Fight Aging! Newsletter, December 22nd 2014

December 22nd 2014

Herein find a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress on the road to bringing aging under medical control, the prevention of age-related disease, and present understanding of what works and what doesn't when it comes to extending healthy life. Expect to see summaries of recent advances in medicine, 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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  • SENS Fundraiser Success!
  • Progress in α-Synuclein Immunotherapy
  • A Review of Collagen Cross-Linking in Aging
  • "So Does Ibuprofen"
  • Preparation is Vital for a Good Cryopreservation
  • Latest Headlines from Fight Aging!
    • Yeast is Useful in the Study of Aging, But Has its Limits
    • Periodontitis and Amyloid-β, Another Good Reason to Take Better Care of Your Teeth
    • Another Promising Example of Adoptive T Cell Therapy
    • On Studying the Epigenetics of Twins in Aging and Disease
    • An Interview with Bill Maris of Google Ventures
    • Mitochondrial DNA Amounts Correlate with Frailty and Mortality
    • Global Life Expectancy Has Risen by Six Years Since 1990
    • Theorizing on Interactions Between Telomeres and the DNA Damage Response in Cellular Senescence
    • Sensory and Neuronal Influences on Fly Longevity
    • Why do Some Muscles Show Fewer Signs of Aging?


The SENS Research Foundation funds and coordinates rejuvenation research, various ongoing programs that aim to build the foundations of real, working treatments to reverse the causes of aging. Aging is a matter of accumulating cellular and molecular damage, all of which can in principle be repaired, and where in most cases there is a very clear, planned path ahead to the creation of the necessary biotechnologies for repair. The Foundation staff identify the areas most in need of help in the modern research community: stem cell research needs very little assistance, for example, while work on removal of cross-links in tissues would still be going nowhere and have next to no funding if not for the efforts of the SENS Research Foundation and its allies. The work of the Foundation is very important, as it directly speeds progress towards an end to the pain, suffering, and disease caused by aging.

This year a group of us assembled a sizable matching fund, and on October 1st challenged the community to donate, with all donations going to expand the SENS Research Foundation's scientific programs. The generous matching fund founders were Christophe and Dominique Cornuejols, Dennis Towne, Håkon Karlsen, Jason Hope, Methuselah Foundation, Michael Achey, Michael Cooper, and Fight Aging! Over the past three months, more than 500 people have donated in support of SENS rejuvenation research, and I'm pleased to note that the challenge has been met. As a result of your efforts one hundred and fifty thousand will be added to the Foundation research budget in the coming year.

This is no small thing: early stage biotechnology research is not as expensive as you might think. This much money can cover the contributions of several talented young researchers to a year-long program of cutting-edge investigation into one particular cause of aging and the therapies that may help to treat it. Your efforts collectively make a real difference - and not just because you are helping to fund progress in research. Successful fundraisers held in public demonstrate that practical efforts to bring an end to degenerative aging do have a strong base of support, and that in turn attracts others to support this cause. Success in grassroots fundraising is also a very necessary part of bringing high net worth philanthropists and traditional funding sources to support these research programs. People capable of making very large donations for research never lead from the front, but rather always join in at a later stage. They are cautious and very conservative in what they support. They rely on people like us to light their way and illuminate the worthy causes by the fact that we are gathering to speak out and materially support these goals.

So celebration is called for: we set out to raise money for to expand the most important medical research in world, and we did just just that. If you missed out, it is never too late to donate, however. Another matching grant is now in place for the last few weeks of the year, provided by yet another generous supporter. Here is the latest from the SENS Research Foundation:

Fight Aging Challenge Grant Completed

SENS Research Foundation is pleased to announce that you, our generous supporters, have helped us to achieve our Fight Aging Challenge Grant Goal. Every dollar you gave us was tripled by the group of generous donors at Fight Aging! We are so very grateful to everyone who contributed on SRF's behalf. We thank you all. Our #GivingTuesday challenge, in which SRF's own Aubrey de Grey offered to match funds given was also met on December 2nd. Thanks to Aubrey and everyone who helped make our first #GivingTuesday a success.

New Challenge Begins Today!

Everyone at SRF is thrilled at the success of these recent fundraising endeavors, but as a nonprofit we depend on continuing support. We are excited to note that a new challenge grant has been received from Ronny Hatteland, AutoStore - Software Developer. For every dollar we receive from now until the end of the year (December 15 - 31st), the first ten thousand will be matched by Ronny's generous gift. Ronny says, "The work of the SENS Research Foundation gives us all a chance to secure ourselves a healthy future and an extended lifetime to continue to embrace all that life has to offer us. I am very pleased to support SENS Research Foundation and I encourage all of you to join me."

You can donate to the SENS Research Foundation at their website, and since it is a 501(c)3 charitable organization all donations are tax deductible.

PROGRESS IN α-SYNUCLEIN IMMUNOTHERAPYα-synuclein-immunotherapy.php

The protein α-synuclein is involved in Parkinson's disease in much the same way that β-amyloid is involved in Alzheimer's disease. These particular misfolded proteins accumulate with age to form deposits in everyone's brain tissues, but this is seen to occur to a much greater extent in those suffering from the related neurodegenerative condition. There is a lot of research to suggest that this accumulation of amyloid or synuclein is driving disease pathology and death of brain cells, but equally there is a lot of research to suggest that this is far from a complete picture of all that is going wrong in the failing biochemistry of the aged brain. You'll see a lot more debate on the role of amyloid in Alzheimer's disease because work on α-synuclein has not been a going concern for as many years, while many people are becoming impatient with the lack of meaningful treatments resulting from amyloid-focused research programs. That may or may not result from issues with the theories or the focus on amyloid: just as AIDS researchers had to build the next generation of biotechnologies and knowledge to work with viruses, Alzheimer's researchers have had to build much of the modern basis for understanding and working with the cellular metabolism of the brain along the way. These all remain works in progress.

Regardless, we are entering an age in which it is becoming feasible to substitute action to change the state of a diseased brain in place of painstaking investigations of the unaltered disease process. If it is possible to selectively remove β-amyloid or α-synuclein without greatly altering other biochemistry, for example, then observing the results should go a long way towards settling questions over the role of protein aggregates in age-related neurodegenerative disease. Positive outcomes can then also provide the springboard for developing a therapy based on removal of these misfolded proteins.

