Fight Aging! Newsletter, October 19th 2015

October 19th 2015

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.

This content is published under the Creative Commons Attribution 3.0 license. You are encouraged to republish and rewrite it in any way you see fit, the only requirements being that you provide attribution and a link to Fight Aging!

To subscribe or unsubscribe please visit:


  • Stretch Goals for the Mitochondrial Repair Research Crowdfunding Project: 40,000 Raised, 10 Days Left
  • Building the Tools to Work with Glucosepane Cross-Links
  • Cryonics is Still the Only Viable Backup Plan
  • A Demonstration of Mitochondrial DNA Editing with CRISPR
  • Long Term Effects on Health: is it the Sitting, or the Immobility?
  • Latest Headlines from Fight Aging!
    • James Bedford Becomes the Longest Surviving Human
    • A Reddit AMA with the BioViva CEO
    • Obesity is Harmful, and Studies that Suggest Otherwise Made Overly Simplistic Use of Data
    • Christine Peterson on Technology and Longevity
    • Transposable Elements in Aging
    • More on Copy Number Variations and Mortality Rates
    • The Agelessness of Anemones
    • In Search of Specific Mechanisms By Which Smoking Accelerates Aging
    • On The Popular Press and Its Misrepresentation of Research
    • Arguing that Alzheimer's is a Mitochondrial Disease


It is by now the established model for crowdfunding efforts to keep going for the full span of time allotted at launch and add stretch goals if the original target is reached early. The mitochondrial repair research project running at hit its 30,000 goal at the end of last month, and so now we have stretch goals - see below for the updates.

The funds raised by this initiative will be used by the SENS Research Foundation to further in-house efforts at their Bay Area research center to apply allotopic expression to the whole mitochondrial genome. This involves gene therapy to introduce versions of all mitochondrial genes of interest into the cell nucleus, while amending the proteins produced in ways that ensure they will be transported back into the mitochondria where they are needed. This in effect creates a backup source of protein machinery needed for correct mitochondrial function and should make mitochondria, the cell's power plants, immune to the consequences of accumulating damage to their DNA, something that is thought to be a significant contributing cause of aging. Working allotopic expression therapies for all mitochondrial genes should be a cheap one-shot rejuvenation treatment, mass produced infusions that are the same for everyone and effective for everyone.

The groundwork for this approach has been laid over the past decade, some of it funded by early donors to the SENS Research Foundation. Across the pond those years of research have blossomed into commercial efforts at Gensight, where allotopic expression of a single mitochondrial gene is being developed as a therapy for the inherited condition Leber's hereditary optic neuropathy. A lot of money is going towards that effort, which should go a long way towards making the underlying technology robust and palatable to regulators. That in turn allows researchers interesting in treating the damage to mitochondrial DNA in aging to focus on expanding the application of allotopic expression to all relevant portions of the mitochondrial genome.

Since donations to this crowdfunding initiative go to the SENS Research Foundation, the Fight Aging! matching fundraiser will match all such donations made on the 1st of this month or later, the date on which our fundraiser launched. The generous philanthropists who put up the funds for our 125,000 matching fund will match all donations made to the SENS Research Foundation until the end of this year - or until the fund runs dry, which I hope will happen first. There is 90,000 or so left in the fund at this time. What are you waiting for?

MitoSENS Mitochondrial Repair Project: Updates

Hi everyone, thanks so much for your support in reaching our initial goal! I'm proud to announce that we have just received a donation from a local company in the form of a large quantity of free DNA primers. We used the donation to design a huge set of primers that we can use to make dozens more mitochondrial targeting sequences (MTSes) to test for their ability to target proteins to the mitochondria. So instead of the 3 that we've tested so far we could test many different ones that we suspect might be good candidates as stretch goals for this campaign.

If we reach a total of 45,000 we can test all of these MTSes on ATP6 and see if we can bring it up to full activity.

If we reach a total of 60,000 we can also test all of these targeting signals on a 3rd gene, Cytochrome B, which has long been a challenging gene for us and others in the field to make functional. If we can get this gene working, we should be able to make any gene in the system work.

In addition, we are excited to announce matching funds! Several of you have asked for this. Every donate to the Mitochondrial Repair Project will be matched by an equal amount that will go directly into the SENS Research Foundation general fund to support all the great research we do at SRF. Thanks to Fight Aging! for helping to organize this fund to match your donations!


Good news from the SENS Research Foundation arrived today: the programs targeting harmful cross-links in human tissues are starting to make concrete progress. The occasion is marked by a publication in the prestigious journal Science that covers the establishment of one of the first basic tools needed to work with glucosepane, the most important constituent of age-related human cross-links.

Cross-links are sugary compounds known as advanced glycation end-products that form in the extracellular matrix as a natural byproduct of metabolic processes. They glue together proteins and alter the physical properties of the tissue as their numbers grow. Fortunately most are short-lived, but some hardy forms of glucosepane cross-link can linger for a lifetime, as our biochemistry hasn't evolved the mechanisms needed to remove them. These cross-links are a major cause of the reduced elasticity in skin and blood vessels that occurs with aging, among many other issues, but even blood vessel stiffening taken on its own is enough to kill people through hypertension, distortion of cardiovascular system tissues, and eventual catastrophic failure of the heart or blood vessel integrity.

The important thing to realize about glucosepane and research into cross-links is that next to no tools and methodologies exist to allow researchers to work with this compound in tissues and cell cultures. This is one of many small blind spots in the life sciences, places where the lack of basic development, documentation, and tooling has led to company after company, research group after research group deciding to do something else with their limited funds rather than be forced into building every last part of the basic toolkit they'd need to even get started. So while biotechnology has advanced by leaps and bounds on every side, every individual along the way made a rational short-term decision not to touch this area of research - and this despite the fact that it is a big, obvious target for the development of therapies that could help to extend healthy life and treat or prevent a wide range of age-related conditions that cause a great deal of suffering and death. Getting on with the thankless work of building the tools needed for glucosepane research was taken up some years ago by the SENS Research Foundation as a part of their efforts to unblock the road to rejuvenation therapies.

