can get our process working in cells before we move into whole mice.

Are you guys considering or taking advantage of the power of deep learning to accelerate your research into aging?

We are definitely interested in this. Alex Zhavoronkov, one of our foremost associates, now runs a company named Insilico Medicine which is spearheading that approach.

Now we have great results how long do you think it will be before we can do the same with the other 11 genes and are these genes technically any more or less challenging than the two already done?

Yes, there is reason to believe that some of the other 11 will be harder than ATP8 and ATP6. In fact, ATP6 is itself much harder than ATP8 and our results with that aren't as strong as with ATP8. We have some technologies that we've tested already that seem to work a bit with the harder genes and we're layering on additional levels of mitochondrial targeting and import. The hard thing is how complicated it gets when we start combining multiple targeting strategies together and quantifying their affects. We are building a rigorous system so that we can test variables in a matrix and clearly determine what works and what doesn't.

How long do you think it will take before we can reverse surface level aging : hair loss, gray hair and wrinkles? Which of the 7 damages types do we need to solve to make it happen?

Wrinkles are mainly from crosslinking, an area that was pretty much stalled for 20 years until our breakthrough publication in Science last October; still a way to go but we're now making rapid progress. Hair loss and grey hair are mostly a cell loss problem, and rejuvenating the epidermal stem cell population (as well as melanocytes specifically) is something a lot of people are making good progress on; check out the work of Elaine Fuchs and Fiona Watt and Colin Jahoda especially. The main thing to keep in mind here on the science side is that the technologies needed to rejuvenate appearance and to rejuvenate internal organs are broadly the same. And on the broader picture, just as we don't care whether people give us money for selfish reasons or for humanitarian reasons just so long as they give it, we also appreciate that changing the zeitgeist of the longevity quest is inextricably linked with hastening the science.

How can grassroots activism most effectively be leveraged to hasten the defeat of aging?

The key thing is to tackle both feasibility and desirability together, which paradoxically means tackling them separately. People are scared to get their hopes up, and they dismiss the feasibility issue because they have already decided that success would be a bad idea, and at the same time they dismiss the desirability issue because they have already decided that the whole concept is a pipe dream. So, first force your interlocutor into understanding that that linkage is logically absurd and thus into addressing the two questions separately. Then, give them the best arguments.

What about mitochondrial diseases that are caused by point mutations in the mitochondrial DNA? Won't these misfolded proteins still being produced compete with the corrected proteins now being produced by your imported RNA?

This is a hard question. We don't really know how effectively our engineered genes will compete with existing mutant (or non-mutant for that matter) proteins. We and others have done some work on it, but the answers aren't satisfying for me yet. We are at the conceptual stages of designing a rigorous method of quantifying this. It is not clear that mutant proteins much exist in "normal" aging though, so it might be a non-issue for aging but a very important question for inherited mitochondrial disease. Recently a new mouse model has been developed that accumulates deletions at an accelerated rate. It is a "binary system" that allows the problem to be activated in a tissue-specific manner by crossing with specific other mice, so it's very versatile. I expect that it will be quite useful.

Robert K. Naviaux, mitochondrial expert, asserts that their dual (or even primary) function is as an exquisitely sensitive alarm system, triggering the 'cell danger response' to chemical or microbial threats. How does this sit with the understanding so far in the MitoSENS project?

I'm going to give a snap reply that our mitoSENS project might not help this kind of "homeostasis" problem, if that problem isn't caused by the loss of mitochondrially encoded genes. Mitochondrial are indeed complex organelles with much cross-talk with the rest of the cell so our philosophy is always that the underlying problem needs to be addressed. If the problem is in the nuclear genes then that's what needs to be fixed. If the problem is in the lysosome - resulting in reduced mitochondrial turnover - then we need to fix the lysosome rather than the mitochondria. It is often forgotten that mitochondria are constantly recycled even in non-dividing cells, and thus that the only damage they can possibly accumulate other than as a side-effect of something extramitochondrial is DNA damage, and only then if somehow mutant mitochondrial DNA is selected for. Historical aside: after Harman first suggested the role of mitochondria in aging in 1972, the only published reaction by anyone prominent was that Alex Comfort in 1976 rejected it on exactly this basis. He did not, of course, consider the bizarre possibility that mutant mitochondrial DNA could be selected for, which was only shown in 1993.

You've mentioned that SENS 1.0 therapies, when perfected, will add maybe around 30 years of healthy lifespan. Does that mean that it's impossible for them to work indefinitely long without needing any improvements? If so, why?

Yes, that's what it means. Here's an example that may explain it: crosslinking. Once we are able to break glucosepane, we'll be able to reduce crosslinking by a big factor - for sake of argument let's say 50% - but we won't be breaking any other crosslinks. Thus, eventually the total amount of crosslinking will return to old-age levels even if we blitz the glucosepane every year. So, we need to carry on with the introduction of therapies that hit the next most abundant link, and the next, etc.

Do you think we will see major steps and results in mice in the next 5 years?

Yess, there's a chance of that; I'd say in 6-8 years there's at least a 50% chance. And by "major" I mean robust mouse rejuvenation, i.e. seriously life-extending interventions that start in middle age. For first generation human therapies my current 50% prediction is 20-25 years. We might see human gene therapies in patients with mitochondria disease in much shorter periods of time. If these work the chances of it working on aging increase dramatically!

I want to ask about the potential for CRISPR to impact longevity research. Could CRISPR potentially do this? If so, is CRISPR accurate enough?

CRISPR is getting very, very error-free now, so I am sure it will be a big tool in implementing SENS. We have developed a way to use it in combination with a bacterial virus; our method allows the insertion of lots of DNA (even up to 100kb potentially) in one go, into a defined location on the chromosome, so we would aim to do all the aspects of SENS that require new genes that way - mitochondrial DNA backups of course, but also enzymes to degrade waste products, and suicide genes to eliminate death-resistant toxic cells. Increased accuracy means a lower probability that a given CRISPR construct will do a bad thing, which in turn means that we can introduce more constructs (whether all at the same time or over repeated administrations) while remaining at an acceptable risk of bad things, which in turn means we can hit more cells.

Is it ever too late to start studying microbiology? What are some things an aspiring longevity researcher should take into account before dedicating themselves to such a cause?

No, never too late - whether microbiology, molecular biology, or any other biology. The main thing to take into account when starting out is that you shouldn't specialise too soon, because aging affects the body at every level of organisation, hence to have the best insighhts you need a god grounding in every area of biology.

How old do you think the youngest person is today that will never have a chance to benefit from the coming longevity revolution?

I prefer to answer the converse question, how old is the oldest person who will benefit! I still think that person could be in their 60s, or even 70 now. Remember, though, that will be a person who would naturally live to 110 without SENS.

Since you began your public mission to now, has progression of our knowledge in the field of gerontology progress exceeded your expectations?

It's gone more slowly than I expected, but only because it has continued to be crippled by lack of funding. We're doing our best, but another digit on our pathetic 4M annual budget would probably treble our rate of progress.

It seems that recently there's been a bit more attention into anti-aging/gerentology research from mainstream research institutions. How has that affected the work you do at SENS?

It's huge that really respected people like Craig Venter and Peter Diamandis are in this now, as well as really respected companies like Google. It's making a lot of previously skeptical people take notice, and we are hopeful that it will soon translate into better funding - we really need that. As for variety of lines of thought, the more the better: the main problem SENS had in years past in gaining general expert acceptance was that too many experts had already become wedded to particular prior ideas.

Given that yeast cells don't have some of the seven classes of SENS damage to worry about, wouldn't it be easier to first create a line of yeast cells that can be kept indefinitely youthful? Or is this in fact more difficult than creating an indefinitely youthful multi-cellular organism as intra cellular damage can no longer be continually spread between daughter cells?

Much easier, yes, but that's exactly what makes it not informative for translation to the clinic. The second half of your question makes less sense though, because multicellular organisms that matter, i.e. complex ones, have plenty of long-lived non-dividing cells as well as dividing ones. Only simple ones like Hydra can combat aging in the way you describe.

Has Calico reached out to you and your team at all?

We reached out to Calico very energetically when they were getting going but they basically blew us off. We are dismayed that they are not taking advantage of our expertise. Maybe they will start to do so eventually.

Any plans to translate the research into a gene therapy for a specific inherited mitochondrial disease?

Well to get into the nitty gritty a little bit, there are exceedingly few patients who have been discovered to have mutations specific to ATP8, less than 5 that I know of. ATP6 has more, but still very few. The gene therapy advancement that needs to happen is to get gene therapy technology approved that can be used outside of the eye. Then it will be easier to get these individual mitochondrial gene therapies approved.

What increase in health and lifespan can we expect from solving just mitoSENS out of the seven SENS fields?

Maybe there will be synergistic health affects of applying more than one, but less than seven fundamental rejuvenations, but we won't know until we try. There is some evidence that just tampering with mitochondria can improve the health of old rodents.

Back at the outset of the SENS research programs, the estimated cost to prototype allotopic expression of all 13 oxidative phosphorylation mitochondrial genes in mice was ~150M and ten years. MitoSENS has had probably something like a 10-15M investment (very fuzzy number). What is your current thinking on remaining costs and time now that the project is 20-25% of the way towards a prototype?

We've spent a lot less than 10M on this project so far. Total from all groups working in the field must be much much more than 15M. I will get it working in mice for much less than 150M.