Immunotherapy, the use of components of the immune system to achieve therapeutic goals, is one of the most promising of today's new biotechnologies. The immune system has evolved many capabilities that researchers would like to take advantage of in medicine, such as selective destruction of cells and removal of some types of metabolic waste products. Immune cells can in principle be steered towards specific targets, and in recent years some success has been obtained in making this happen for misfolded proteins such as β-amyloid or α-synuclein. Below you'll find a long overview of some present efforts in this direction provided by the folk at the SENS Research Foundation, who have great interest in spurring progress in this field of research. Immunotherapies can in theory do more than just help in treating late stage disease, but might also be tuned to eliminate a range of contributing causes of degenerate aging, such as accumulations of amyloid and senescent cells. Get rid of these and the other unwanted aspects of aged tissue and the process of aging can be slowed, halted, and even turned back given effective enough treatments: it is all just a matter of damage repair.

Bold Leaps Forward for α-Synuclein Immunotherapy

Lewy bodies (LB) and other intracellular α-synuclein (AS) aggregates accumulate in the aging nervous system, and a high burden of such aggregates are hallmark neuropathological signs of Parkinson's disease (PD), Lewy body dementia (LBD), multiple systems atrophy (MSA), and other synucleinopathies. Loss of dopaminergic (DA) neurons in the substantia nigra (SN) to aging processes and toxicity are chiefly responsible for the most overt motor symptoms of PD, and it is on the basis of these symptoms that PD is clinically diagnosed. But prior to the onset of motor symptoms, AS pathology is already present in the peripheral nervous system of aging and especially future PD subjects. It is becoming increasingly clear that LB along with other neuronal protein aggregates are key drivers of "normal" cognitive aging.

In a previous post, we surveyed an exciting new development in rejuvenation biotechnology: the sudden emergence and rapid progress toward the clinic of vaccine- and antibody (Ab)-based immunotherapy to remove α-synuclein aggregates from the aging brain. Therapies applying this paradigm to clear β-amyloid protein (Aβ) plaques and soluble aggregates from patients with Alzheimer's disease (AD) is an extremely active field of research, with multiple active and passive Aβ vaccines currently in human clinical trials.

In the earlier posting, we also surveyed research in applying this same paradigm to α-synuclein (AS) aggregates. Since that post, there have been exciting developments in the progress of the two most advanced of these immunotherapies: PD01A, the AS-targeting active vaccine from Austrian biotechnology startup AFFiRiS AG, developed using its patented "AFFITOME" neo-antigen discovery platform of molecular mimicry; and PRX002, a humanized monoclonal Ab (mAb) under development from Prothena Corp PLC, the successor of aggregate-clearing immunotherapy pioneer Élan Pharmaceuticals. In the ensuing months, the two companies have published detailed, promising animal studies of their immunotherapies, including preclinical efficacy studies in animal models of human synucleinopathies. And both immunotherapies are now advancing through early-stage human clinical trials.

The entry of these two AS-targeting rejuvenation biotechnologies into human clinical testing would seem to mark an inflection point. As recently as two years ago, there was little evidence of any academic or biotech industry interest in pursuing clearance of AS as a therapeutic approach to PD, LBD, or other synucleinopathies of aging: after a promising 2005 report, there had been virtual silence. Today, two AS aggregate-clearing immunotherapies have advanced into human testing, with one using an active vaccine approach and the other a passive mAb infusion strategy. Either or both may prove effective. One might speculate that each of these damage-repair therapeutics may exhibit differential targeting of particular AS species or brain regions, as different clinical synucleinopathies exhibit distinct regional localizations and conformations of AS pathology.

You should read the whole thing, as there are some interesting points made in the concluding sections regarding the ongoing siloing of knowledge in many scientific programs relevant to future human rejuvenation treatments. Medical research is enormously broad as well as deep nowadays, and no one researcher can see more than a sketch of what is going on elsewhere. So it is the tendency of researchers in one field to fail to see the opportunity to combine their narrow focus on treatment with those of other distantly removed research groups. Thus otherwise promising lines of research are dropped because the resulting therapies should be best applied in conjunction with, say, stem cell treatments, or removal of other metabolic wastes, or some other biotechnology.


Many types of metabolic waste and byproduct molecules are generated by the normal operation of cellular metabolism. You can't run an engine without exhaust or a factory without waste generation. The majority of these unwanted outputs are swept away to be broken down and recycled by a panoply of varied housekeeping mechanisms, but unfortunately this is not not the case for all of them. Some hardy forms of waste linger, accumulating throughout life, and this problem becomes worse in later years as all of the systems in our biology lose their effectiveness due to damage. The damage of aging in living beings is an accelerating downward spiral because it also degrades the very mechanisms that are in place to repair it on an ongoing basis.

Cross-links in the complex structures of the extracellular matrix are a consequence of some classes of metabolic waste, such as advanced glycation end-products (AGEs). The properties of any given tissue are determined by the nanoscale structure and arrangement of proteins in the extracellular matrix, but cross-links degrade that structure by chaining these proteins together. A growing level of cross-linking can reduce elasticity in softer tissues such as skin or blood vessel walls, for example, and that loss of elasticity has serious consequences for health. Similar loss of structural properties can occur for tissues where strength or ability to bear load are the important factors. There are a lot of different types of AGE, many of which are short-lived because a healthy biochemistry is quite capable of removing them. Some are long-lived and resilient, however, such as glucosepane that accounts for the overwhelming majority of AGEs in old human skin.

Despite breaking down AGEs being an obvious potential target for therapies, and this research meshing well with the strengths of the pharmaceutical industry, it is actually the case that very little work takes place on ways to safely remove persistent AGEs from tissues. It can be argued that this is in part due to a high profile failure in AGE-breaker drug development not so many years ago, but also because there are few tools and laboratories capable of working with glucosepane in any meaningful way. It is an odd oversight, one of those scientific blank spots that perpetuates itself because every group than might choose to work on this area looks at the absence of basic tools and then moves on to something easier and more likely to return a profit. The SENS Research Foundation is at present funding a research program to fix this situation by building the tools needed to work with glucosepane.