As for all such research programs coordinated by the SENS Research Foundation, this work was funded by philanthropic donations, including yours and mine made in past years. If you like what you see here, note that we're matching your donations to SENS rejuvenation research for the rest of this year. Giving money to SENS research is a great way to help ensure that more progress occurs in the years ahead, moving down the road towards therapies capable of bringing aging under medical control, preventing age-related disease, and greatly extending healthy life.

As an aside, you'll see that the publicity materials quoted here talk about diabetes front and center. This is because the lifestyle disease of type 2 diabetes is where the funding is for cross-link research: yet another example of aging as the red-headed stepchild of medical science, locked in a closet and fed scraps, ignored in comparison to its potential for alleviating suffering and preventing death. In reality the real relevance is aging and the treatment of aging. Arguably the cross-link biochemistry of diabetic patients is somewhat removed from that of a healthy individual, as short-lived cross-links, including those that arrive in the diet, become much more important as a source of harm to organs in such a dysfunctional metabolism. It is a whole different picture, in which some facets overlap, but of course research establishments must ever follow the funding.

SRF-Funded Glucosepane Paper in Science

A new study funded by the SENS Research Foundation sheds greater light on diabetes and aging through a synthetic process. The new process will allow researchers to study glucosepane, a key molecule involved in diabetes, inflammation, and human aging. Glucosepane is considered to be a critical chemical link in both diabetes and aging. It is also an independent risk factor for long-term microvascular complications in diabetes. With access to synthetic glucosepane, scientists will now be able to generate tools to examine the role this molecule plays in human health and perhaps, develop molecules to inhibit or reverse its formation.

Glucosepane contains a rare isomer of imidazole, which has never before been observed in natural molecules, other than those in the glucosepane family. The researchers developed a new methodology for synthesizing this imidazole form that requires only eight steps.

"We are extremely proud to have supported this project and the developments leading to better insights on diabetes and aging. To have Science recognize the accomplishment of this team doesn't just demonstrate the value of our contribution to medical research; it helps raise awareness that the SENS Research Foundation approach can lead to better insights about aging and age related disease."

Concise total synthesis of glucosepane

Glucosepane is a structurally complex protein posttranslational modification that is believed to exist in all living organisms. Research in humans suggests that glucosepane plays a critical role in the pathophysiology of both diabetes and human aging, yet comprehensive biological investigations of this metabolite have been hindered by a scarcity of chemically homogeneous material available for study. Here we report the total synthesis of glucosepane, enabled by the development of a one-pot method for preparation of the nonaromatic 4H-imidazole tautomer in the core. Our synthesis is concise (eight steps starting from commercial materials), convergent, high-yielding (12% overall), and enantioselective. We expect that these results will prove useful in the art and practice of heterocyclic chemistry and beneficial for the study of glucosepane and its role in human health and disease.


Front and center, the primary plan for longevity for people in middle age and younger today is to help push through enough of the right medical research. Your body is aging, accumulating damage, but methods of repairing that damage are slowly edging their way towards clinical application. Once in the clinic they will slowly become better. At some point the improvement in repair methodologies will add healthy life expectancy for older people faster than a year with every passing chronological year. Everyone with access to the latest stable medical technology at that point will have beaten the curve: they will no longer suffer and die due to aging. The question is where that point occurs in your life span, indeed whether it occurs in your life span, and that is where activism and funding comes in. You can't make yourself younger (yet), but you can help to speed up the development process: it is certainly moving at far below optimal speed at the present time.

That is the primary plan, and for every primary plan there must be a backup plan. Never bet on just one horse. The backup plan for evading the end that comes with death by aging is cryonics: low-temperature preservation of the fine structure of the brain on clinical death. Cryopreservation organizations will maintain the data of your mind in its physical form for the decades it will take for restoration to active life to become a viable possibility. That will, at minimum, require near complete control over cellular biochemistry and regeneration, as well as a mature molecular nanotechnology industry capable of repairing broken cell structures, removing cryoprotectant from tissues, and similar tasks. None of these goals are impossible or unforeseen, it is just that the necessary technologies don't exist today. Preserved individuals have all the time in the world to wait, of course.

A backup plan is never as good as the primary plan. That is why it is the backup plan. In order to be cryopreserved you have to undergo a very unpleasant set of experiences; you have to age and you have to die, and do so naturally with little help, since our backwards legal systems don't allow for assisted euthanasia in a constructive way that can mesh with cryonics protocols and organizational procedures. Further, in comparison to remaining alive and healthy thanks to the development of working rejuvenation treatments, cryonics will for a long time to come be a leap into the dark with an unknown chance at ultimate success. It is still infinitely better than any of the other possible choices open to the billions who will die too soon to benefit from near future rejuvenation therapies.

Strangely, after four decades of organized operation cryonics remains a tiny, niche, non-profit industry. This is the case for reasons that remain unclear and much debated. Cryopreservation is certainly a far better option than the many strange things people choose to have happen to their bodies following clinical death, usually for no better reason than everyone else does it. Is it little more than the fact that you have to prepare some time in advance to make it cost-effective via life insurance? The reluctance to embrace cryopreservation over the grave and oblivion may have some of the same roots as the reluctance to support research into the treatment of aging as a medical condition and extension of healthy life spans. At root all it would really require for cryonics to grow to become a dynamic and competitive industry is for more people to sign up and express interest.

In recent years the popular press have transitioned from ridicule to balanced respect on the topic of cryonics, and the level of attention has increased. I think at least some of this has to do with growing interest in treating aging as a medical condition, though the relationship may be indirect: people who influence opinions tend to support both life extension and cryonics research and development. In the past decade we've seen a growing acceptance of the transhumanist ideals for longevity and the defeat of death that were first discussed realistically and robustly over the course of the 1960s to the 1980s. Many more people are now on the inside of what was once a small intellectual circle, and visionary thinking from that time is now taken as a foregone conclusion for technological development. That said, journalists are ever journalists and still largely miss the very important difference between freezing, which is something that cryopreservation seeks to avoid, and vitrification, which is the goal of modern procedures. Freezing produces ice crystals which are highly damaging to tissues, whereas vitrification minimizes that outcome.