If I understand correctly, the CYB protein is about 50% larger than ATP6. After your "many failed attempts", do you now have an understanding of what is preventing its import into the mitochondria, and, if so, what can be done to work around it?

CYB is both bigger and thought to be more "hydrophobic" than other mitochrondial proteins. I really like working on CYB though for two reasons: One is that I think that once we solve CYB we will have solved all 13 genes. The other is that CYB is the only mitochondrially encoded subunit of OxPhos complex III, which makes it a very simple system to study. We have cells that are null for CYB (similar to, but more simple than the cells that we used in the current publication) so we have a great system to test our innovations in.

Do you think that allotopically expressing ATP6 and ATP8 could have a measurable life extension effect in mice? Or it's more probable that all 13 genes must be allotopically expresed in order to see some improvement?

I think we would need to do all 13 to get some health affect in normal wild type animals, but there might be some tricks we can use to get it to work on some mutant mouse models.

With the advent of CRISPR, would it make more sense now than it did previously to code the cell to make catalase and target it to regularly be delivered to the mitochondria?

Catalase (and other anti-oxidants) can prevent some damage, but not reverse it. I'm more excited about the current generation of mitochondrially-targeted drugs that can act as anti-oxidants and/or mitochondrial activity boosters (in various ways). I'm betting that these next generation drugs will be even more effective than "natural" methods of preventing mitochondrial damage transgenically and we know that they will be easier to get approved by the FDA.

The Inevitability of the Transhumanist Vision

The article I'll point out today opens by distinguishing capitalized Transhumanism from lower case transhumanism. These are visions of the future grown in that fertile square of ground whose corners are marked by contemporary science fiction, the cutting edge of engineering, the cutting edge of science, and the entrepreneurial community. The real entrepreneurial community, I mean, the people who quietly get things done, not the loud internet-focused groups that you tend to read about in the media. Transhumanism with a small t is a simple description of what we will achieve with technology: we will transform ourselves and surpass all present limits upon the human condition. We will eliminate pain and suffering from the world. We will become enormously powerful and knowledgeable. We will live in perfect health, if not forever, then certainly for a very, very long time. This is inevitable, a flowering that will continue a long-running exponential trend in technology, the limits of which are still far distant from where we stand today. Transhumanism with a capital T is a movement, initially to forge, discuss, and spread the concepts of transhumanism, but more the case nowadays to work on implementing the first of the necessary technologies. Being a movement, Transhumanism will fade as it succeeds. There are no such things as tableists when there is a table in every room, after all.

Still, you can't wander far in the biotechnology, space development, and artificial intelligence communities without bumping into a Transhumanist, and that is without even mentioning the fields of rejuvenation research or cryonics. Or, as is increasing likely today, you'll bump into someone who expects much the same future and makes much the same arguments about technology and its uses, but who wouldn't consider himself or herself a Transhumanist. That is what I mean when I say that the movement fades to the degree that it succeeds. The ideas hammered out by a small number of people in the 1980s and 1990s have now more or less become the mainstream of serious thought about the future. An important lesson here is that you might be absolutely and completely correct, but if you are saying something that differs from the current mainstream, it will still take twenty years for people to come around to your way of looking at the world. Another lesson is that you should pay attention to science fiction writers; they are usually at least as far ahead as the better scientists when it comes to interpreting science and exploring possible consequences, and typically considerably better at organizing their message.

As we enter the era in which rejuvenation biotechnology is slowly becoming a reality, it is worth recalling the debt we owe to the people who propagated and expanded the concepts of radical life extension before the turn of the century, around the time at which the Usenet transitioned to the early web. We should also not forget those who carried out early projects and fundraising as well, a number of whom are no longer with us. I gained my introduction to transhumanism around that time, and I think unlikely I'd be quite as sensibly focused on the long game of an end to aging without that exposure to the energetic idea factories of the Extropy Institute, cryonics advocates, and related Usenet communities of the time. Outside those groups, there was all too little ambition, all too little vision, and all too little science among those who talked about intervention in aging. It is no coincidence that of the people involved in those transhumanist communities, many have gone on to found or become in involved in transformative efforts in a variety of fields. This a process still underway, and the companies, non-profits, and technologies grown from the seeds sown twenty years ago are still young, still in the process of becoming. What we are doing today is supporting and reinforcing work that is increasing known and appreciated, a far different activity from founding an entire field with ideas alone, but just as vital. Twenty years from now, several types of rejuvenation therapy will be available in the clinic, and some of will have seen that process through, end to end, getting old over the course of it. It is a golden age we live in, but what is to come is far brighter and more valuable yet.

The author under discussion in the article here, like many journalists, is clumsy with the science, but more pertinently looks too hard for balance. Better medicine at a lower cost is better medicine at a lower cost. Less suffering and death is less suffering and death. There is no downside. Yet all too many otherwise sensible people strive to find things to be gloomy about. Would you rather live with the medicine of today or the medicine of sixty years ago, when the research community was still struggling to treat heart disease and many dangerous infections in an effective way? This isn't a hard question to answer, but why do people struggle so greatly when presented with the idea of a world in which everyone simply suffers to a much lesser degree than they do today? If you want to see someone run a mile, show them a better life, or at least that is how it seems to me some days.

Transhumanism Is Inevitable

"Transhumanism is becoming more respectable, and transhumanism, with a small t, is rapidly emerging through conventional mainstream avenues," Eve Herold reports in her astute new book, Beyond Human. While big-T Transhumanism is the activist movement that advocates the use of technology to expand human capacities, small-t transhumanism is the belief or theory that the human race will evolve beyond its current physical and mental limitations, especially by means of deliberate technological interventions. "I began this book committed to exploring all the arguments, both for and against human enhancement. In the process I have found time and again that the bioconservative arguments are less than persuasive."

Herold opens with a tale of Victor Saurez, a man living a couple of centuries from now who at age 250 looks and feels like a 30-year-old. Back in dark ages of the 21st century, Victor was ideologically set against any newfangled technologies that would artificially extend his life. But after experiencing early onset heart failure, he agreed have a permanent artificial heart implanted because he wanted to know his grandchildren. Next, in order not to be a burden to his daughter, he decided to have vision chips installed in his eyes to correct blindness from macular degeneration. Eventually he agreed to smart guided nanoparticle treatments that reversed the aging process by correcting the relentlessly accumulating DNA errors that cause most physical and mental deterioration. Science fiction? For now.

The killer app of human enhancement is agelessness - halting and reversing the physical and mental debilities that befall us as we grow old. Herold focuses a great deal of attention on the development of nanobots that would patrol the body to repair and remove the damage caused as cellular machinery malfunctions over time. She believes that nanomedicine will first achieve success in the treatment of cancers and then move on to curing other diseases. "Then, if all goes well, we will enter the paradigm of maintaining health and youth for a very long time, possibly hundreds of years," she claims. Perhaps because research is moving so fast, Herold does not discuss how CRISPR genome-editing will enable future gerontologists to reprogram old cells into youthful ones. Herold effectively rebuts bioconservative arguments against the pursuit and adoption of human enhancement. One oft-heard concern is that longevity research will result in a nursing-home world where people live longer but increasingly debilitated lives. That's nonsense: The point of anti-aging research is not to let people be old longer, but to let them be young longer. Another argument holds that transhuman technologies will simply let the rich get richer. Herold notes that while the rich almost always get access to new technologies first, prices then come down quickly, making them available to nearly everyone eventually. She is confident that the same dynamic will apply to these therapies.

This Is What Immortality Looks Like

There's a day in the not-too-distant future when incorrigible smokers, having blackened their lungs beyond function, will have access to a shiny new artificial pair; when cancer patients will mobilize microscopic nanobots in their bloodstreams to eradicate disease; when diabetes will be nothing more than a bad memory on account of an effective blood-sugar management system. People who are alive today will be taking advantage of such medical developments. Meet Victor, the future of humanity. He's 250 years old but looks and feels 30. Having suffered from heart disease in his 50s and 60s, he now has an artificial heart that gives him the strength and vigor to run marathons. His type 2 diabetes was cured a century ago by the implantation of an artificial pancreas. He lost an arm in an accident, but no one would know that he has an artificial one that obeys his every thought and is far stronger than the original. He wears a contact lens that streams information about his body and the environment to his eye and can access the internet anytime he wants through voice commands. If it weren't for the computer chips that replaced the worn-out cells of his retina, he would have become blind countless years ago. Victor isn't just healthy and fit; he's much smarter than his forebears now that his brain has been enhanced through neural implants that expanded his memory, allow him to download knowledge, and even help him make decisions.

While 250 might seem like a ripe old age, Victor has little worry about dying because billions of tiny nanorobots patrol his entire body, repairing cells damaged by disease or aging, fixing DNA mistakes before they can cause any harm, and destroying cancer cells wherever they emerge. With all the advanced medical technologies Victor has been able to take advantage of, his life has not been a bed of roses. Many of his loved ones either didn't have access to or opted out of the life-extending technologies and have passed away. He has had several careers that successively became obsolete due to advancing technology and several marriages that ended in divorce after he and his partners drifted apart after 40 years or so. His first wife, Elaine, was the love of his life. When they met in college, both were part of a movement that rejected all "artificial" biomedical interventions and fought for the right of individuals to live, age, and die naturally. For several decades, they bonded over their mutual dedication to the cause of "natural" living and tried to raise their two children to have the same values.