Here I'll point out an open access review on the topic of cross-links in the collagen structure of the extracellular matrix, with a focus on tendons in particular:

The role of collagen crosslinks in ageing and diabetes - the good, the bad, and the ugly

The non-enzymatic reaction of proteins with glucose (glycation) is a topic of rapidly growing importance in human health and medicine. There is increasing evidence that this reaction plays a central role in ageing and disease of connective tissues. Of particular interest are changes in type-I collagens, long-lived proteins that form the mechanical backbone of connective tissues in nearly every human organ. Despite considerable correlative evidence relating extracellular matrix (ECM) glycation to disease, little is known of how ECM modification by glucose impacts matrix mechanics and damage, cell-matrix interactions, and matrix turnover during aging. More daunting is to understand how these factors interact to cumulatively affect local repair of matrix damage, progression of tissue disease, or systemic health and longevity.

Various approaches have been taken to prevent formation of AGEs (for an excellent review see "Characteristics, formation, and pathophysiology of glucosepane: a major protein cross-link"). For instance, a reduced alimentary glucose uptake has been shown to be beneficial, as have approaches seeking to breakdown or block intermediate molecular interactions. Further efforts have shown potential benefit in "protecting" amino acid residues by agents that competitively bind aldehydes. Complementing these preventative approaches, some therapeutic approaches have sought to break existing AGE crosslinks.

Contrary to the mentioned preventative approaches, crosslink breaking can reverse AGE crosslinking and its deleterious effects on tissue mechanics and matrix remodeling. Since AGE crosslinks in tendon are only secondary complications of diabetes, most anti-AGE work has been done in other tissues (such as skin and arteries). However, their potential effectiveness was first demonstrated using rat tail tendon. In any case, as far as we are aware there is no study testing the ability of crosslink breaking therapies to ameliorate the predisposition of tendon to mechanical damage, or promote "healthy" tissue remodeling at a repair site.


Every few years a new hot thing emerges in the field of drug candidates to slow aging. It was sirtuins for a while and then rapamycin and there will be others in due course. This happens because it is very possible to raise funding, start a company, and make a lot of money from this sort of thing even if - as is always the case to date - nothing of significance ever comes of it in terms of treatments that can actually extend life. As I've said in the past, this all seems like a really great cover story for the real scientific goal of amassing detailed data on the operation of cellular metabolism. The stated goals of slowing aging serve to draw in investment that would otherwise be hard to find at the needed levels: metabolism is ferociously complex, and trying to map it is chewing up billions of dollars. This is work that should be done, and the faster the better, but I think it disingenuous to talk of any real possibility that significant human life extension can result from it in the next few decades.

For real progress in treating aging an entirely different direction in scientific strategy is needed. Not mining the natural world for drug candidates that might slow down aging in poorly understood ways by altering poorly understood metabolic mechanisms, but rather deliberately aimed efforts to repair the known and comparatively well understood forms of damage that cause aging. We can bypass the need for a full and detailed understanding of how this damage interacts with every part of our metabolism to cause aging by taking the well validated and time-proven list of fundamental differences between old tissue and young tissue - a list of forms of cellular and molecular damage - and then repairing those differences. There is even a detailed set of research plans leading to treatments that can achieve this goal, which is a very large departure from the world of slowing aging through metabolic manipulation, where there is no plan to speak of and nowhere near enough knowledge to create one.

This is not even to mention the fact that slowing down damage accumulation can never be as good as repairing damage in terms of benefits delivered, and slowing further damage can do very little for old people who are already very damaged. The old need repair, and repair as a strategy is simply better overall in any case. It continues to amaze me that the clearly far worse, far more expensive, far less understood approach to treating aging is the one that dominates in this small research community.

In any case, every time a new overhyped drug candidate to slow aging emerges people get excited about it. Short memories, if you ask me. But the next time that someone you know in the community becomes fired up about early stage development of an age-slowing drug candidate that extends life in animal studies you can offer some needed perspective by saying "but so does ibuprofen." And what does ibuprofen do for life span in humans? Nothing meaningful enough to show up in five decades of trials, studies, and worldwide usage.

Ibuprofen Use Leads to Extended Lifespan in Several Species, Study Shows

"We first used baker's yeast, which is an established aging model, and noticed that the yeast treated with ibuprofen lived longer. Then we tried the same process with worms and flies and saw the same extended lifespan. Plus, these organisms not only lived longer, but also appeared healthy." The treatment, given at doses comparable to the recommended human dose, added about 15 percent more to the species lives. In humans, that would be equivalent to another dozen or so years of healthy living.

The three-year project showed that ibuprofen interferes with the ability of yeast cells to pick up tryptophan, an amino acid found in every cell of every organism. Tryptophan is essential for humans, who get it from protein sources in the diet. "We are not sure why this works, but it's worth exploring further. This study was a proof of principle to show that common, relatively safe drugs in humans can extend the lifespan of very diverse organisms. Therefore, it should be possible to find others like ibuprofen with even better ability to extend lifespan, with the aim of adding healthy years of life in people."

Enhanced Longevity by Ibuprofen, Conserved in Multiple Species, Occurs in Yeast through Inhibition of Tryptophan Import

Aging is the greatest risk factor for many diseases, which together account for the majority of global deaths and healthcare costs. Here we show that the common drug ibuprofen increases the lifespan of yeast, worms and flies, indicative of conserved longevity effects. In budding yeast, an excellent model of cellular longevity mechanisms, ibuprofen's pro-longevity action is independent of its known anti-inflammatory role. We show that the critical function of ibuprofen in longevity is to inhibit the uptake of aromatic amino acids, by destabilizing the high-affinity tryptophan permease. We further show that ibuprofen alters cell cycle progression. Mirroring the effects of ibuprofen, we found that most yeast long-lived mutants were also similarly affected in cell cycle progression. These findings identify a safe drug that extends the lifespan of divergent organisms and reveal fundamental cellular properties associated with longevity.