Dying is the last thing anyone wants to do - so keep cool and carry on

Call the headquarters of Alcor in Scottsdale, Arizona, and you are greeted by a recorded message. "If you would like to report the death or near-death of an Alcor member," says a chirpy midwestern voice, "please press two." The Alcor Life Extension Foundation - to give it its full title - has an unexceptional grey concrete exterior that resembles a regional bank branch. Inside, however, are the bodies or brains of 138 dead people, stored in vats of liquid nitrogen in the hope that, at some point in the future, advances made in science will be capable of bringing them back to life.

This is cryonics - the preservation of animals and humans at extremely low temperatures. And in America, business is booming. Last month, Alcor took receipt of its 138th patient: Du Hong, a Chinese science-fiction writer who died of pancreatic cancer at the age of 61 and whose family contacted Alcor shortly before her death to have her brain preserved. Brain-freezing starts at 100,000 and is cheaper than the full-body option, which costs more than twice that amount. Alcor, which describes itself as a not-for-profit organisation, insists that all fees go directly back into running costs.

Brain Freeze: Those looking to cheat death turn to cryonics - being frozen in liquid nitrogen - to one day live again

"I believe that my identity is stored inside my physical brain," says Carrie Wong, president of the Lifespan Society of British Columbia, an advocacy group that works to promote and protect access to cryonic preservation. "So if I can somehow preserve that, maybe at a future time technology and medical science will advance to such a point that it may be possible to repair the damage of freezing me in the first place and also what killed me back then," says the 27-year-old, who concedes such a feat could be hundreds of years in the future. "It's not possible now, but nobody can really argue it's not possible in the future because that's arguing about what future technology is capable of."

The Cryonics Institute, a non-profit organization founded in 1976 by Robert Ettinger, operates a preservation facility near Detroit, where about 100 pets and 135 humans are suspended in tanks called cryostats. "The actual cryostats are just giant thermos bottles with liquid nitrogen, there's no electricity to fail," says president Dennis Kowalski, a 47-year-old Milwaukee firefighter and paramedic who became interested in cryonics in his 20s.

About 1,250 people, including a number of Canadians, are signed up for CI's service. Membership costs 28,000, which is typically paid for through life-insurance policies. While acknowledging that he and others who intend to be frozen are often "looked at as a bunch of kooks," Kowalski views cryonics as being like a clinical experiment - and one that beats the alternative. "I'll be the first to admit it may not work. And everyone who's signed up should understand cryonics may not work and there are no guarantees."


Here I'll point out a technology demonstration of mitochondrial gene editing via CRISPR, something that should be of general interest, though debatable relevance to work on mitochondrial repair at the present time. The development of CRISPR, an efficient low-cost method of genetic editing, has opened a lot of doors. In the course of a few short years since the first practical demonstration, use of CRISPR has made genetic engineering projects accessible and affordable to a vastly greater number of researchers than was previously the case. As an infrastructure advance it is about as transformative as the development of induced pluripotency was for the stem cell research community. Cost and difficulty are very important determinants of the pace of progress in a field, and sharp reductions in both of those for genetic engineering suggests that the next decade is going to be very interesting indeed.

The use of transcription activator-like effector nucleases (TALENs) is one of the candidate next generation genetic engineering technologies that was developed prior to CRISPR, though work continues even now. It is promising, but clearly not starting fires to the same degree that CRISPR is: again, it is all about relative degrees of cost and difficulty. Still, you may recall that it was quite exciting to see TALENs working for mitochondrial DNA back when that was first demonstrated.

Mitchondrial DNA (mtDNA) is distinct from nuclear DNA. It is a circular genome made up of a few leftover genes that is resident in each of the hundreds of mitochondria present in every cell. Mitochondria are the evolved descendants of symbiotic bacteria, and their primary - but far from only - activity is to act as power plants, generating chemical energy store molecules that are used to power cellular activities. They still behave much like bacteria: fusing, dividing, passing molecules and even large portions of their internal structures back and forth between one another. Other processes within a cell monitor the state of mitochondria, and flag damaged ones for destruction, recycling their component parts. Somewhere in all of these interacting processes of generation and destruction, there are ways in which mitochondrial DNA can be come damaged, losing the blueprints for vital protein machinery used in some modes of energy store generation. These damaged mitochondria are in some way privileged, more able to evade destruction at the hands of quality control mechanisms despite their dysfunction. They quickly overtake the entire mitochondrial population of a cell - so quickly that researchers don't have a good view of how exactly the process happens; they only see before and after snapshots. That cell then becomes harmful and dysfunctional, exporting damaged proteins and reactive molecules into the surrounding tissue. The accumulation of such cells over time is one of the contributing causes of degenerative aging.

So as you can see, the ability to edit mitochondrial DNA to fix it is of potential interest. But what can be done here? Can the existence of these dysfunctional cells be fixed for a long enough period of time via a global gene therapy of some sort that directly delivers replacement genes to mitochondria? Or will the continued presence of broken variants just quickly overwhelm any freshly delivered working variants? After all, the damaged variants already achieved that goal in the cells they have taken over, and they are still there in large numbers. There has been sufficient doubt on that front for the research groups involved in efforts to repair damaged mitochondria to adopt other, less direct approaches. These include allotopic expression, in which copies of mitochondrial genes are placed into the cell nucleus, altered in ways that ensure the proteins produced can find their way back to the mitochondria where they are needed. Development of that approach for inherited mitochondrial diseases is at a fairly advanced stage, but it has yet to be applied to aging. With a large fall in the cost and difficulty of mitochondrial gene editing, it may be worthwhile revisiting this picture, however. I'm sure some researchers will do just that in the years ahead.

Efficient Mitochondrial Genome Editing by CRISPR/Cas9

Mitochondria play roles in many important cellular functions. Mitochondria contain their own genome, which encodes 13 proteins that are subunits of respiratory chain complexes, as well as two rRNAs and 22 mitochondrial tRNAs. Due to the critical roles of genes encoded by mtDNA, maintenance of mitochondrial genome integrity is quite important for normal cellular functions. Mitochondrial DNA are, however, constantly under mutational pressure due to oxidative stress imposed by radicals generated by oxidative phosphorylation or an imbalance in the antioxidant defense system in aging or disease processes. Damage to mtDNA, such as point mutations or deletions, contributes to or predisposes individuals to a variety of human diseases.