Then, one day, Victor unexpectedly had a massive heart attack. Having a near-death experience shook him to the core. When Victor asked his cardiologist whether he would live to see his new grandchild born, the answer was, "Probably not." His cardiologist disapproved of his refusal to accept an artificial heart. Artificial hearts had completely replaced biological heart transplants because they could not be rejected by the body, were widely available, and were far more durable than biological hearts. Victor's life after the surgery was remarkable. He suddenly had more energy and mental clarity than he had enjoyed for 20 years. In fact, it was only then that he realized how terribly sick he had been. The fluid in his lungs and the swelling in his body completely disappeared, and he told Elaine that he felt like an entirely new man. His long-held ideology about aging and dying "naturally" suddenly seemed stubborn and irrational. He noticed that even though Elaine was relieved and grateful that he was still alive, she wasn't changing her mind about her own dedication to allowing the aging process to proceed without any drastic intervention. Elaine's death was the hardest thing Victor had ever had to face. She stuck by her decision to accept only palliative care, and within three months, she had passed away at home with their children and grandchildren around her. Her death was peaceful, but Victor was anything but at peace. His last days with Elaine were greatly complicated not only by grief but by an irreconcilable anger at her. He was unable to accept her decision to reject the nanotech cure that had already saved millions of lives.

Trying too hard, I feel. We already live bathed in the pathos of lost lives; deaths past, deaths to come, all crosses we must bear, and none of this by our choice. How, again, is less of that a bad thing? How is it so terrible for aging and death and health to in fact be choices, fully under our control?

Methuselah Foundation on Organovo's Progress in Kidney Tissue Models

Some years ago now, how time flies, the Methuselah Foundation funded the tissue engineering company Organovo when it was still in its earliest startup stages. That investment continues to do well, in all senses, as Organovo has gone on to build a range of technologies relating to bioprinting and growth of sections of functional tissue from cells. The folk at Organovo recently announced a new product for research and development initiatives based on manufacture of kidney tissue to order, and the Methuselah Foundation principals took the opportunity to point out to supporters just how far things have come. The funds invested in Organovo were provided by donors like you and I, given in the hopes that the Methuselah Foundation could put them to good use in advancing the state of the art. In this, as in many other areas, success has followed success. As other companies are funded by the Methuselah Foundation and SENS Research Foundation, such as Oisin Biotechnologies, we'll be seeing more of this sort of thing in the future.

To all our Supporters and Friends,

We have some exciting developments we want to share with all of you who have given your time and financial support! Methuselah Foundation's goal, from its beginning, has been to extend healthy human life. Our mission is to make 90 the new 50 by the year 2030. Your financial support continues to make it possible for the foundation to explore and implement science that is bringing our goal closer, both for our supporters, and for all the rest of humanity. Over eight years ago we had a shared vision with Organovo to create "New parts for People" - viable human tissue with the goal to create bioidentical human organs and 3D tissue to, among other things, alleviate the organ shortage plaguing the entire world. This shared vision motivated the Methuselah Foundation to provide the seed money that would allow Organovo to begin its work on this goal. It's worth noting that at the time we invested foundation funds into Organovo it was the most turbulent financial landscape this country had seen since the 1929 stock market crash, while the goals we were all pursuing were still considered next to impossible by most. Still, we saw the need to consider Return On Mission ahead of potential Return On Investment.

From the very beginning, we have been judiciously opportunistic in leveraging donated funds. The exciting news we want to share with you bears out what an effective strategy this is: this past week, Organovo announced it had created the world's first ever 3D architecturally correct human kidney tissue assays. Those in the scientific and medical fields can recognize the significance of this achievement, and we also want to talk to you about some of the amazing implications that this brings. (You can also read their press release).

According to the National Institutes of Health developing a new intervention or treatment currently takes about 14 years and can cost nearly 2 billion. Despite this effort, failure rates can still be as high as 95%. Some 30% may fail because they are toxic, despite promising pre-clinical trials. Another 60% that show promise in animal testing do not work on humans. This means years can go by before patients can receive any benefit from all this hard work. All that now has the potential to change. With the ability to create architecturally correct 3D human tissue, we can cut off as much as a decade of time and hundreds of millions, even billions in wasted drug development funding. The ability to test with viable human tissue is also making animal testing (already illegal in the EU) obsolete!

What else does this mean? It will mean that due to the greatly reduced costs, more drugs can be tested, faster and vastly more accurately - exponentially increasing the rate we find new and better SENS-relevant interventions and cures. Tantalizingly, there have been drugs in the past that were pulled from the shelves because, although they were effective for 99% of the population, a tiny number of people experienced adverse effects, resulting in such drugs being pulled from the market. Viable human tissue testing will allow companies to test for the genetic markers that react negatively to otherwise effective drugs and screen for them. This means access to many more drugs and treatments that can now be made available for those for whom the treatments are effective, and held back from those who would have adverse reactions.

There are yet many more exciting advances to come and you will find them outlined in greater detail at the Methuselah Foundation blog in upcoming posts. We will also update you in future emails and videos at our website to give the advances we are making. Remember, it is your support that has made this possible! You can show your continuing support for our work by donating, and please feel free to share this news with your friends and colleagues! We look forward to sharing the fruits of our future achievements together!

Sincere thanks to you all,

Methuselah Foundation

P.S. You might also read an interesting perspective on Organovo's achievement from one of the leading 3D printing blogs.

Organovo Announces Initiation of Commercial Contracting for ExVive Human Kidney Tissue

Organovo, a three-dimensional biology company focused on delivering scientific and medical breakthroughs using its 3D bioprinting technology, today announced that it has begun commercial contracting for its second tissue service, the ExVive Human Kidney. This kidney proximal tubule model is a natural expansion of the Company's preclinical product and service portfolio, allowing customers to study the effects of drug exposure on a key portion of the human kidney relevant to drug discovery and development.

The ExVive Human Kidney has demonstrated important functional aspects that offer significant value in preclinical testing, including: (1) Demonstrated proximal tubule function for more than four weeks, as measured by gamma-glutamyl transferase (GGT) production; (2) Tissue-like complexity that supports the detection of injury, compensation, and recovery; (3) Physiological expression of key transporters as measured by gene and protein expression, which allows for the assessment of kidney toxicity and drug:drug interactions by modeling normal tissue function; (4) Modulatable activity of key renal transporters P-gp, SGLT2, and OCT2, demonstrating a high correlation to difficult to replicate human biology; (5) Demonstrated toxicity of model kidney toxicant cisplatin, and inhibition of toxicity when blocking OCT2 function, demonstrating specific inhibition of cisplatin transport through a known transporter; and (6) Barrier function (permeability) comparable to in-vivo values, as measured by trans-epithelial electrical resistance (TEER).

Organovo launches second 3D bioprinted tissue service, the ExVive Human Kidney

ExVive Human Kidney, a 3D bioprinted proximal tubule model, will allow for clients and researchers to better study the effects that drugs and certain treatments have on the human kidney, effectively opening the doors for advanced drug discovery and development. So far, a number of commercial orders for the innovative product have already been placed with Organovo. According to a press release, the 3D bioprinting company is also already collaborating with a number of toxicology panels and transporter studies as part of an early access program for their new product. Organovo has made a name for itself within the 3D bioprinting industry for its innovative and disruptive bioprinted tissue services. Both the ExVive Human Kidney and Liver products offer the unique opportunity for pharmaceutical researchers to replicate complex cell-cell interactions and elements of tissue architecture to test and determine the effects of drugs on the organ. The company's 3D bioprinted tissues have opened the doors for more rapid and cost efficient drug discovery process.

A Visual Introduction to SENS Rejuvenation Research

The SENS Research Foundation has assembled a set of narrated cellular biochemistry animations that serve as an introduction to the various distinct projects that make up the field of rejuvenation biotechnology. The videos outline the forms of cell and tissue damage that are the root cause of aging and age-related disease, as well as the classes of therapy that could, once constructed, either repair that damage or bypass it entirely. Since aging is exactly an accumulation of damage and the consequences of that damage, repair of the damage is the basis for rejuvenation, the reversal and prevention of degenerative aging and all age-related disease. The goal for the near future is to align ever more of the research community and its funding institutions with this goal, and make real progress towards bringing an end to the pain, suffering, and disease of aging.

Introducing SENS - Metabolism, Damage, Pathology

Many things go wrong with aging bodies, but at the root of them all is the burden of decades of unrepaired damage to the cellular and molecular structures that make up the functional units of our tissues. As each essential microscopic structure fails, tissue function becomes progressively compromised - imperceptibly at first, but ending in the slide into the diseases and disabilities of aging. SENS Research Foundation's strategy to prevent and reverse age-related ill-health is to apply the principles of regenerative medicine to repair the damage of aging at the level where it occurs. We are developing a new kind of medicine: regenerative therapies that remove, repair, replace, or render harmless the cellular and molecular damage that has accumulated in our tissues with time. By reconstructing the structured order of the living machinery of our tissues, these rejuvenation biotechnologies will restore the normal functioning of the body's cells and essential biomolecules, returning aging tissues to health and bringing back the body's youthful vigor.

ApoptoSENS - Clearing Senescent Cells

Senescent cells began their existence skin cells, or as related cells that normally play supporting roles in other organs, but were forced into an abnormal state where they lost the ability to divide and reproduce themselves as a protective response to some danger. In addition to halting growth, senescent cells secrete abnormally large amounts of proteins that inflame the immune system and degrade the normal supporting tissue architecture. The relatively small number of such cells in a youthful tissue is so small as to be harmless, but after decades of accumulation, the number becomes large enough that their abnormal metabolic state begins to pose a threat to surrounding, healthy tissues. Larger numbers of senescent cells in a tissue make it more vulnerable to the spread of cancer, contribute to inflammation, and skew the local activity of the immune system.