The goal of taking decades and billions to add just a few years to adult life expectancy doesn't fill me with glee. If that much time and money are to be expended, and I am to become old waiting, I want far better expected outcomes for success: decades of healthy life and rejuvenation, not pills to very slightly slow down the remaining decline. Fund research into repair biotechnologies after the SENS model, not the same old drug development programs that gave us a better knowledge of sirtuins and little else.


The cryonics industry provides the only alternative to the grave for people who will age to death prior to the advent of rejuvenation treatments. Sadly, even after four decades of service this remains a small industry and only a tiny fraction of those who die choose to take advantage of what is offered: low temperature preservation sufficient to maintain the fine structure of the brain until such time as the means for revival are created. Everyone else is gone to dust and oblivion, beyond any hope of returning. A number of people have put in a lot of time and effort to describing how the revival of cryopreserved individuals might be achieved under various scenarios, but the bottom line is that it would require some form of mature molecular nanotechnology industry and all its applications, such as swarms of accurately controlled nanorobots, coupled with the sort of precise control over cellular biochemistry, growing from the present cell research community, that we might envisage being the state of the art five decades from now. None of that is impossible or implausible, it is just far away. But if you are stored in liquid nitrogen you have all the time in the world to wait. Many patients have waited for decades already.

The essence of a good cryopreservation is speed. Reaching storage temperature after perfusion with cryoprotectant chemicals that prevent ice crystal formation must happen as soon as possible following clinical death so as to prevent as much loss of structure and cell death as possible. That preservation must happen after natural death is an artifact of the modern legal battle over euthanasia and other aspects of self-determination in end of life decisions: it is illegal to end your own life in most regions and illegal for anyone to help you in near all. Since people can't choose their time, the whole process becomes much more expensive and uncertain. Standby teams and equipment must be on call, for example, and there are any number of accidental circumstances that can delay cryopreservation simply because the time and place cannot be chosen. Further, what if you suffer a condition that destroys your brain along the way? The courts have not been sympathetic to that situation in the past.

Given this legally-ordained environment, I can't emphasize enough just how important it is to be organized and prepared. You can't just sign up as a member with one of the providers like Alcor or the Cryonics Institute and sit back. You must have a plan in place for accidents and unexpectedly fast declines, and you must have a standing plan for the end of your life before it becomes apparent that things are heading that way. When it does happen you'll have other things on your mind, after all.

The Alcor staff posts cryopreservation notices on an ongoing basis that are quite informative from the point of view of learning what not to do, as well as providing a catalog of slings and arrows that can interrupt even the best laid plans. Just the four reports below illustrate that this is often no walk in the park, and the human body fails in unexpected ways and at unexpected times. Alcor and other cryonics organizations try to go above and beyond even when members and their supporters leave little room to create a good outcome in the present legal environment. Beyond that, these notices also put a human face to many of these patients, those generous enough to allow their preservation to be public. These are people just like you and I who are looking ahead to a brighter future, but, like so many of those presently alive and in the later stages of life, have no hope of living to see the rejuvenation treatments that lie just around the corner, relatively speaking. So near and yet so far.

Camelia Petrozzini Becomes Alcor's 130th Patient

Camelia Petrozzini, Alcor member A-2745, was pronounced legally dead on December 1, 2014 in Chicago, Illinois. Petrozzini, a whole body member, became Alcor's 130th patient on December 2, 2014. A-2745, a member who was on Alcor's Watch List due to stage 4 lung cancer, was planning on relocating to Scottsdale to enter into hospice when her remaining time was short. Despite an expectation that she had a few months remaining, she was taken into the hospital in serious condition in late November. Alcor was not notified of her admission until the family called to say her physician expected she had 8-12 hours remaining. Alcor contacted Suspended Animation and requested an immediate deployment to Chicago. While the response team was on the way, Alcor was able to convince the hospital to heparinize the patient, provide chest compressions and immediately begin to cool in the morgue, if she passed before the team arrived.

The patient passed 12 ½ hours later, roughly 60 minutes before Suspended Animation arrived at the hospital. Numerous issues delayed the transfer of the patient out of the hospital but a broken elevator proved to be too much to make the last commercial flight out for the day. To avoid a straight freeze, an air ambulance was secured and the patient arrived at 4 am into Scottsdale, around 21 hours after pronouncement. A neuro procedure commenced and was followed by a quick clean up and reset as another standby had commenced locally.

A-2454 Becomes Alcor's 129th Patient

Confidential Alcor member A-2454 was pronounced legally dead on September 16, 2014 at 7:36 am (Arizona time) in Pittsburgh, PA. A-2454, a whole body member, became Alcor's 129th patient the same day. On the evening of the first day of Alcor's annual Board Summit, we received an emergency Telemed notification that an 87-year-old member had suffered a respiratory arrest following a choking incident and was at a hospital in a suburb of Pittsburg, PA. The individual had been placed on a ventilator, during which a 36-hour therapeutic hypothermia protocol was induced, in an attempt to diminish the damage to the brain and heart caused by the period of prolonged hypoxia.

The deployment committee discussed the likelihood of the individual surviving this event, and based upon the preliminary information provided by the medical providers it was considered quite high. The reporting family member, who previously had his mother cryopreserved with Alcor, considered the situation more grave and was determined to have a standby initiated. He offered to pay for the costs associated with the standby if it did not result in a suspension.

Based upon this request, Alcor decided to send Aaron and his team to the hospital. After the 36-hour protocol ended, it was determined that the individual had zero brain function remaining and the family decided to terminate life support. Within 10 minutes of withdrawing the ventilator, the patient's heart arrested and the team began stabilization and cool down immediately. An air ambulance was used and paid for by the family with hopes that the reduced travel time might mitigate the damage and increase the perfusability of the brain. Unfortunately, extensive cerebral edema had already occurred and was visible upon establishing the burr holes resulting in the perfusion attempt being stopped shortly thereafter.