Despite the huge potential of mitoTALEN-mediated mtDNA editing, more user-friendly and efficient alternative methods are necessary to overcome difficulties in mtDNA modification either for correction of dysfunctional mtDNA or for producing dysfunctional mtDNA in order to create mitochondria-associated disease models.

Here we report a novel approach to generate mtDNA dysfunction with the CRISPR/Cas9 system. Cas9, widely used for genome editing, showed distribution to mitochondria as well as the nucleus. Expression of FLAG-Cas9 with gRNAs designed to target mtDNA resulted in cleavage of mtDNA and alterations in mitochondrial integrity as determined by Western blots for some mitochondrial proteins. Moreover, regular FLAG-Cas9 was modified to contain mitochondrial targeting sequence instead of nuclear localization sequence (NLS) in order to localize it to mitochondria (namely, mitoCas9). MitoCas9 robustly localized to mitochondria; together with gRNA targeting of mtDNA, specific cleavage of mtDNA was observed, demonstrating its functional application for mtDNA editing.

These results together demonstrate the successful application of CRISPR/Cas9 in mitochondrial genome editing and suggest the possibility for in vitro and in vivo manipulation of mtDNA in a site-specific manner.


Today I'll point out a study whose authors believe that the the fairly new consensus on sitting as a bad influence on long-term health is essentially mistaken. That there is a correlation between time spent sitting and mortality has been one of the more interesting results to emerge in recent years from the sea of statistical data on long-term health in humans. If this was just a matter of more time spent being sedentary correlating with higher mortality rates this would not be remarkable; that is the expected outcome in the middle range of the dose-response curve for moderate levels of exercise. No, what drew attention was the fact that time spent sitting seemed to be an independent risk factor for common causes of mortality, unrelated to the time spent exercising. In that model, you can be diligently jogging every day, but spend an extra hour in a chair while your equally diligent peers are standing and your life expectancy is worse.

If you look at the last five years you'll see a sudden blossoming of studies correlating time spent sitting down with telomere length, cancer rates, arterial stiffness, and all sorts of other measures of health and the slow slide into old age and disease. Given that people who are more sedentary do sit more we should probably take it as read that many of these studies are essentially unrelated to the interesting point above - they are picking up on the standard, well-worn correlation between poor health, lower life expectancy, and sedentary behavior. Still, some very large data sets show signs of this independent relationship between sitting and higher mortality rates.

One of the other interesting results to come out of large statistical studies of health in the past few years is the degree to which low levels of activity appear to make a difference. Things along the lines of puttering around in the garden or washing dishes have only been well quantified in large studies with the comparatively recent advent of low-cost accelerometers such as those present in mobile devices nowadays. With that data in hand, this sort of low-level exercise seems to be beneficial enough to need to be taken into account.

This leads us back to sitting: is it is the sitting, or is it the lack of puttering around that is contributing to this correlation, assuming that causation is involved and flows from the level of activity to quality of health? The researchers here argue that past conclusions on sitting are misinterpreting the issue, and immobility is the problem - sitting makes no difference if considered independently of exercise levels. That said, this is one study of a few thousand people, which at the moment is to be weighed against opposing studies with probably somewhere near a hundred times as many participants. As ever, more research is needed, but hopefully the whole business of how to eke out an extra year or three of health in old age via lifestyle choices of this sort will become a moot point soon enough to matter for those of us considering it today.

Sitting for long periods not bad for health

New research has challenged claims that sitting for long periods increases the risk of an early death even if you are otherwise physically active. The study followed more than 5000 participants for 16 years, making it one of the longest follow-up studies in this area of research, and found that sitting, either at home or at work, is not associated with an increased risk of dying. The participants included 3720 men and 1412 women drawn from the Whitehall II study cohort.

The study participants provided information on total sitting time and on four other specific types of sitting behaviour (sitting at work; during leisure time; while watching TV; and sitting during leisure time excluding TV) as well as details on daily walking and time spent engaged in moderate to vigorous physical activity. Age, gender, ethnicity, socioeconomic status, general health, smoking, alcohol consumption and diet were all taken into account. The study showed that over the 16 year follow-up period none of these five sitting measures influenced mortality risk. Future work will consider whether long periods of sitting are associated with increased incidence of diseases such as heart disease and type II diabetes, and will investigate the biological mechanisms that underpin previously observed associations between sitting time and health outcomes.

Associations of sitting behaviours with all-cause mortality over a 16-year follow-up: the Whitehall II study

Sitting behaviours have been linked with increased risk of all-cause mortality independent of moderate to vigorous physical activity (MVPA). Previous studies have tended to examine single indicators of sitting or all sitting behaviours combined. This study aims to enhance the evidence base by examining the type-specific prospective associations of four different sitting behaviours as well as total sitting with the risk of all-cause mortality.

Over 81,373 person-years of follow-up (mean follow-up time 15.7 ± 2.2 years) a total of 450 deaths were recorded. No associations were observed between any of the five sitting indicators and mortality risk, either in unadjusted models or models adjusted for covariates including MVPA. Sitting time was not associated with all-cause mortality risk. The results of this study suggest that policy makers and clinicians should be cautious about placing emphasis on sitting behaviour as a risk factor for mortality that is distinct from the effect of physical activity.


Monday, October 12, 2015

James Bedford was the first person to be cryopreserved following death, and unlike the others from that early era of cryonics he remains preserved today, nearly fifty years later, at the Alcor facility. It is an open question as to the degree to which the crude preservation methodologies of the time damaged the fine structure of his brain due to ice crystal formation, making restoration a far more complex project, requiring far more advanced future technologies. Even taking that into account restoration is a theoretical possibility, a project that lies within the bounds of the laws of physics as we understand them, which is more than can be said for all of Bedford's peers. They are gone to the grave and oblivion, beyond any hope of a renewed life in the future.