The most straightforward approach to dealing with these cells is to destroy them. There are two main approaches that could be used to achieve this: (1) develop a drug that is toxic to the unwanted cells, or that makes them commit suicide, but that doesn't harm healthy, normal cells; or (2) stimulate the immune system to selectively seek out and kill the target cells. The most likely way to selectively target these abnormal cells would be to make use of the distinctive molecules that occur on their surfaces. Luckily, different cell types tend to have different things on their surfaces, which play particular parts in their specialized roles in the tissue, so it is a matter of identifying and targeting cell-surface markers that are specific to these abnormal cell types.

AmyloSENS - Dissolving the Plaques

The most well-known form of extracellular junk is beta-amyloid: the stifling, web-like material that forms plaques in the brains of patients with Alzheimer's disease, and also (more slowly) in everyone else's, and impairs cognitive function. There are also a variety of similar aggregates that form in other tissues during aging and contribute to age-related diseases, including islet amyloid in type 2 diabetes and senile cardiac amyloidosis, which is a major contributor to heart failure. In fact, there is some evidence that senile cardiac amyloidosis may be the main cause of death in people who survive beyond age 110.

Extracellular aggregates can be removed from the brain and other areas of the body by specialized antibodies that hone in specifically on them and remove them from the tissue. There two main ways to introduce these antibodies into a person: "active" and "passive" vaccines. "Active" vaccines introduce a small fragment of the amyloid to stimulate the cells of the immune system to target the amyloid and remove it. "Passive" vaccines involve making the antibodies outside of the body, and introducing them directly via injection. More recently, a third and extremely promising variation on this approach has been developed. Researchers have discovered that a subset of human antibodies have catalytic activity against a particular antigen, breaking it down into smaller and less harmful fragments instead of trapping it for removal or destruction by other immune cells.

GlycoSENS - Breaking Extracellular Crosslinks

Many of the major structural features of the body are built out of proteins that are laid down early in our life, and then more or less have to last for a lifetime. The healthy functioning of these tissues relies on these constituent proteins maintaining their proper structure. Such proteins are responsible for the elasticity of the artery wall, the transparency of the lens of the eye, and the high tensile strength of the ligaments, for example. But occasionally, blood sugar (and other molecules in the fluids in which these tissues are bathed) will react with these proteins, creating chemical bonds called crosslinks. Crosslinks act like molecular "handcuffs," taking two neighboring proteins that were previously able to move independently of one another and binding them together.. In the case of the artery wall, for instance, the crosslinking of strands of the protein collagen prevents them from spreading apart from one another to accommodate the surge of the pulse being driven forward by the pumping action of the heart. As more and more strands of collagen become crosslinked together over time, the blood vessels to become ever more rigid, leading to a gradual rise in systolic blood pressure with age. With the loss of the cushioning effect provided by free-moving collagen in the blood vessels, the force of the surge of blood that is driven into the arteries by the pumping action of the heart is carried directly to organs like the kidneys and the brain, damaging to the structures that filter our blood and that connect the functional regions of our brain, and putting us at risk of a stroke.

Fortunately, the crosslinks that occur as chemical accidents in our structural tissues have very unusual chemical structures, which are not found in proteins or other molecules that the body makes on purpose. This should make it possible to identify or design drugs that can react with the crosslinks and sever them, without breaking apart any essential structural bystanders. So the search is on now to develop new and more human-specific crosslink breakers. It's now known that the single greatest contributor to total unintentional collagen crosslinking in humans is a very complex molecule called glucosepane; therefore, drugs that cleave this molecule are likely to have the strongest rejuvenative effect on tissue elasticity.

RepleniSENS - Replacing Lost Tissues

Every day, our cells are damaged by both tiny molecular-level insults and by obvious trauma. Some of these damaged cells are repaired, but others are either destroyed, or forced into a dysfunctional 'senescent' state where they can no longer divide, or commit 'cellular suicide' (apoptosis) for the greater good of the body. Some of the lost cells are replaced by the pools of specialized, tissue-specific stem cells, but the degenerative aging process makes these stem cell pools less effective at repair over time. The net result is that over the course of many decades, long-lived tissues like your brain, heart, and skeletal muscles begin to progressively lose cells, and their function becomes increasingly compromised.

The solution to this problem involves the rejuvenation biotechnologies with which most people are most familiar: cell therapy and tissue engineering, the science of growing organs for transplant in an artificial, biodegradable scaffold outside the body. The foundations of this form of medicine lie in the transplantation of organs and tissues that we already use to replace the blood of chemotherapy patients or the kidneys of dialysis patients. In addition to replacing lost, dying, or dysfunctional cells, the ability to engineer new cells and tissues gives us an opportunity to use them as delivery systems for other rejuvenation biotechnologies.

LysoSENS - Reversing Heart Disease

The proteins and other constituents of our cells are all eventually damaged as the result of biochemical accidents that occur during normal metabolism, or simply outlive their usefulness. Cells have a variety of systems for breaking down and recycling such unwanted materials, allowing them to clear garbage out of the way and reuse the raw materials. One such system is the lysosome, a kind of cellular "incinerator" that contains the most powerful enzymes in the cell for breaking mangled molecules down into manageable pieces. However, sometimes these constituents are so badly fused together that not even the lysosome is able to tear them apart. And if something can't be broken down in the lysosome, there's nowhere else for it to go: it just stays there until either the lysosome disastrously ruptures, or the cell itself is destroyed.

Since the root of the problem is that the lysosome is unable to break down all of these stubborn waste products, the most direct solution is to supply them with new enzymes that can degrade those wastes. And fortunately, we know that enzymes capable of breaking down these materials exist - specifically, in the soil bacteria and fungi that help to decompose dead bodies. If such enzymes didn't exist, then the planet would be ankle-deep in the undegraded lysosomal wastes left over from the cells of 600 million years of animal life on this planet. So the idea would be to identify the enzymes these organisms use to digest lysosomal wastes, modify them a bit to help them work in the slightly different environment of the human lysosome, and then deliver them to where they need to go in our cells.

OncoSENS - Stopping Cancer at the Starting Line

Two types of damage accumulate in our genes as we age: mutations and epimutations. Mutations are damage to the DNA sequence itself, whereas epimutations are damage to the "scaffolding" of that DNA, which controls how and when genes get turned on in the cell. For practical purposes, both mutations and epimutations ultimately harm us in the same way: by causing abnormal gene expression. So what kind of harm can the changes in gene expression resulting from (epi)mutations cause? The one that most people know about is cancer, which is the result of a series of (epi)mutations that happen in sequence in the cell, leading to its uncontrolled growth.

Fortunately, a strategy to achieve extremely strong protection against cancer does exist, although its implementation is extremely challenging. This strategy is based on the one inescapable vulnerability that all cancer cells share in common: their absolute need to renew their telomeres. Because cancer cells reproduce at a furious pace, they quickly reach the ends of their telomeric "ropes," and need to find a way to lengthen them again in order to keep going. Successful cancer cells are the ones that have evolved mutations that exploit one of the cell's two systems for renewing telomeres: either a primary system called telomerase, or in a few cases an "alternative" system appropriately called Alternative Lengthening of Telomeres (ALT). If a nascent cancer can't find a way to seize hold of the telomerase-lengthening machinery, their telomeres will run down, their chromosomes will fray, and the cell will be destroyed before it can kill us. So despite their diversity, all cancer cells share one critical thing in common: they are absolutely dependent for their survival on their ability to hijack telomerase (or, less frequently, ALT). This fact has led the search for drugs that inhibit telomerase activity in cancer cells to become one of the hottest areas of cancer research today.

MitoSENS - Preventing Mitochondrial Aging

Mitochondria are the living machines within cells that act as their "power plants," converting the energy-rich nutrients in our food into ATP that directly powers biochemical reactions in the cell. Unlike any other part of the cell, mitochondria have their own DNA (mtDNA), separate from the DNA in the cell's nucleus, where all the rest of our genes are kept. Just like real power plants, mitochondria generate toxic waste products in the process of "burning" food energy as fuel - in this case, spewing out highly-reactive molecules called free radicals, which can damage cellular structures. And the mtDNA is especially vulnerable to these free radicals, because it is located so close to the center of its production. At worst, a free radical "hit" to the mtDNA can cause major deletions in its genetic code, eliminating the mitochondria's ability to use the instructions to make proteins that are critical components of their energy-generating system. Lacking the components needed to produce cellular energy the normal way, these mutant mitochondria enter into an abnormal metabolic state to keep going - a state that produces little energy, while generating large amounts of waste that the cell is not equipped to metabolize. Perversely, the cell tends to hang onto these defective, mutant mitochondria, while sending normal ones to the recycling center, so if just one mitochondrion suffers a deletion, its progeny quickly take over the entire cell.

It would be ideal if we could prevent mitochondrial deletions from happening, or fix them after they've occurred before they can do harm; unfortunately, the state of the science is nowhere near the point where this would be a realistic goal. Instead, the MitoSENS strategy is to accept that mitochondrial mutations will occasionally happen, but engineer a system to prevent the harm they cause to the cell. We can do this by putting "backup copies" of the mitochondrial genes into the nucleus, where they cannot be damaged by free radicals generated in the mitochondria. That way, even if the original genes in the mitochondrial are deleted, the backup copies will be able to supply the proteins needed to keep normal energy production going, allowing the cellular power plants to continue humming along normally and preventing them from entering into the toxic, mutant metabolic state.