Hal Finney Becomes Alcor's 128th Patient

Hal Finney, Alcor member A-1436 who chose the whole-body option, was pronounced legally deceased on August 28, 2014 at 8:50 am at the age of 58, in Scottsdale, Arizona. That same day, Hal became Alcor's 128th patient. Hal, who has had cryopreservation arrangements with the Alcor Foundation for over 20 years, was diagnosed with ALS five years ago and placed on Alcor's Watch List and then monitored over the years as his disease process continued to advance. He made it clear that once he lost the ability to communicate, he did not want his vital functions supported any further but should be allowed to cease functioning and promptly be cryopreserved. "It was actually extremely reassuring as the reality of the diagnosis sunk in," Hal wrote in 2009. "I was surprised, because I've always considered cryonics a long shot. But it turns out that in this kind of situation, it helps tremendously to have reasons for hope, and cryonics provides another avenue for a possibly favorable outcome."

Hal's long-stated wishes were to come to Scottsdale once he lost the ability to communicate with family and friends. When that time arrived, he was flown to Scottsdale by air ambulance with his wife, Fran, at his side. Hal and Fran Finney arrived in Scottsdale, Arizona on Tuesday August 26 where Hal was checked into ICU of a hospital near Alcor where the Alcor response team was set-up and waiting. After the family had a chance to say their goodbyes, Hal's ventilator was disconnected and he was allowed to breathe naturally, all while medical providers ensured that he had no conscious awareness of the process. Defying doctors' expectations, he didn't draw his final breath until 38 hours later, shortly before 9:00 am on Thursday August 28. Immediately after pronouncement of legal death, Alcor's standby team went into action, restoring circulation, ventilation, administering an array of medications, and initiating external cooling. Cryoprotective perfusion - to eliminate ice formation - has been completed and Hal is now undergoing cool down to -196C for long term storage where he be cared for until the day when repair and revival may be possible.

Robert Revitz becomes Alcor's 127th Patient

Alcor member, Robert Revitz (A-1963) moved to Scottsdale specifically to be close to Alcor after he started his membership in 2002. He attended monthly Board of Director meetings and local meet-ups when he was able. Struggling from congestive heart failure in addition to bone cancer, he was occasionally admitted into local hospitals for respiratory relief. Alcor's Medical Response Director, Aaron Drake, closely monitored Robert's health for several months.

In 2014, he fell at home where he fractured his hip and never fully recovered following hip replacement surgery. His primary care physician referred him to hospice-at-home in August as his health declined to the point where he could no longer care for himself. Hospice nurses who were caring for him provided frequent updates and eventually called to say that he had taken a turn for the worse. Preferring to conduct a standby in a controlled environment rather than an individual's home, Robert was transferred by ambulance into the same hospital that Alcor typically uses and a standby began. On August 15th, 2014, less than 24 hours after being admitted Robert, a neuro member, was pronounced and became Alcor's 127th patient.


Monday, December 15, 2014

Much insight into the mechanisms of aging and metabolism in mammals has been obtained from studies of yeast, which might seem a little odd at first glance. Nonetheless many aspects of aging and variations in response to circumstances such as calorie restriction are fairly universal and certainly very ancient from an evolutionary perspective. They are shared across a broad range of species, and thus it can be cost-effective to run rapid studies in very short-lived species that are very unlike us. There are nonetheless important differences between these species and limits to what can be learned, however, and the research community is probably approaching these limits.

This is a very readable open access paper on the subject of whether or not yeast studies in aging are past their time, but note that the full paper is in PDF format only:

The success of experimental biology was possible due to the use of model organisms. It is believed that the mechanisms of aging have a universal character and they are conserved in a wide range of organisms. Yeast are a very popular model organism. The use of the budding yeast Saccharomyces cerevisiae as a model organism of gerontology was based on two essential assumptions. The first of them is that the existence of the reproduction limit of each single cell is a consequence of the aging process. In other words, it was assumed that unavoidable death of each individual cell is not a side effect of the chosen strategy of reproduction (budding), as was postulated, but of the aging process. The second assumption was that as the number of daughters produced by a single cell is rather independent of the conditions of growth and on the time that reproduction takes, therefore the age and longevity of yeast can be expressed as a number of the daughter cells produced, instead of units of time. In that case the conclusions drawn from the studies based on such unusual units cannot be directly applicable for other organisms. The comparison can be made only if the units used are at least proportional.

The definition of aging encompasses two different, although probably causally connected phenomena. The term senescence describes various adverse effects which decrease efficiency of vital processes and lead to visible structural changes of the organism. Unavoidable death of individuals seems to be a direct consequence of aging. From evolutionary point of view, aging is treated in two ways, as a programmable or not programmable process. Programmable theories treat aging as a process of adaptation, which is a specific mechanism leading to the altruistic death of an individual for the benefit of the population, and thus preventing a too high density of a population (Medawar Theory). However non-programmable theories treat aging as a kind of trade-off between investment in reproduction and maintenance of the somatic cells. In this sense, priority lies in reproduction while aging is just a stochastic accumulation of damage that leads to impairment of functions and consequently to death. This opinion, which is probably right, has been recently challenged because a number of arguments were collected suggesting a quasi-programmable character of the proximal causes of death. The hyperfunction hypothesis, can be considered a part of the theory of antagonistic pleiotropy. Both seem to explain at least some aspects of the aging process.

Study of the aging process requires to designate certain universal criteria that would allow for their analysis regardless of the type of the model organism used. One such criterion which also corresponds to the definition of this process is to increase the mortality rate as a function of time and a decrease in fertility. However, these criteria even though adequate for many organisms, have raised some doubts as to their versatility, especially if we take into consideration the phenomenon of 'negligible senescence'. This term was introduced in relation to the specific group of organisms for which the mostly used criteria for aging cannot be used. This group includes among others turtles, rockfish or mole-rats. In these species a typical decrease in fertility or increased mortality with age is not observed. Also, no changes indicating a 'progressive loss of function' with age were observed there. Thus, the question arises about the universality of the aging process in the living world and universality of the mechanisms of aging.

Monday, December 15, 2014β-another-good-reason-to-take-better-care-of-your-teeth.php

Periodontitis produces chronic inflammation that is associated with a raised risk of cardiovascular disease and worse cognitive decline in aging. At some point in the near future researchers will be able to control or eliminate the mouth bacteria that cause periodontitis, but for the moment we're all stuck with diligent maintenance as a primary strategy. Here is another good reason to keep up with that work:

The accumulation of amyloid-β (Aβ) plaques is a central feature of Alzheimer's disease (AD). First reported in animal models, it remains uncertain if peripheral inflammatory and/or infectious conditions in humans can promote Aβ brain accumulation.