Jeanne Louis Calment is listed as the longest-living (verified) human being in history. She was born on February 1875 and died on 4 August 1997, at the age of 122 years, 164 days. As of October 2, 2015, Ms. Calment's record has been broken by cryonaut Dr. James Bedford, who is maintained in cryopreservation by the Alcor Life Extension Foundation.

Bedford was born on April 20, 1893. As of today, October 6, 2015, he has survived for 122 years, 167 days. It is true that Bedford is not currently alive. But neither is he dead. When Alcor transferred him from an old, customized vessel back in 1991, it was clear that the original ice cubes created at the time of preservation were intact. We have no good information on the quality of the ultrastructural preservation of his neural tissue. But we can say that he has remained cryopreserved since 1967, and so deserves the title of longest-surviving human being in history!

Monday, October 12, 2015

BioViva is a small group that recently announced they have moved ahead with a human test of telomerase and myostatin-related gene therapies as a potential method to modestly slow the effects of the aging process. Their initial goals are to get things moving in this part of the field by taking this step forward, observing the results, and raising funding for further development efforts to try to lower the costs of this sort of approach. The BioViva CEO Liz Parrish, who is also the initial test subject, recently hosted an AMA (ask me anything) event at Reddit's /r/futurology community. Her comments below are lightly edited for continuity, since they are pulled from numerous distinct answers to questions posted by the community:

I am patient zero. I will be 45 in January. I have aging as a disease. To take on this role myself was the only ethical choice. I am happy to step up. I do feel we can use these therapies in compassionate care scenarios now but we will have to work them back into healthier people as we see they work as preventive medicine.

The genes targeted are human telomerase reverse transcriptase (hTERT) and follistatin (FST). In animal models neither FST nor hTERT have increased the risk of cancer. We expect to see the same result on myself, and to that effect we are measuring all known cancer biomarkers. The gene therapies on my body are to measure the effects on humans. There is plenty of animal research to support these gene therapies but no one was conducting human tests. We are using both visual biomarkers, MRI and a panel of blood and tissue testing including work on telomere length and epigenetic testing. We are collecting as much data as we can, but unfortunately we currently don't have the coverage rate for this therapy, how much of the tissue of the body is affected. Depending on the tissue and vector used we ultimately expect to see similar rates of transfection as seen in mice, which is somewhere between 5 to 60%.

We are working as hard as we can to bring it to the world as quickly and safely as possible. We will will evaluate monthly and within 12 months we will have more data. If the results are good we hope to have something to the general public, that is cost acceptable, in 3-5 years. Our goal is to build laboratories that will have the mission of a gene therapy product at a reduced cost. Gene therapy technology is much like computing technology. We had to build the super computer which cost 8 million in 1960. Now everyone has technologies that work predictably and at a cost the average person can afford. We need to do the same with these therapies. What you will get in 3-5 years will be vastly more predictable and effective that what we are doing today and at a cost you or your insurance can cover .

We need a lab that works solely to bringing those costs down. We would need about 1 - 1.5 million to build one lab to focus on this. We can expand as needed. I would love to crowdfund this project but I do not know how to get good results at that scale - I think the price tag is high for that modality. We are raising investment to do offshore clinical trials. Many USA companies do this. If we can cut costs we will be able to bring back a treatment that people can afford.

Tuesday, October 13, 2015

Researchers here reinforce the point that, yes, being obese is bad for your health, and that a few prior studies that suggested otherwise were mistaken. In any field there are always going to be studies that appear to go against the grain to provide contradictory results. Most of the time these are errors of interpretation; scientific research is hard and complicated, and as a consequence a lot of published work is incorrect in some way. That is why one should never take any single paper in isolation, but look at it in the context of the broader field. In the case of excess fat the broader field has provided a mountain of evidence to show that adding and maintaining more fat tissue causes worse health, greater medical expenditures, and a shorter life expectancy.

It is unfortunate that some factions within our society are willing to cherry pick research to support and propagate the mistaken belief that being overweight is safe and has no effect on health. Everyone who has managed to get themselves into a deep hole wants to be told that they are just fine and haven't caused any harm, but that doesn't make it true.

Researchers set out to solve a puzzle: Why is it that study after study shows obese or overweight people with cardiovascular disease outliving their normal weight counterparts? Would this phenomenon, referred to as the obesity paradox, hold up when approached within different parameters? According to their latest research, the answer is no. When accounting for weight history in addition to weight at the time of survey and when adding in smoking as a factor, obesity is harmful, not helpful, to someone with cardiovascular disease. "There are claims that ... it's good to be obese when you have cardiovascular disease, that if you have fat stores, maybe you'll live longer. It's conceivable that there are health advantages. But we show they are overwhelmed by the disadvantages of being obese, once you control for these two sources of bias."

The researchers started with data from more than 30,400 participants of the National Health and Nutrition Examination Survey between 1988 and 2011. The survey is a nationally representative sample considered the gold standard in the United States. Of those participants, 3,388 had cardiovascular disease. Most research of this type looks only at weight at time of survey. For example, if a participant who long weighed 300 pounds lost one-third of his mass by the time he weighed in, he would be counted at 200 pounds. Not including weight history, however, "would be like classifying a lifelong smoker who quit the day before the survey as a non-smoker, even though we know that if you're a lifelong smoker you carry those risks over even if you stop smoking."

Adding weight history "turns out to have a profound effect on the findings," eliminating the mortality advantage for those who are overweight or obese. Incorporating the second factor, smoking, also contributed to resolving the paradox. Smokers are less likely to be obese, and those who are obese are less likely to smoke. This correlation is much stronger for those with cardiovascular disease, so the researchers limited their pool to lifelong non-smokers. Accounting for weight history makes the obesity paradox disappear. Excluding smokers? That's when being obese equates to significantly higher mortality for those with cardiovascular disease.

The researchers said these results could improve disease treatment, since some clinicians may use the obesity paradox in patient care decisions. "There's every reason to imagine that clinicians are at least confused, and in some cases, are believing that being overweight or obese is a good thing among people with cardiovascular disease, diabetes and other conditions for which a paradox has been demonstrated." Conditions like stroke, kidney disease and high blood pressure, for example. "This may be trickling down into clinical decision making, which is concerning because we don't think it's a real finding."