Stroke Patients Tend to be Biologically Older, as Measured by DNA Methylation

Today I thought I'd point out one of the recent results to emerge from the discovery that DNA methylation patterns correlate well with age. These patterns best correlate not with chronological age, but with biological age, as they reflect the pace at which cell and tissue damage has accumulated. They are thus a potential biomarker capable of distinguishing natural variations in the pace of aging between individuals. The authors of the paper linked below show that, per their chosen forms of DNA methylation assessment of age, stroke patients tend to be biologically older. This all ties together very well: age-related diseases are caused by an accumulation of molecular damage. That damage takes the same form in every individual, and thus the cellular reactions to that damage are much the same. These reactions include alterations in DNA methylation, a part of the epigenetic system of controls that determine whether and how rapidly various proteins are manufactured from their genetic blueprints. Variations in aging between individuals take the form of more or less damage at a given age, and thus these methylation patterns reflect an earlier or later age by level of damage. More damage means a greater risk of biological systems failures, such as chronic age-related disease or incidents like stroke.

The paper below is but one example of a range of initiatives focused on building and trialing accurate biomarkers of biological age. DNA methylation patterns are the best and most advanced of these to date; there has been something of a blossoming in this part of the field as researchers eagerly apply and attempt to validate this class of biomarker. For example, a recent study showed that older age as assessed by a methylation clock correlates with higher mortality. This isn't just about the gloomy matter of being able to quantify exactly where in the downward spiral of degenerative aging any one particular individual might be, however. The real advance in the state of the art that accompanies a reliable biomarker for aging is the ability to quickly and cheaply assess the potential of newly developed rejuvenation therapies. At present the only way to figure out whether something works or not is to, at minimum, run a lifespan study in a large enough number of mice to ensure statistical significance. That is something that tends to cost millions and take years, and such a high level of required investment means that there is far less experimentation and development than might otherwise be the case. But if that can be cut down to a month-long study with a biomarker test at beginning and end? Well, a much larger set of laboratories and projects now become contenders - and, as an added bonus, the proposals that don't in fact work will be quickly winnowed rather than lingering on in a state of uncertainty.

One thing to take away from this particular paper is that there is a still a fair way to go for DNA methylation - or another approach to a biomarker of biological age - to reach desirable levels of accuracy. It is still better than other candidate biomarkers, but at present would only be capable of detecting fairly large effects if used to assess interventions intended to slow or reverse the aging process. That might be good enough for the type of therapies proposed in the SENS vision of rejuvenation biotechnology: large positive effects on molecular damage and aging are the goal, after all. As work on the SENS approach of senescent cell clearance progresses, we'll soon enough be seeing DNA methylation biomarkers used as a matter of course in mouse studies of that rejuvenation treatment, I'd imagine.

Ischemic stroke patients are biologically older than their chronological age

Ischemic stroke (IS) is a complex age-related disease with high mortality and long-term disability. Despite current attention to risk factors and preventive treatment, the number of stroke cases has risen in recent decades, likely because the aging population has increased. Stroke pathogenesis involves a number of different disease processes as well as interactions between environmental, vascular, systemic, genetic, and central nervous system factors. Approximately 10% of IS occurs in individuals younger than 50 years, which is called "young stroke". In older patients, stroke remains associated with the traditional risk factors: hypertension, hypercholesterolemia, diabetes mellitus, and obesity.

The epigenetic marker that has been studied most extensively is DNA methylation (DNAm), which is essential for regulation of gene expression. This mechanism consists of the covalent addition of a methyl group to a cytosine nucleotide, primarily in the context of a CpG dinucleotide. This dinucleotide is quite rare in mammalian genomes (~1%) and is clustered in regions known as CpG islands. Methylation of the CpG island is associated with gene silencing. DNAm is dynamic, varies throughout the life course, and its levels are influenced by lifestyle and environmental factors, as well as by genetic variation. Given its dynamic nature, epigenetics has been referred to as the interface between the genome and the environment.

Age-related changes in DNA methylation are well documented, and two recent studies used methylation measured from multiple CpGs across the genome to predict chronological age in humans. Hannum et al created an age predictor from whole blood DNA, based on a single cohort of 656 individuals aged 19 to 101 years. Horvath developed a multi-tissue age predictor using DNA methylation data from multiple studies. Both models are based on the Illumina BeadChip. The difference between chronological age and methylation-predicted age, defined as average age acceleration (Δage), can be used to determine whether the DNAm age is consistently higher or lower than expected. These age predictors are influenced by clinical and lifestyle parameters, they are predictive of all-cause mortality, indicating that they are more suggestive of biological age than of chronological age.

Age is one of the main risk factors for stroke. We hypothesized that biological age would be even more closely associated with stroke risk, and that "young stroke" patients may be undergoing accelerated aging, with a higher biological than chronological age. We examined a cohort of 123 individuals, 41 controls and 82 patients with IS, matched by chronological age. We initially used two approaches described in the literature to predict biological age, the Hannum and Horvath methods. The average biological age of controls showed a mean Hannum-predicted age higher than their chronological ages by a mean of 1.1 years; their Horvath-predicted age was lower than their chronological ages by 4.6 years. In patients with IS, we observed a Hannum-predicted age higher than their chronological age by a mean of 3.3 years, statistically significant compared to controls. Their Horvath-predicted age was lower than their chronological ages by 3.2 years. DNAm age had a strong positive correlation with chronological age in control samples (0.93 for both Hannum and Horvath methods, and 0.94 between the Hannum- and Horvath-predicted ages). In IS cases, the correlations were lower (0.83 for the Hannum method, 0.72 for the Horvath method, and 0.82 between the two. Although both age predictors showed high accuracy in our samples, Hannum DNAm age performed better, with fewer differences in chronological age in controls and better correlation in patients with IS than the Horvath method.

The sensitivity analysis evaluating which age predictor performed better in our study determined that the Hannum predictor was superior. This is likely because this method is constructed on the basis of DNA methylation data from whole blood, like our data, while the Horvath method is constructed on a range of different tissues and cell types. In conclusion, we found that IS status was associated with a significant increase in Hannum DNA methylation, likely as a consequence of the accumulation of cardiovascular risk factors, and near signification with Horvath method. Patients with IS were biologically older than controls, a difference that was more obvious in young stroke. This could open up the possibility of useful new biomarker of stroke risk.

Latest Headlines from Fight Aging!

A Profile of Kelsey Moody and Ichor Therapeutics

Kelsey Moody's Ichor Therapeutics is one of number of biotech ventures to have emerged from the SENS rejuvenation research community over the past decade. Earlier this year Fight Aging! invested a small amount in Ichor's initiative to push forward with the development of clearance of metabolic waste compounds from the lysosome. The company will be building upon work carried out at the SENS Research Foundation in order to create a therapy for age-related macular degeneration, as the existence of these waste compounds appears to be an important root cause of retinal damage. I think that Moody's talent for the business side of things is quite well illustrated by the fact that he can engineer the publication of a press article like this one:

Inside a laboratory tucked in the LaFayette hills south of Syracuse, a small biotech company is quietly developing drugs that may show promise to treat, prevent and possibly even reverse macular degeneration, a disease that's a leading cause of vision loss. The new drug therapies being developed and tested are designed to work on two varieties of the eye disease: age-related macular degeneration and juvenile-onset macular degeneration, said Kelsey Moody, who founded the biotech company Ichor Therapeutics in 2013. Moody was a second-year medical student when he started his company with a 540,000 grant from Life Extension Foundation, a Florida-based non-profit that funds research in aging, age-related diseases and ways to extend human lifespan. Ichor has so far attracted more than 3.2 million from investors, foundations and local government.

Moody says he's particularly interested in age-related diseases because he said they don't get as much attention and visibility as other types. If the treatments for macular degeneration work, the enzymes, derived from several sources, will be available as an injection. Moody is in what he calls "stealth mode" right now as he works to test the validity of the treatments, so he's not giving away too many details about them. He plans to publish his findings once he, in conjunction with Syracuse University, secures patents to protect his work. Age-related macular degeneration is the leading cause of vision loss and blindness in people older than 50. Moody said his team believes macular degeneration is caused in part by "junk that accumulates in the eye" over time. Just so much debris can build up in the eye before it begins to cause problems, he said. There are multiple types of this substance that accumulate, and Moody said it may cause the eye disease or it could be a side effect of it. He said Ichor has developed "therapeutic" enzymes that break down that "junk" or particles. "Either we hit a home run and cure the disease or, if that fails, we have the answer to the important question of what happens when we get rid of the junk."

Dr. Szilard Kiss, an ophthalmologist and an associate professor of ophthalmology at Weil Cornell Medical College, who is familiar with research into this condition and read up on Moody's work, said Moody is aiming at the A2E molecule which is one of the components of that toxic buildup. Other researchers are working on this as well, but without success to date. "It's a tough nut to crack, as it's difficult to soak up that A2E. If what Ichor is doing works and can treat the dry form and prevent the wet form of macular degeneration, it would be really great." Robert P. Doyle, a Syracuse University chemistry and biology professor and an associate professor of medicine at SUNY Upstate Medical University, agrees with Kiss. "The science behind what Ichor is doing is very sound," said Doyle, who is working with Moody to patent the drug treatments. "The technology is very new, and there's no reason it won't work, but it will of course have to be validated." Doyle, who says he and Moody will publish a paper soon, said Moody excels both as a research scientist and as a businessperson. "He's done an awful lot of scientific research in his career before starting his own company, but he also has an MBA and is good at business. He has good ideas and he is willing to have them challenged. He's fearless."