Periodontal disease, a common chronic infection, has been previously reported to be associated with AD. Thirty-eight cognitively normal, healthy, and community-residing elderly (mean age, 61 and 68% female) were examined. Linear regression models (adjusted for age, apolipoprotein E, and smoking) were used to test the hypothesis that periodontal disease assessed by clinical attachment loss was associated with brain Aβ load using 11C-Pittsburgh compound B (PIB) positron emission tomography imaging.

After adjusting for confounders, clinical attachment loss (≥3 mm), representing a history of periodontal inflammatory/infectious burden, was associated with increased PIB uptake in Aβ vulnerable brain regions. We show for the first time in humans an association between periodontal disease and brain Aβ load. These data are consistent with the previous animal studies showing that peripheral inflammation/infections are sufficient to produce brain Aβ accumulations.

Tuesday, December 16, 2014

Adoptive T cell therapies are one of the most promising methodologies for immunotherapy at the present time. This small trial is for pediatric cancer, and one might argue that you'd expect better results from immunotherapy in children, however. The aged immune system is much less effective at all of its jobs. As is the case for stem cell therapies and their issues in treating the old, we can hope that the challenge of immune aging will simply be an incentive for the research community to develop means to overcome it so that cancer immunotherapies can work at peak effectiveness. After all, cancer in children is rare in comparison to cancer in the old. The economic incentives thus steer developers to put considerable effort into enabling cancer treatments to work well for the old, given a promising line of research to work on.

11 of the 13 patients treated thus far in a clinical trial using genetically reprogrammed T cells to treat relapsed acute lymphoblastic leukemia have achieved complete remission, confirmed by highly sensitive tests designed to detect minute amounts of cancer cells. The trial includes patients with acute lymphoblastic leukemia who have relapsed after a bone marrow transplant and typically have only a 10% to 20% chance of survival with standard treatment. Using immunotherapy, which reprograms the body's T cells to hunt down and destroy cancer cells, researchers have seen an 85% complete remission rate. "In this population of patients, a treatment with a 20% response rate would be considered a success. Having 11 out of 13 patients achieve a complete remission is incredible, but we will keep working until we have 100% in remission."

In the first phase of the trial, [researchers] treated 13 patients with relapsed acute lymphoblastic leukemia using cancer immunotherapy. This phase was designed to demonstrate the safety and efficacy of cancer immunotherapy as a treatment for leukemia and to determine the optimal dose of engineered T cells to administer to patients. Of the 13 patients treated, 12 responded to the treatment and 11 achieved complete remission. One of these patients has since relapsed; the remaining ten are in ongoing remission. The second phase of the trial, which is expected to begin in 2015, will allow even more patients to be treated with what researchers determine is the optimal dose of reengineered T cells. "Our goal is to eventually offer immunotherapy to patients when they are first diagnosed with cancer so they don't have to endure transplants or prolonged chemotherapy and radiation."

Tuesday, December 16, 2014

Collections of twins are the closest that researchers can get in humans to an ideal study situation in which a large number of genetically identical individuals follow the same life courses. Comparison studies with as many factors as possible made the same are a good way to tease out relevant details from an exceedingly complex system that is still poorly understood as a whole. That system here is the sum total of human cell and tissue biology, and its changing operation over the course of a life span: the map of metabolism is at present really only a sketch of the outlines, and contains many large blank areas when it comes to the precise details. An example of the use of twin studies is to identify twin pairs where one has a medical condition and the other does not (a set of "disease-discordant" twins), a situation that should make it much easier to identify important differences and thus more quickly identify the most relevant biochemical mechanisms involved in the development and progression of that medical condition.

Monozygotic (MZ) twins share nearly all of their genetic variants and many similar environments before and after birth. However, they can also show phenotypic discordance for a wide range of traits. Differences at the epigenetic level may account for such discordances. It is well established that epigenetic states can contribute to phenotypic variation, including disease. Epigenetic states are dynamic and potentially reversible marks involved in gene regulation, which can be influenced by genetics, environment, and stochastic events. Here, we review advances in epigenetic studies of discordant MZ twins, focusing on disease.

The study of epigenetics and disease using discordant MZ twins offers the opportunity to control for many potential confounders encountered in general population studies, such as differences in genetic background, early-life environmental exposure, age, gender, and cohort effects. Recently, analysis of disease-discordant MZ twins has been successfully used to study epigenetic mechanisms in aging, cancer, autoimmune disease, psychiatric, neurological, and multiple other traits. Epigenetic aberrations have been found in a range of phenotypes, and challenges have been identified, including sampling time, tissue specificity, validation, and replication. The results have relevance for personalized medicine approaches, including the identification of prognostic, diagnostic, and therapeutic targets. The findings also help to identify epigenetic markers of environmental risk and molecular mechanisms involved in disease and disease progression, which have implications both for understanding disease and for future medical research.

Wednesday, December 17, 2014

The latest Google Ventures annual report has a third of new investments going to the life sciences and health in the past year. This is of interest principally in the context of Calico Labs and its focus on finding ways to treat aging. This interview provides a little more insight into motivations and goals - such as a strong focus on genetics as a path ahead, something that I think, unfortunately, is going to greatly limit the practical outcomes of these initiatives in terms of years of healthy life added.

Genetics and metabolic studies will broadly improve medicine and drive the creation of new and better tools in biotechnology, as does all new knowledge. Yet we all age in the same way and due to the same underlying processes: genetics are not a big factor in the grand scheme of things, and really only play a larger role in the end stages of aging, the faltering and failure of a very damaged biological system. Alteration of genetic programs and the operation of our metabolism to slow aging is not easy and not the best way forward: the optimistic best near future outcome of drugs that can modestly slow aging is of next to no use to people already old. The best way forward for treating aging is to work on SENS-like strategies of repair of the known forms of cellular and molecular damage that cause aging so as to build actual, working rejuvenation treatments that stop people from being old at all. This is a completely different strategic approach to medicine to that taken by the community focused on the overlap of genetics and aging, but one that has yet to gain the support it merits:

Calico was my idea. I'm super proud of it. It came from a thesis I had that no one was studying aging at the genetic level. What is aging, versus the diseases we associate with aging. Say you have cancer, you have this broad thing we call cancer, we're going to irradiate you, and pump this poisonous material into you and hope more of the bad stuff dies than the good. That is going to seem so medieval when we can fix it on a genetic level, and foundation medicine are the first steps to diagnosing it on a genetic level. Not just, you have breast cancer, but what exactly is going on in the that tumor. That is step one. You can see the path ahead to personalize medicine for people.