Tuesday, October 13, 2015

Christine Peterson is co-founder of the Foresight Institute, one of the oldest of the numerous research and advocacy organizations that emerged from the transhumanist community of the 1980s and 1990s, focused on the development of molecular nanotechnology. Her position on longevity and technology is similar to that of Ray Kurzweil, in that there is to my eyes too much of an emphasis on taking action now via optimization of supplements and diet, something that I think cannot produce sufficient benefits to merit the investment in time required. Further, you'll never in fact know whether or not your investment in time is actually helping, and the size of the best possible result in terms of healthy life gained is still tiny. From my point of view the only way out of the hole we're in with respect to aging is medical research after the SENS model of repairing the cell and tissue damage that causes aging. Everything else is a distraction.

The October 1, 2015 podcast of The Optimized Geek featured Foresight Co-Founder and Past President Christine Peterson: A Glimpse at the Future Lifespan of Humans (55 minutes). Christine explained the development of nanotechnology in three stages. Currently we are moving from the first stage focus on nanomaterials, like stain-resistant pants, into the second phase, dominated by nanoscale devices. The most exciting change change will come with the third stage, in which systems of molecular machines will operate with atomic precision. In responding to a question on what we might see in the next ten years, Peterson suggested that although nanotechnology in that time frame would still be mostly about nanomaterials and simple nanodevices, one of the most interesting applications would be in health, giving the example of more effective diagnosis, imaging, and treatment of cancer through enhanced targeting specificity.

What might advanced nanotechnology look like 30 years from now? Peterson began with the question: What limits do the laws of physics set on what we can build with systems of molecular machines able to build with atomic precision, including inside the human body? One of many applications would be correcting DNA mistakes and mutations cell by cell. Other targets could be damaged proteins and plaques from Alzheimer's, etc. With this level of technology, lifespans would not be limited by aging or traditional diseases, but only by accidents that destroyed the brain, leading to estimated lifespans on the order of 10,000 years. With technology to record the molecular structure of brain, back-up copies of individual brains could be made, eliminating even the 10,000 year limit.

Peterson described "the quantified self" and "biohacking" as taking an engineering approach to making changes and improvements in our bodies. Approaches range from the traditional, like diet, exercise, and stress reduction, to the more exotic, like supplements to improve brain chemistry, or to improve health and longevity. Peterson cautions however, that while taking supplements is easy, figuring out which supplements to take is difficult. Although not of immediate use for those who want to take action now to improve their health and longevity, for those who want to advance research in longevity, Peterson recommended Aubrey de Grey's SENS Research Foundation.

For those who, due to illness or advanced age, will not be able to survive until the future when aging is cured and disease eliminated, Peterson addressed the question of whether there is available today some form of suspended animation to maintain a body until it can be repaired. In the early days of "cryonics", recently deceased bodies were placed at low (liquid nitrogen) temperatures for preservation. Later, certain chemicals were introduced as antifreeze to reduce biological damage caused by freezing. More recent technology has introduced improvements that have been tested on donated organs that are reversible; that is, a viable organ can be recovered from low temperature preservation. Arrangements can be made with cryonics organizations - the largest one is Alcor Life Extension Foundation - to implement for you the best suspended animation technology available at the time that you need it. Peterson shared that she is signed up for it because "I do not see a down side."

Wednesday, October 14, 2015

Transposable elements are parasitic DNA sequences that have attached themselves to the genome over the course of evolutionary history. They are rigorously suppressed in normal cellular operation, but that suppression appears to fail with age, leading more cells to suffer replication of these transposable elements. This activity shows up in senescent cells, for example.

Some researchers, such as the authors of the paper linked here, argue that rising activity of retrotransposons - or transposable elements - in our DNA are a cause of aging. This is a subgroup of those who think that, more generally, accumulated stochastic nuclear DNA damage is a cause of aging above and beyond paving the way to higher levels of cancer. It is thought to disarray the activities of cells to a large enough degree to disrupt tissue function. As for transposable elements, the data can be argued either way: while the correlations are strong and DNA damage is shown to raise cancer risk, there is no good experimental evidence to demonstrate that nuclear DNA damage in isolation significantly contributes to aging in other ways across the current length of a human life span, nor to definitively answer the question of whether transposable element mobilization is closer to being a root cause or closer to being an end consequence in aging.

As in many of these mechanisms, the best and fastest approach to obtaining that answer would be to repair the damage and see what happens - assuming that repair to be feasible. For stochastic DNA damage, this is becoming somewhat more practical as a future possibility with the falling cost of gene therapy and improved techniques such as CRISPR, but the challenge here is substantial: how to fix different forms of damage in every cell. Short of full-blown molecular nanotechnology, the development of complex programmable machines built of DNA or similar, capable of figuring out what to fix in situ inside a cell, I see few options.

Understanding the molecular basis of ageing remains a fundamental problem in biology. In multicellular organisms, while somatic tissue undergoes a progressive deterioration over the lifespan, the germ line is essentially immortal as it interconnects the subsequent generations. Genomic instability in somatic cells increases with age, and accumulating evidence indicates that the disintegration of somatic genomes is accompanied by the mobilisation of transposable elements (TEs) that, when mobilised, can be mutagenic by disrupting coding or regulatory sequences. In contrast, TEs are effectively silenced in the germ line by the Piwi-piRNA system.

Here, we propose that TE repression transmits the persistent proliferation capacity and the non-ageing phenotype (e.g., preservation of genomic integrity) of the germ line. The Piwi-piRNA pathway also operates in tumorous cells and in somatic cells of certain organisms, including hydras, which likewise exhibit immortality. However, in somatic cells lacking the Piwi-piRNA pathway, gradual chromatin decondensation increasingly allows the mobilisation of TEs as the organism ages. This can explain why the mortality rate rises exponentially throughout the adult life in most animal species, including humans.