Mitochondrial DNA and the Longevity of Birds

Evidence for the relevance of mitochondrial damage to the progression of degenerative aging can be found in many places, such as when comparing species with divergent life spans and metabolic needs. Birds and bats have significantly higher metabolic rates than we ground-based mammals, but along with that they also have much longer life spans than you might expect given their size. So the thinking goes, the evolutionary adjustments to mitochondria, the power plants of the cell, that were needed for flight have also produced a greater resistance to the mitochondrial molecular damage that contributes to aging. As this open access paper shows, there are mitochondrial differences that seem significant for longevity even between bird species. This isn't to say that we should be trying to alter our mitochondria via gene therapy to make them more like longer-lived species, however. No, we should instead take this and other similar research as indicators that more funding and attention should go towards rejuvenation therapies that focus on mitochondrial repair, ways to completely remove this contribution to aging rather than just slowing it down.

Mitochondria play an essential dual role in homeotherms by encoding proteins that form the essential components of the mitochondrial energy generation pathway, oxidative phosphorylation (OXPHOS). OXPHOS generates heat that is used to maintain the organism's body temperature and energy that is utilised for synthesis of adenosine triphosphate (ATP) to perform work. This is achieved "at the cost" of reactive oxygen species (ROS) and free radical production due to electron leakage from the respiratory chain. The mitochondrial theory of ageing suggests that ROS contribute to a progressive accumulation of somatic mutations in DNA during an individual's lifetime leading to both a decline in the bioenergetic function of mitochondria and to cell apoptosis associated with ageing and has been associated with a wide range of age-related diseases, but the relationship between ROS levels and ageing is not a simple one.

As an originally free-living prokaryotic organism that was engulfed by a precursor of the modern eukaryotic cell about two billion years ago, cytoplasmic mitochondria have retained their own plasmid-like circular genome (mitochondrial DNA, mtDNA). Mitochondrial genome regulation is vital for normal assembly and functional operation of the complexes involved in oxidative phosphorylation (OXPHOS), and therefore, for ATP production and metabolic homeostasis. Many of these functions are fundamental cellular processes and hence the mitogenome organisation appears highly conserved across vertebrates. In birds, several different arrangements of mitochondrial gene order have been observed and in some species the noncoding control region (CR) sequence with the adjacent genes have been duplicated creating a second non-coding region sometimes referred to as the pseudo control region (YCR). YCRs appear to have originated independently and sporadically in several distantly related taxa across the avian phylogeny.

Birds have several biochemical and life characteristics that should increase the risk of reactive oxygen species (ROS) damage to their mtDNA relative to mammals. Such characteristics include higher metabolic rates, higher body temperatures, higher blood glucose levels, seasonally high blood lipid levels and very high total lifetime energy expenditures. As such one would reasonably predict that relative to mammals, birds should age faster and have higher mutation rates rendering them more prone to cancer and other pathologies. Yet, paradoxically, most birds live longer compared to similar sized mammals in absolute and relative terms and although estimated mutation rates vary greatly across avian phyla, they are on average up to four times lower than those in comparable mammals. To the best of our knowledge, the presence of two sets of CR sequences is mainly an avian specific phenomenon, and the relationship between this feature and mitochondrial function has not been fully investigated. Considering the extraordinarily long life spans of birds and the pivotal role of the mitochondria in energy metabolism, the major aim of the work presented here is to explore the possibility that the additional sequences in the YCR are associated with variation in avian longevity.

Around 60% of the variation in lifespan of higher animals can be explained by body mass: animals that diverge from this basic allometry of life span may harbour unique longevity enhancing features and their study may lead to new insights into the evolutionary forces shaping longevity and aging. To explore a possible link between YCR duplication and longevity, we correlated longevity/body mass with presence/absence of YCR sequence for a total of 92 avian families. We detected a relationship between a duplicated control region and longevity. This, we believe, strongly argues for a positive functional role of these duplicated sequences in those species that carry them. We hypothesize that there are two, not incompatible, possibilities that relate to the mitochondrial ageing hypothesis. Extra control region sequences may result in constant increased mtDNA copy number and/or increased flexibility and speed of cellular response when increased metabolism is required to cope with environmental stresses. This mechanism might effectively lower local ROS damage from increased metabolic throughput during periods of stress response. A second possibility is that extra copies of the control region sequences protect mtDNA from the age related effects of sequence losses and hence offer the opportunity for species to retain higher levels of functional mitochondria into later life, hence slowing the negative effects of accumulated mitochondrial deletions on senescence. Alternatively, our results may simply reflect a molecular marker of long-lived species, rather than being the causative agent for that longevity. Our results suggest that even if truly causative the associated effect is a relative minor one accounting for around a 15% difference in life expectancy for an average sized family with and without the YCR.

More Evidence of a Role for Transposons in Aging

Of late researchers have been investigating a possible role for transposable elements, or transposons, in degenerative aging. These are DNA sequences that can move around in the genome, and the incidence of such movement increases with age. This fits in with the general consensus that stochastic mutation of nuclear DNA is a cause of aging, through disarray of normal cellular operations. This view is disputed in some quarters by the suggestion that outside of cancer risk the effect isn't significant over the present human life span in comparison to other forms of damage. In the case of transposons, whether it is a cause or consequence of other age-related changes in cellular biology is still up for debate. The work here adds a little more to the evidence already in hand:

A new study increases and strengthens the links that have led scientists to propose the "transposon theory of aging." Transposons are rogue elements of DNA that break free in aging cells and rewrite themselves elsewhere in the genome, potentially creating lifespan-shortening chaos in the genetic makeups of tissues. As cells get older, prior studies have shown, tightly wound heterochromatin wrapping that typically imprisons transposons becomes looser, allowing them to slip out of their positions in chromosomes and move to new ones, disrupting normal cell function. Meanwhile, scientists have shown that potentially related interventions, such as restricting calories or manipulating certain genes, can demonstrably lengthen lifespans in laboratory animals. "In this report the big step forward is towards the possibility of a true causal relationship. So far there have been associations and suggestions that to all of us make sense, but you need the data to back up your opinion."

In one set of experiments, the team visually caught transposable elements in the act of jumping around in fruit flies as they aged. They inserted special genetic snippets into fat body cells, the equivalent of human liver and fat cells in flies that would glow bright green when specific transposable elements move about in the genome. Under the microscope the scientists could see a clear pattern of how the glowing "traps" lit up more and more as the flies aged. The increase in transposon activity was not steady as flies grew older. The data show that the timeframe in which transposable element activity really begins to increase is tightly correlated with the time when the flies start to die. Several experiments in the paper also show that that a key intervention already known to increase lifespan, a low-calorie diet, dramatically delays the onset of increased transposon activity.

To further explore the connection between transposon expression and lifespan, the team tested the effects of manipulating genes known to improve heterochromatin repression that are not only found in flies, but also in mammals. For example, increasing expression of the gene Su(var)3-9, which helps form heterochromatin, extended maximal fly lifespan from 60 to 80 days. Increasing expression of a gene called Dicer-2, which uses the small RNA pathway to suppress transposons, added significantly to lifespan as well. For all the new results, the researchers say it's still not quite time to declare outright that transposons are a cause of aging's health effects. But new experiments are planned. For example, the team will purposely encourage expression of transposable elements to see if that undermines health and lifespan. Another approach could be to use the powerful CRISPR gene editing technique to specifically disable the ability of transposable elements to mobilize within the genome. If that intervention affected lifespan, it would be telling as well.

Signs that Earlier Physical Prowess has a Longevity Cost in Humans

It is fairly well settled in evolutionary theory that there is a trade-off between short-term development versus longer-term tissue maintenance. Species that mature and reproduce quickly tend to have shorter life spans. This relationship also exists when comparing natural variations between individuals within the same species, and here researchers present evidence for this effect in human populations.

Generalized life history theory postulates a trade-off between development and maintenance explaining the considerable variation of traits like age at maturation, age at first reproductive event, number of offspring, size and lifespan across and within species. It is debated whether the variation in human lifespan can also be explained by such trade-offs. Observational studies in women have shown early and above average fecundity to come at a cost of longevity. The life history of men has no distinct mark of the end of development as menarche in women, but negative correlations between number of offspring and life-span after age 50 have also been reported for males. This could be explained as males invest more in physical strength and growth, which is associated with attractiveness and dominance, two traits important for male fitness.

Professional athletes push their physical performance to the maximum and keep accurate track of these achievements. Consequently, their personal record is an accurate representation of the age of their peak performance. Under the assumption that professional athletes train at maximum intensity, this peak performance is an accurate read-out of the maximal physiological capacity of the individual. Because athletes compete intensely, the rank of peak performances is an accurate comparison of these maximal physiological capacities of athletes. According to theory of life history regulation, the period before the peak performance could be considered as development, while the decline in physical capabilities after setting a personal record is a hallmark of the ageing process.