New ideas are scary. If you said to most people in 1900, would you like to live to be 100, they would have said no thank you, it seems to so unimaginably bad. Now people expect to live to be 70 or 80, and if you asked if they wanted to live to 100 most would probably say yes. Now ask them if they want to live to 200 and most would say, I don't know about that. But the reality is if you were going to die tomorrow and someone offered you another 10 years, most people would take those 10 years. And the beauty of it is you can always opt out. If you don't that extra time, you can always opt out of the system, but I don't have an interest in opting out of the system, nor do I want the people that I love opting out. It's not about scary immortality. What if your grandmother didn't have to die of congestive heart failure or some debilitating stroke where she can't move half her body? Wouldn't that be a good thing? I find that generally when I can talk to people about it and take some of the scary unknown away it becomes less intimidating.

Wednesday, December 17, 2014

Researchers here find an association between the amount of mitochondrial DNA (mtDNA) in tissues and the risk of frailty and mortality. The less mitochondrial DNA you have, the worse off you are likely to be, or so it seems. It is an interesting result, though at this point we can only speculate about how this relates to the role of mitochondrial DNA damage in aging. The many processes involved in mitochondrial dynamics are collectively exceedingly complex and the amount of mitochondrial DNA in cells has no direct relationship to its quality, yet both can impact health.

[Researchers] analyzed the amount of mtDNA in blood samples collected for two large, human studies that began in the late 1980s and tracked individuals' health outcomes for 10 to 20 years. After calculating how much mtDNA each sample contained relative to the amount of nuclear DNA, the team looked at measures of frailty and health status gathered on the studies' participants over time. On average subjects who met the criteria for frailty had 9 percent less mtDNA than nonfrail participants. And, when grouped by amount of mtDNA, white participants in the bottom one-fifth of the study population were 31 percent more likely to be frail than participants in the top one-fifth. "It makes intuitive sense that decreased mtDNA is associated with bad health outcomes. As we age, our energy reserves decrease, and we become more susceptible to all kinds of health problems and disease."

The researchers also analyzed the age at which participants died. In one of the studies, high levels of mtDNA corresponded to a median of 2.1 extra years of life compared to those with the lowest levels of mtDNA. Using data from both studies, the team found that those with mtDNA levels in the bottom one-fifth of the population were 47 percent more likely to die of any cause during the study period than were those in the top one-fifth. They also found that women had an average of 21 percent more mtDNA than men. This could play a small role in why women live two to four years longer than men on average. The research team would like to take repeated blood samples from individuals over several years to learn if and by how much mtDNA levels decrease over time. What the investigators saw in the current study is that, averaged over the population, an increase of 10 years in age corresponded to 2.5 percent less mtDNA.

Thursday, December 18, 2014

Life expectancy at birth is a statistical measure, internally consistent and useful for comparisons across time. Insofar as it has a real meaning it is the average expected life span of a person born now if medical technology going forward exactly repeated past availability and cost over the life spans of people presently at the end of life. Obviously that won't happen, but nonetheless this is still a useful way to keep track of progress. Since it is a measure from birth it is greatly influenced by childhood mortality and mortality due to infectious disease, and indeed much of the gains in life expectancy over the past two centuries have been due to reductions in causes of death while young. That is no longer the case now in most parts of the world, however, and ongoing gains have more to do with reduction of mortality in later years.

This study confirms other work that shows the ballpark growth in life expectancy at birth is something like one year with every four calendar years. Adult life expectancy is also climbing, but more slowly - perhaps one year each decade. This present pace will change as the research community starts to deliberately target aging for treatment, which has not previously been the case. Past gains in life expectancy at age 30 or 60 due to improvements in medicine have been somewhat incidental, side-effects rather than deliberately obtained results.

Global life expectancy for both sexes increased from 65.3 years in 1990, to 71.5 years in 2013, while the number of deaths [per year] increased from 47.5 million to 54.9 million over the same interval. Global progress masked variation by age and sex: for children, average absolute differences between countries decreased but relative differences increased. For women aged 25-39 years and older than 75 years and for men aged 20-49 years and 65 years and older, both absolute and relative differences increased. Decomposition of global and regional life expectancy showed the prominent role of reductions in age-standardised death rates for cardiovascular diseases and cancers in high-income regions, and reductions in child deaths from diarrhoea, lower respiratory infections, and neonatal causes in low-income regions.

For most countries, the general pattern of reductions in age-sex specific mortality has been associated with a progressive shift towards a larger share of the remaining deaths caused by non-communicable disease and injuries. For most communicable causes of death both numbers of deaths and age-standardised death rates fell whereas for most non-communicable causes, demographic shifts have increased numbers of deaths but decreased age-standardised death rates. Global deaths from injury increased by 10.7%, from 4.3 million deaths in 1990 to 4.8 million in 2013; but age-standardised rates declined over the same period by 21%. For some causes of more than one hundred thousand deaths per year in 2013, age-standardised death rates increased between 1990 and 2013, including HIV/AIDS, pancreatic cancer, atrial fibrillation and flutter, drug use disorders, diabetes, chronic kidney disease, and sickle-cell anaemias.