Wednesday, October 14, 2015

Researchers here investigate copy number variations in the context of a long-lived human study population, finding similar results to those obtained from other studies. Copy number variations in the genome are one of the forms of inherited difference between individuals. Stretches of DNA have duplications or deletions, leading to more or fewer copies of specific DNA sequences. In recent years, with the growing availability of genetic data, an increased frequency of copy number variations has been shown to correlate with higher mortality rates in human studies, and some specific variations seem to be sufficiently uncommon in older people to suggest that they cause harm over the long term in some way.

It is worth considering that the purpose of progress in science is to gain more knowledge of this sort of intricate relationship between DNA differences and natural variations in life span - to understand how the system works if left to its own devices. The purpose of progress in medicine, however, is to make these differences irrelevant by intervening in our biology to prevent disease and dysfunction. Methods of repairing the causes of aging will in due course lead to rejuvenation treatments and people who never enter the late stage of life, heavily damaged, in which genetic variations become important determinants of how far a failing body can limp along. There isn't all that much of an overlap between the genetics of aging and the effective treatment of aging: the former is the study of what happens when you cannot treat aging, and all of our attention should be focused on efforts to dig ourselves out of that position.

In this study, we explored the impact of copy number variation on mortality at the extreme end of life by performing a genome-wide investigation of the association between CNVs and prospective mortality in nonagenarians and centenarians. As our main result, we found that an increase in the average CNV length significantly associated with a higher mortality, as did an increase in the total part of the genome occupied by deletions. These findings are consistent with the results of a previous study in which the burden of large deletions was found to be associated with higher mortality, suggesting that longer CNVs, especially deletions, are more disadvantageous. The identified association between a higher CNV burden and increased mortality is generally in line with the proposed role of genome instability, that is, a decrease in genome maintenance and hence an accumulation of genomic changes, in lifespan and suggests that even among the very old, the load of genomic alterations is linked to differences in mortality.

Among the specific deletions and duplications, four deletions were consistently associated with higher mortality across the study populations, as were a single deletion in women and two deletions in men. These seven nominally significant CNVs are surrounded by numerous genes, of which two, TRPM3 and STARD13, have previously been implicated in the regulation of human lifespan. The STARD13 gene has moreover been associated with plasma levels of amyloid beta peptides that, among other things, play a role in Alzheimer's disease and hypertension. In addition, also the CCDC3 and IRAK1BP1 genes could be speculated to play a role in human lifespan, as they have been reported to inhibit inflammation, and the majority of the other genes are involved in cell adhesion, which has previously been linked to longevity and age-related diseases. In addition to their more direct effect on genes, for example, alteration of gene dosage and gene disruption, CNVs may also affect regulatory regions or other functional regions that influence gene expression. Only a few of the seven CNVs found to potentially associate with mortality in long-lived individuals in this study contain known regulatory elements, however.

In conclusion, we found that the genomewide CNV burden, specifically the average CNV length and the total CNV length, associates with higher mortality in long-lived individuals. Our results indicate that CNVs might be important contributors to the genetic component of human longevity and prompt further investigation.

Thursday, October 15, 2015

Here, a few notes on the study of sea anemones, among which are examples of negligibly senescent species. These are comparatively rare species in which individuals do not seem to suffer the effects of degenerative aging, or where they do it is considerably less pronounced than in their near relatives. In lower animals the degree to which individual immortality is possible in principle appears to be greater. The continual and highly proficient regeneration of the sort seen in lower animals such as hydras and anemones, in which every body part can be regrown from a remnant, falls by the wayside somewhere on the way to the evolution of a complex brain and central nervous system, however. It remains an open question as to what of use to medicine can be learned from the study of the biochemistry of negligibly senescent species that are very distant from us:

Sea anemones are soft bodied animals that attach themselves to rocks and coral reefs in shallow waters. There are more than 1,000 species of anemone, varying in size from a few centimetres to more than a metre across. They live in every ocean, from the warmest to the coldest. "As far as we know, these are immortal animals. They live a very long time - one was documented to have lived 100 years. They don't have old age. They live forever and proliferate, just getting bigger." If you cut off their tentacles, they grow new ones. Even if you cut off their mouths they grow new "heads." As long as they are not poisoned or eaten, as is often the case, they seem to go on and on.

They appear to avoid ageing and the adverse effects that humans experience over time. "You should see tumours in these animals, but we have very few descriptions of that. They are constantly replenishing themselves without getting cancer." Instead of ageing, anemones seem to stay young and fully functioning. "If I look at a sea anemone today and compare it to a week later the same structure will be there but many of the cells will have been replaced." How it does this isn't clear. "We would love to be able to find a gene or pathway that allows it to avoid ageing. Sea anemones are the simplest animals we know of that have a nervous system - it's not organised in the same way as ours, but they do have a network of neurons that allows them to respond to stimuli and be very active predators. Genetically, sea anemones share a lot with us. We found a lot of similarities we had not seen when comparing humans to fruit flies or nematodes."

Thursday, October 15, 2015

Smokers have significantly worse health and die younger than the rest of us, with much of this thought to be due to inflammation and other immune system effects. Researchers here look at some of the proteins for which altered levels are already known to be associated with aging and longevity in humans and mice, in particular FGF-21, finding differences between smokers and non-smokers:

The average life span of smokers is more than 10 years shorter than that of non-smokers, and it is said that smoking is a factor which accelerates aging. However, the details of the mechanism which accelerates aging due to smoking was not yet clear. A research group found that smoking habits affected the aging-related molecule α-klotho (αKl) in blood serum. In addition, this group also elucidated that smoking causes a rise in blood serum concentration of fibroblast growth factor (FGF)-21, a factor related to metabolism which has gained attention in recent years.

The group focused on the relationship between smoking and aging, examining the involvement of Klotho in the advancement of aging due to smoking. It was found that the levels of FGF-21 related to metabolism, α-Klotho, and interleukin(IL)-6, a cytokine related to inflammation, were significantly higher in smokers than in never-smokers. In addition, the blood serum concentration of α-Klotho rose in stressful conditions such as lack and sleep and being under emotional stress outside of smoking. FGF-21 is negatively-correlated to adiponectin, which is known as a cytokine related to metabolism, and the rise in FGF-21 in smokers is thought to suggest a metabolic disorder.