We used a unique historical cohort of 1055 Olympic track and field athletes from 41 different nationalities from the Olympic Games from 1896 through 1936. Track and field is a large group of similar sports for individual performance where the results are measured on a continuous scale. Technological advancements contribute only little to basic body functions like running, throwing and jumping, which are critically dependent on physical strength and coordination. Athletic games are therefore an ideal group of sports to use in this study. Mean age at personal record was 24.9 years. Mean age at death was 72.1 years. To compare peak performance of athletes from different disciplines and sexes we standardized age at, and rank of the personal record per discipline and sex. Athletes who had a peak performance one standard deviation earlier showed 17-percent increased mortality rates compared to those who reached their personal record later in life. Independent of the age of their personal record, athletes who ranked one standard deviation higher than their peers showed 11-percent increased mortality rates compared to those who were ranked lower.

It is tempting to speculate about the underlying biological mechanisms of this developmental constraint. Some have suggested that growth and subsequently, larger size, result in a body which costs more energy to maintain, explaining the higher pace of ageing. The mTOR pathway, which regulates growth in early life and pace of ageing in late life, is a potential molecular pathway that can explain for the observed trade off. Others have suggested that hormonal regulation of development and maintenance could play a role, as has been observed for the GH-IGF signaling pathway explaining the size-life span trade off in domestic dogs, and the muscle mass-immune competence trade-off mediated by testosterone observed in primates and other species. All mechanistic explanations are plausible and it needs to be studied which pathways are causal, and at which we can intervene to secure longer and healthier lives.

The War on Aging

It is always pleasant to see the emergence of new advocacy efforts that support the sort of rejuvenation research carried out by the SENS Research Foundation, and here I'll point out one that I had not noticed until quite recently. That there are enough people out there working on projects of this nature for things to slip past is a positive sign in and of itself. The community of supporters is growing.

First and foremost it is important to understand that aging is not something mystical or incomprehensible. Aging with all its symptoms and all its associated diseases is caused by the accumulation of damage in our bodies over time coupled with a lack of repair thereof. These damage types are at the root of all the degenerative processes that happen to the human body as we get older as well as all the diseases of old age. It turns out there are comprehensive answers on how to effectively combat and reverse each of these damage types already. Research with the focus on ending aging is happening in independent laboratories around the world, mostly funded and coordinated by the SENS Research Foundation. In short: By repairing the body using treatments that we are capable of developing using today's technology we can effectively treat and reverse aging. This is extremely good news!

Why have I not heard about this in the news? It's really quite frustrating. New concepts, rejuvenation research in particular (just try talking to anyone about it), tend to take a while to catch on and in this case time will mean the difference between life and death, health and suffering for millions. There is this notion that living longer translates to a prolonged period of frailty and suffering when this research is about the exact opposite: restoring youthful vigor. To most people rejuvenation remains an impossible pipe dream because they don't pay attention or take the time to inform themselves about medical advances or progress in research. They have their viewpoint defined by pro-aging movies and other popular media. As long as the general population does not change their mind about how they feel about rejuvenation research, governments and the mainstream media won't take it up as a serious field of research. History has shown how much resistance there is towards new ways of thinking and how irrational that resistance seems when looking back. The more radical the idea, the bigger the resistance. To believe that aging is avoidable or indeed reversible may be the most fundamental paradigm shift that humanity has ever had to go through and as ridiculous as this may sound to future generations, we currently live in a world where most people frown upon the idea of being young and healthy for as long as they desire.

What can I do to support rejuvenation research? Put simply: New medical technologies don't fund themselves. The future we get is the future we choose to invest in. The war on aging has already begun. It is happening now and it can be won within our lifetime if we push to reach human longevity escape velocity. The SENS Research Foundation is spearheading the movement and has the most feasible and comprehensive approach to curing aging. They are a non profit organization, their research is thorough, well documented and transparent so it is easy to follow along with their progress, plans and goals. That is why our vote goes to them for support. We live in an exciting time where we have the chance to see a world free of involuntary suffering, frailty and death from aging and age related diseases, but if we want to be around to see this world become a reality we need to do our part in supporting the research. The most important part is continuous funding and advocacy. Talk about this subject matter with other people, spread awareness and excitement and sign up for a monthly donation on the SENS Research Foundation website today for a future unbounded by an inevitable age-related demise.

Working to Characterize the Epigenetics of Cellular Senescence

The accumulation of senescent cells is one of the causes of aging. If even 1% of the cells in a tissue become senescent, that small fraction has been shown to have very damaging effects on the function and behavior of the majority non-senescent cells. The most direct path towards addressing this problem is to selectively destroy senescent cells throughout the body every few years, and companies such as Oisin Biotechnologies and UNITY Biotechnology are working towards that goal. Many researchers are more interested in altering the behavior of senescent cells for the better, however, something that I see as an inferior path, but that fits more closely with the scientific impulse to completely map senescence as a cellular phenomenon: to produce a full understanding of the molecular biology of the processes involved. Fortunately, the sort of mapping work shown here should also make it easier to selectively target senescent cells for destruction in the years ahead.

Researchers have succeeded in identifying genes that control cellular senescence - permanently arrested cell growth. The process involved treating liver cancer cells using anticancer drugs of various concentrations, inducing apoptotic cell death and cellular senescence, and comparing gene expression levels. By developing drugs that suppress the activity of these genes, this discovery has potential applications for creating new highly-effective anticancer drugs, or use in anti-aging drugs. Living organisms experience various stresses during their lifespans. These stresses include radiation, ultraviolet rays, and chemical substances that directly damage DNA and cause cancer. Organisms are able to speedily repair DNA when it is damaged, but when the damage is severe, they manifest two different cell responses: apoptosis - a type of controlled cell death - and cellular senescence, which permanently suspends cell growth. Both these responses prevent the cell which suffered DNA damage from proliferating and becoming cancerous.

The research group had previously discovered that cell senescence was effectively induced by using low concentrations of anticancer drugs on cancerous cells. If cancerous cells are treated with a low concentration (10 μM) of the anticancer drug etoposide this induces cell senescence, and if they are treated with a high concentration of the drug (100 μM) this induces apoptosis. For this research, they treated cancerous cells under three different conditions: A) with no etoposide; B) with a low dose of etoposide (10 μM); and C) with a high dose of etoposide (100 μM). They then used DNA microarrays to identify the genes in which a rise in transcription levels could be observed. They predicted that genes which showed increased expression in response to treatment B were mainly related to cell senescence, genes expressed in response to C were mainly those involved in apoptosis, and among the genes which specifically showed increased expression in B compared to C would be genes that play an important role in implementing cell senescence.

There were 126 genes where three times as much expression was recorded under treatment B compared to A, and 25 genes that showed twice as much expression in B compared to C. These 25 genes are expected to express specifically in senescent cells since the other factors caused by DNA damage are removed, and researchers confirmed that the genes involved in causing cell senescence were among them. If we can develop a drug that targets and regulates the activity of the genes that control senescence identified in this research, by administering it together with conventional anticancer treatment we can limit the emergence of senescent cells and potentially increase the effectiveness of cancer treatment. Additionally, it has been reported that one of the causes of individual aging is the accumulation of senescent cells. This means that drugs which control cell senescence could have potentially large benefits for the development of anti-aging medication products.

Surveying Views on Enhancement Technologies, such as Longevity Therapies

You'll no doubt recall that the Pew Research Center ran a survey a few years back showing that most people didn't want to live longer lives, were that possibility on offer through progress in medical science. There are indications that this result is obtained because the mistaken assumption that people make is that longevity assurance therapies would lead to a longer period of old age rather than a longer period of youthfulness. Later studies suggest that people are all for longer lives if that prospect is explicitly tied to remaining healthy and youthful. Pew Research more recently followed up with a related survey on selection of enhancement technologies to expand or increase human capacities, resulting in a similar set of data for some of the technologies that will become available in the near future. For my money, there are clearly large differences between what people say at the dawn of a new technology, and what they later do when that technology is available.

For millennia, humans have been dreaming about vaulting past our biological limits, from natural constraints on our intellect and physicality to our very mortality. But now, according to some researchers and futurists, we may be on the cusp of a scientific revolution that could give each of us an opportunity to cross these boundaries and live longer and stronger than any human being before us. And yet, a pair of Pew Research Center surveys on life extension and human enhancement show that many U.S. adults are not ready to embrace these possibilities, whether it be in their own lives or in society more broadly. In our 2013 survey on radical life extension, 56% of adults said they would not want to live at least 120 years, which is considered the current upper limit of the human life span. Likewise, roughly two-thirds of adults in our 2016 poll on human enhancement said they would not want a brain chip implant to improve their cognitive abilities (66%) or synthetic blood to augment their physical abilities (63%). American adults were somewhat more open to the possibility of using gene editing to reduce the risk of serious disease in babies, with 48% saying they would be interested, but a similar share (50%) said they would not want to use the technology on their baby.

For many people, both potential advancements also raised concerns about increasing social inequality. Two-thirds of those polled about radical life extension thought the option would only be available to the wealthy. At least as many in the human enhancement survey shared this concern, saying that moving forward with the three emerging technologies outlined in the survey - brain implants, synthetic blood and gene editing for babies - would increase inequality because they would only be available to those who are well-off. Two-thirds of American adults also said scientists would offer life extension technologies before their impact was fully understood. Again, this wariness is matched and even exceeded in the human enhancement survey; more than seven-in-ten adults said brain, blood and gene enhancements would be employed before their effects were fully understood.