Thursday, December 18, 2014

Cells can enter a senescent state in response to damage, ceasing to divide. This reduces the risk of cancer under most circumstances, but is also a part of the wound healing process. This isn't all good, however. Senescent cells secrete factors that harm surrounding tissue function over the long term, and the growing numbers of these cells with age is one of the causes of age-related disease and dysfunction. Researchers here look more deeply into how various mechanisms in a cell conspire to cause senescence. They are aiming to produce a more unified view of the varied entry points to this cell state. You should scroll down in the open access paper to the diagram near the end - this is a collection of mechanisms that really benefits from a visual explanation:

Genome integrity is preserved by the DNA damage response (DDR) that, in the presence of DNA damage, arrests the cell cycle progression while coordinating DNA repair events. If damage is not resolved, cells can enter into an irreversible state of proliferative arrest called cellular senescence. In the past years, a strong link between telomere-initiated cellular senescence and organismal ageing has emerged, [where aging is] associated with accumulation of markers of cellular senescence and DDR persistence at telomeres.

Since the vast majority of the cells in mammals are non-proliferating, how do they age?Telomere-initiated cellular senescence seems to be a plausible mechanism to explain the ageing-associated functional decline of proliferating tissues in vivo. However, it is reasonable to assume that some other mechanisms may be in place in non-proliferating cells in which no telomeric attrition due to the end replication problem is expected to occur, either because these cells are quiescent or differentiated. Surprisingly however, we and others have shown that telomeres might have a central role in senescence establishment independently from their shortening.

In these reports, random DNA damage [leads] to DDR activation that preferentially persists at telomeres over time. Cells with persistent DDR activation show a senescent phenotype that cannot be prevented by exogenous expression of telomerase, further excluding a contribution of telomere shortening. The mechanism proposed to explain this phenomenon is the suppression of effective DNA repair at telomeres by TRF2, a telomeric DNA binding protein. Consistent with this model, DDR activation at telomeres is more frequent in mouse and baboon tissues from aged animals, when compared with their young counterparts. This observation also suggests that having long telomeres may have an important drawback, since more telomeric DNA can offer a wider target for random DNA damage that cannot be repaired. Indeed, in different mammalian species, telomere length and lifespan are inversely correlated.

Friday, December 19, 2014

Life spans in short-lived animals can be made to vary far more in response to circumstances than the life spans of longer-lived animals. In the case of calorie restriction there is an evolutionary explanation in that if periods of famine are longer in relation to length of life there is a selection pressure for the response to scarcity to induce greater longevity in individuals. There will probably be similar explanations for the many other ways in which a given approach can extend life in mice or flies or worms far more than it can in longer-lived mammals.

One of the discoveries made in studies of fly longevity is that neural sensing plays a strong role in guiding life span variations. Flies in fact have all sorts of interesting peculiarities in their linkage between metabolism and aging, such as the great importance of intestinal function to longevity, and the sensory influences discussed below, but it remains to be seen how many of these are of any real relevance to mammals.

The goal of Dr. Pletcher's lab is to identify and investigate genetic mechanisms that are important in aging and age-related diseases in humans by focusing on equivalent, conserved processes in the fruit fly model, Drosophila melanogaster. He views aging as a "physiological behavior" and is seeking to understand the neural mechanisms of its coordination and execution. In a recent seminar at the Buck Institute, Dr. Pletcher discussed how substances like water and sugar can initiate changes in aging processes by specifically affecting sensory neurons. His lab found that in flies, bitter tastes have negative effects on lifespan while sweet tastes had positive effects. Interestingly, the ability to taste water had the most significant impact: flies that couldn't taste water lived up to 40% longer. One possible explanation for these results is that flies that can't taste water might compensate for this perceived water shortage by converting large amounts of their own body fat into water.

"We are interested in learning how social interactions and sensory perception affect lifespan and healthspan. We are currently collaborating with a few mouse labs to answer these questions. Some of the studies we are conducting involve putting mice on a restricted diet while housing them near other mice that get to eat food. We then ask whether deprivation in this type of environment affects glucose intolerance or other physiological characteristics in the dietary restricted mice. Ultimately, we want to understand how environmental perception affects lifespan. We want to determine what's happened in cells that cause lifespan changes at the molecular level. However, we are also interested in determining whether there's a specific region of brain where lifespan is consistently manipulated when you stimulate those neurons - in another word, a longevity regulatory center."

Friday, December 19, 2014

Not all muscles in the body age equally, it seems, and those surrounding the eye are spared many of the degenerative changes that occur elsewhere. Investigating why this is the case may help to inform other lines of research that aim to revert the characteristic age-related decline in stem cell activity, and thereby restore function to increasingly frail tissues. At present groups working on reversal of stem cell aging are largely focused on the stem cell populations associated with muscles, such as satellite cells, as this is where many of the early relevant discoveries occurred, the tissues are easily accessible, and these cell types are fairly well understood and comparatively easy to work with.

Specific muscles are spared in many degenerative myopathies. Most notably, the extraocular muscles (EOMs) do not show clinical signs of late stage myopathies including the accumulation of fibrosis and fat. It has been proposed that an altered stem cell niche underlies the resistance of EOMs in these pathologies, however, to date, no reports have provided a detailed characterization of the EOM stem cell niche.

PW1/Peg3 is expressed in progenitor cells in all adult tissues including satellite cells and a subset of interstitial non-satellite cell progenitors in muscle. These PW1-positive interstitial cells (PICs) include a fibroadipogenic progenitor population (FAP) that give rise to fat and fibrosis in late stage myopathies. PICs/FAPs are mobilized following injury and FAPs exert a promyogenic role upon myoblasts in vitro but require the presence of a minimal population of satellite cells in vivo. We and others recently described that FAPs express promyogenic factors while satellite cells express antimyogenic factors suggesting that PICs/FAPs act as support niche cells in skeletal muscle through paracrine interactions.

We analyzed the EOM stem cell niche in young adult and aged wild-type mice and found that the balance between PICs and satellite cells within the EOM stem cell niche is maintained throughout life. Moreover, in the adult mdx mouse model for Duchenne muscular dystrophy (DMD), the EOM stem cell niche is unperturbed compared to normal mice, in contrast to Tibialis Anterior (TA) muscle, which displays signs of ongoing degeneration/regeneration. Regenerating mdx TA shows increased levels of both PICs and satellite cells, comparable to normal unaffected EOMs. We propose that the increase in PICs that we observe in normal EOMs contributes to preserving the integrity of the myofibers and satellite cells. Our data suggest that molecular cues regulating muscle regeneration are intrinsic properties of EOMs.


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