By contrast, it was shown that in never-smokers, α-Klotho has a positive correlation with IL-6, but this correlation was not found in smokers. Past reports have stated that α-Klotho holds anti-inflammatory effects, so it is thought that the lack of this correlation between α-Klotho and IL-6 in smokers is possible due to the weakening of anti-inflammatory effects of α-Klotho brought about by smoking stress.

Friday, October 16, 2015

Complaining about the way in which the popular press garbles and misrepresents aging research is evergreen. The economic incentives operating on professional journalists mean that they garble and misrepresent everything; it is how they operate. When you can make money by selling garbled, misrepresented stories as news, and spending more to get it right doesn't cause you to make more money, then it is inevitable that the end result is of low quality. Specialist knowledge and effective fact checking are not cheap propositions when compared with the cost of paying for writers. Some people argue that the situation has become worse in this modern age of low-cost communication, but I suspect that it has just become easier to see the true scope of the problem. After all, these days we have easy access to both original source materials and the specialists who know what is actually going on under the hood.

I don't agree with all of the article quoted below, in particular the matter of whether or not advocates and scientists should avoid talking about greatly extending human longevity. I think that it is useful and necessary to talk about radical life extension of decades or centuries. The bounds of any discussion fall somewhere in the middle of its far extremes, and if no-one is talking about complete medical control over aging, then the middle ends up being support for some mediocre goal such as the original Longevity Dividend proposal of finding drug candidates to slightly slow aging in ways that might add five years to the healthy human life span, assuming you're not already old when the drugs arrive. So much more than that is possible and plausible - actual rejuvenation treatments based on repair of the damage that causes aging - but only if there is widespread support and large-scale funding for the work.

The last few years have seen a dramatic increase in the attention given to science intended to increase healthy human lifespan. This increased coverage, as anyone would assume, should have represented a step forward. With astronomically wealthy private entities such as Google in support, many predicted a move toward a more legitimate and widely accepted status for both the industry and its advocates, investors, and experts. However, coverage of research and developments is still being taken out of context and hyped up to the point of farce. The main issue being the media's fixation with the notion of immortality.

The media's obsession with immortality is of course rooted in the need for an attention-grabbing headline. Ignoring the science and focusing on the possible fantastical outcome of living forever is an easy way to reel in readers. The problem with this coverage is that it doesn't show any interest in the actual progress of science, and further alienates the industry, associating the bizarre with the real and critical.

Furthermore, for readers, these attention grabbing headlines are neglecting the actual scientific processes and complexities of anti-aging research. What we are left with is a stripped down version of the industry, which doesn't reflect the developments in healthy life extension, and withdraws from any real in depth analysis. Advocacy coming from among those who are interested in immortality will no doubt increase, but not the awareness amongst the general population, what the industry is really aiming for.

Rather than being seen as a single issue subject, life extension science wants to be seen for what it is, an important and complex area of science aiming to eradicate age-related disease. Real and, in many ways, awful diseases and conditions which blight us later in life, no matter how much our lifespan has increased. For journalists and news outlets covering life extension, instead of conceding in creating clickbait titles which attract one-time readers on the subject, why do they not engage in a debate and provide real analysis, which would more than likely, over time, establish a base of returning readers.

Life extension has been granted its place in mainstream media, which many areas of science would still love to acquire, but this elevated position is currently not doing anyone any favours. With this obsession with immortality, people who could be potential supporters and advocates of healthy life extension are put off. By asking the question 'do you want to live forever?' rather than 'do you want to see more investment in cures for age-related disease?' the media faces the reader with a fantastic and in many ways terrifying notion, instead of one which is entirely practical and more likely to be universally supported. Greater exposure then, of this kind, has a direct negative impact on advocacy.

Friday, October 16, 2015

Researchers here advocate one of the many varied theories on Alzheimer's disease, in this case that the mitochondrial dysfunction that occurs with age is an important root cause of the condition. Over the past twenty years, a sufficient understanding of Alzheimer's to make good progress in producing therapies has expanded to include the need to understand a fairly large chunk of the cellular biochemistry of the brain: it is a complex condition, and given the ongoing struggles to make the initial approach of amyloid clearance work in any practical way, alternative hypotheses are springing up. You might take note of the point made in this paper on the dubious relevance of genetic studies to much of the prevalence of Alzheimer's, given the tiny proportion of cases that are familial versus sporadic. It is worth bearing in mind when reading other research reports from the field:

Alzheimer's disease (AD) is a progressive neurodegenerative disease that represents the most common form of dementia among the elderly. Despite the fact that AD was studied for decades, the underlying mechanisms that trigger this neuropathology remain unresolved. Since the onset of cognitive deficits occurs generally within the 6th decade of life, except in rare familial case, advancing age is the greatest known risk factor for AD. To unravel the pathogenesis of the disease, numerous studies use cellular and animal models based on genetic mutations found in rare early onset familial AD (FAD) cases that represent less than 1% of AD patients. However, the underlying process that leads to FAD appears to be distinct from that which results in late-onset AD. As a genetic disorder, FAD clearly is a consequence of malfunctioning/mutated genes, while late-onset AD is more likely due to a gradual accumulation of age-related malfunction.

Normal aging and AD are both marked by defects in brain metabolism and increased oxidative stress, albeit to varying degrees. Mitochondria are involved in these two phenomena by controlling cellular bioenergetics and redox homeostasis. In the present review, we compare the common features observed in both brain aging and AD, placing mitochondria in the center of pathological events that separate normal and pathological aging. We emphasize a bioenergetic model for AD including the inverse Warburg hypothesis which postulates that AD is a consequence of mitochondrial deregulation leading to metabolic reprogramming as an initial attempt to maintain neuronal integrity. After the failure of this compensatory mechanism, bioenergetic deficits may lead to neuronal death and dementia. Thus, mitochondrial dysfunction may represent the missing link between aging and sporadic AD, and represent attractive targets against neurodegeneration.


Post a comment; thoughtful, considered opinions are valued. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.