Even though the two surveys were conducted separately, they are thematically linked, since research efforts to dramatically extend human life and to "enhance" human beings are occurring in tandem and sometimes together. In fact, the line between the two areas often is blurred. Many scientists and advocates who want to make people stronger and smarter also want to make them healthier and longer-lived, and those who are working to increase longevity and limit the effects of aging in human beings often want to enhance their capabilities as well. One interesting difference between our polling work on life extension and on human enhancement involves the factors that are contributing to these views. It turns out that religion plays a more prominent role in driving people's concerns about human enhancement than life extension. For instance, among highly religious people (based on an index of common measures), only 24% say they would want cognitive enhancement, compared with 44% of those with low levels of religious commitment. A similar gap exists when these two groups are asked about gene editing and synthetic blood.

Lower Protein Synthesis Rates in Long-Lived Nematode Worms

Researchers here look into protein synthesis rates in nematodes engineered to live twice as long via manipulation of the DAF-16 gene, analogous to FOXO in mammals. The goal is to reach for a better understanding of the relationship between various classes of molecular damage, quality assurance mechanisms, repair activities, and rate of aging. This is, needless to say, a very complex topic, full of counterintuitive results and baroque interactions between intricate evolved subsystems of the cell.

Cellular protein quality can be maintained by proteolytic elimination of damaged proteins and replacing them with newly synthesized copies, a process called protein turnover. Protein turnover rates have been estimated using SILAC (stable isotope labeling by amino acids in cell culture) in prokaryotes and eukaryotes. The last decade has witnessed a growing interest in the analysis of whole-organism proteome dynamics in metazoans using the same approach. Progressive decrease in protein synthesis and proteolytic clearance through the autophagosomal and proteasome systems with age results in a strong increase in protein half-life in many species, including nematodes. This finding led to the formulation of the protein turnover hypothesis, stating that the increase in protein dwell time with age results in the accumulation of damaged and misfolded proteins. The progressive decrease in general protein turnover might be responsible for the ultimate collapse of proteome homeostasis in aging cells, possibly also driving the aging process itself.

In this vein, it is expected that increased protein turnover rates would help to maintain a young undamaged proteome and extend the lifespan. However, in yeast and C. elegans, genetically induced attenuation of protein synthesis extends, rather than shortens, the lifespan. Moreover, proteomic studies suggest that low overall protein synthesis is a hallmark of long-lived C. elegans, either by dietary restriction or by mutation in the insulin signaling pathway. Similar findings have been reported for diet-restricted mice. Hence, why does reducing protein synthesis promotes lifespan extension? And how can this be reconciled with the protein turnover hypothesis, which predicts enhanced turnover rates in long-lived organisms? We hypothesized that DAF-16-dependent longevity in C. elegans is supported by differential protein turnover. Downregulating turnover of the majority of proteins could save much energy, which, in turn, could be spent at prioritized maintenance of specific proteins that are crucial to extend the lifespan. To test this hypothesis, we produced a dataset that reveals patterns of intracellular protein dynamics in the C. elegans model and shifts of these patterns that occur in the long-lived daf-2 mutant via DAF-16 activation.

Contrary to our hypothesis, we did not discover a delineated set of proteins with turnover priority in daf-2 mutants. The majority of the detected proteins (56%) exhibit prolonged half-lives in daf-2, whereas turnover of the remaining proteins is unchanged. Only three proteins (CPN-3, ASP-4, and VIT-6) display marginally significant higher turnover rates in daf-2, but they lack a clear biological relationship. One of our most notable observations is the drastic slowdown in turnover of the translation machinery in daf-2 mutants. This slowdown coincides with decreased levels of ribosomal proteins and enzymes with predicted function in ribosome assembly and biogenesis we and others observed earlier and probably relates to the decreased protein synthesis rates in this mutant. Our observation of decreased protein turnover in daf-2 mutants is not entirely surprising. In agreement with our observations, researchers demonstrated extended ribosomal and mitochondrial half-lives in long-lived, calorie-restricted mice. The insulin/IGF1 signaling pathway is a main activator of anabolic metabolism; hence, it is conceivable that mutants in this pathway show reduced protein turnover. This reduction allows the worm to save much energy, which may be diverted to other processes that support longevity, such as the synthesis of trehalose, a chemical chaperone that stabilizes membranes and proteins, for which a role in daf-2 longevity has already been shown.

Cold Plasma Claimed to Spur Wound Healing

Researchers here claim that the use of cold plasma, ionized gas, can improve wound healing. Other research in past years has suggested that tinkering with the electromagnetic environment of tissues can produce changes in cellular behavior, so this isn't completely out of left field. The effects seem fairly marginal at this point, however, and note that this particular study is in cell cultures, not living tissues, though past efforts have looked at effects on animals and people. The outcome of this study suggests that what they are looking at is perhaps some form of hormesis, whereby a little damage triggers greater repair efforts in cells for a net gain, but bear in mind that cell cultures are very different in many ways when compared with actual tissues.

Researchers have found that treating cells with cold plasma leads to their regeneration and rejuvenation. This result can be used to develop a plasma therapy program for patients with non-healing wounds. Non-healing wounds make it more difficult to provide effective treatment to patients and are therefore a serious problem faced by doctors. These wounds can be caused by damage to blood vessels in the case of diabetes, failure of the immune system resulting from an HIV infection or cancers, or slow cell division in elderly people. Treatment of non-healing wounds by conventional methods is very difficult and in some cases impossible. Cold atmospheric-pressure plasma refers to a partially ionized gas (the proportion of charged particles in the gas being close to 1%) with a temperature below 100,000K. Its application in biology and medicine has been made possible by the advent of plasma sources generating jets at 30-40°C.

An earlier study established the bactericidal properties of low-temperature plasma, as well as the relatively high resistance of cells and tissues to its influence. The results of plasma treatment of patients with non-healing wounds varied from positive to neutral. The authors' previous work prompted them to investigate the possibility that the effect of plasma treatment on wound healing could depend on application pattern (the interval between applications and the total number of applications). Two types of cells were used in this study, viz. fibroblasts (connective tissue cells) and keratinocytes (epithelial cells). Both play a central role in wound healing. The first set of samples (cells) was treated by plasma once (A), while the second and the third sets were treated two (B) and three (C) times with 48 and 24 hour intervals respectively. The effect of plasma treatment on cells was measured. In fibroblast samples, the number of cells increased by 42.6% after one application (A) and by 32.0% after two applications (B), as compared to the untreated controls. While no signs of DNA breaks were detected following plasma application, an accumulation of cells in the active phases of the cell cycle was observed, alongside a prolonged growth phase. "The positive response to plasma treatment that we observed could be linked to the activation of a natural destructive mechanism called autophagy, which removes damaged organelles from the cell and reactivates cellular metabolic processes."

A Measure of Just How Beneficial Clearing Cross-Links Might be for the Old

Hypertension, increased blood pressure with age, is caused by stiffening of blood vessels. That stiffening is in turn caused by some combination of cross-linking, cellular senescence, calcification, and inflammation. Cross-linking is probably the largest contribution, but until methods of clearing cross-links are created it will be hard to say for sure. Persistent cross-links are formed when sugary compounds, the vast majority of them based on glucosepane, link together molecules in the extracellular matrix, limiting their range of movement. This causes a loss of elasticity in tissues like skin and blood vessels, and that in turn leads to hypertension, and then everything caused by hypertension: detrimental remodeling of heart tissue, damage to brain and kidneys as small vessels and delicate structures are destroyed, and so forth. The higher the blood pressure the worse the long-term prognosis. This research measures just how many lives might be saved through the development of therapies to clear the cross-links that produce arterial stiffness, something that, sad to say, very few groups outside the SENS Research Foundation are working on:

Intensive treatment to lower systolic blood pressure to below 120 would save more than 100,000 lives per year in the United States. Two thirds of the lives saved would be men and two thirds would be aged 75 or older, according to the study. Current guidelines recommend keeping systolic blood pressure below 140 mm Hg. "When the treatment goal was lowered to a maximum of 120 mm HG, there was a huge reduction in mortality. Few other medical interventions have such a large effect." To determine whether intensive treatment to lower systolic blood pressure could alter mortality, the researchers applied findings from the Systolic Blood Pressure Intervention Trial (SPRINT) to the U.S. adult population.

The SPRINT trial, which included more than 9,350 adults ages 50 and older who had high blood pressure and were at high risk for cardiovascular disease. The SPRINT trial found there was a 27 percent reduction in mortality from all causes when systolic blood pressure was lowered to below 120 mm Hg, compared to the standard care of lowering blood pressure to below 140 mm Hg. While saving lives, an intensive blood pressure regimen also would cause serious side effects. The study estimated that approximately 55,500 more episodes of low blood pressure, 33,300 more episodes of fainting and 44,400 additional electrolyte disorders would occur annually with implementation of intensive systolic blood pressure lowering in U.S. adults who meet SPRINT criteria. Most of these effects would not be expected to have lasting consequences and would be reversible by lowering blood pressure medications.

High blood pressure, or hypertension, is a leading risk factor for heart disease, stroke, kidney failure and other health problems. An estimated 1 in 3 people in the United States has high blood pressure. In the SPRINT study, patients who were treated to achieve a standard target of less than 140 mm Hg received an average of two different blood pressure medications. The group treated to achieve a target of less than 120 mm Hg received an average of three medications. Using data from the National Health and Nutrition Examination Survey, researchers determined that more than 18.1 million American adults met the criteria of patients enrolled in the SPRINT trial. They estimated that, among these 18.1 million adults, fully implementing an intensive regimen to lower systolic blood pressure below 120 mm Hg would prevent approximately 107,500 deaths per year.


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