FIGHT AGING! NEWSLETTER
August 25th 2014
The Fight Aging! Newsletter is a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: both the road to future rejuvenation and 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 medicine, news from the longevity science community, advocacy and fundraising initiatives to help advance rejuvenation biotechnology, links to online resources, and much more.
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- A Brief Letter to the Long Retired
- An Interesting Paper on Calorie Restriction
- Digging Into the Biochemistry of Lizard Tail Regeneration
- Without New Medical Technologies Your Odds of Living to 100 are Extremely Poor
- Reports from Rejuvenation Biotechnology 2014
- Latest Headlines from Fight Aging!
- We Justify What We Have No Choice In, To Our Detriment
- Death is Wrong, Free PDF Version
- Incremental Progress Towards Xenotransplantation
- An Example of a Targeted Viral Cancer Therapy
- Elite Athletes Live Longer
- Mapping Blood Vessel Elasticity in the Brain
- Human Trials of Young Blood Transfused into Old Individuals
- Media Babble on Greatly Extended Human Longevity is Drifting in a Positive Direction
- Supporting Evidence for Mitochondrial Transfer as Therapy
- Cryopreservation at Alcor
A BRIEF LETTER TO THE LONG RETIRED
Life isn't fair, but you've probably figured that out by now. Your body is corroding, and there's nothing great about that. I guess I'm not telling you anything you don't know here.
So try this on for size: in among all of the modern wonders of medicine, many of which you have become familiar with, some few scientists are working on ways to control the causes of aging and thus put a halt to all age-related disease.
"All?" you might well ask. Well, aging is just another medical condition, so why not? We didn't put up with tuberculosis once we could do something about it. Coughing up your lungs just because everyone else up until that point did as much? That would have been silly.
The good news then is that people are working to make the world a better place. The march of medicine continues. The bad news is that control of aging isn't going to happen soon enough for today's oldest, not even in the best of worlds. There is just too much to do, too little money, and too few people working on it.
Wherever there is progress, someone is the last to miss out. Life isn't fair, as you know. But control over aging could happen in time for the children and grandchildren of today's oldest - if there were more funding and more workers.
You could be a curmudgeon and say "to hell with them, let them take their chances on suffering everything I have." I've known some folk who dug themselves into that mindset; pain is an unpleasant companion.
There are more gracious legacies to leave behind, such as doing something to make the world a lasting better place. So why not fund the daylights out of those scientists working on aging? There is a lot to be said for helping to ensure that your children and grandchildren won't have to suffer your pains and indignities.
The short truth of it is that old age is a blessing, but marred by the unwanted failures of the the flesh. Being old used to be a lot worse than it is today, and one day it will be a lot better than it is now. That is all down to the march of medicine, and a few brave souls deciding to improve the world for their descendants.
Will control over the causes of aging arrive in time for your children and grandchildren? That's a question only you can answer. Fund the daylights out of those scientists, I say. You can find most of them at the SENS Research Foundation, and here's a link were you inclined to think about donating:
AN INTERESTING PAPER ON CALORIE RESTRICTION
There is a little debate over mortality and body mass index in humans. The overwhelming majority of epidemiological evidence coupled with animal studies and what is known of the underlying biochemistry shows that being fat is bad for you on a sliding scale: the more fat, the worse off you are. The occasional study turns up to claim the opposite, which is the way things go in science. It doesn't matter how overwhelming the evidence or solid the theories, it is still possible for professional teams to generate contrary data in good faith, by accident or simply via the whims of statistical chance. So last year a study was published suggesting that the moderately overweight do best in old age, having the lowest mortality rates. This was widely debated at the time and, I think, largely successfully dismantled and shown to be a poor result.
Nonetheless, the wheels of scientific publication move slowly, and that published data is referenced in the interesting paper on calorie restriction linked below, which was probably written before last year's debate wound to a close. Regardless, the general thrust of the paper remains worth reading, which is how to reconcile various short and long term data obtained from the study of calorie restriction, some of which appears at first glance to be contradictory. The practice of calorie restriction greatly improves health and extends healthy life spans in animal studies. In human studies it is shown to greatly improve short term measures of health. As to the few primate studies, there is a great deal of debate over what exactly the results of twenty years of data are in fact showing us, and whether that research was carried out in a way that allows all of the useful conclusions we'd like to see. Under the hood, there are many theories and much evidence on how calorie restriction alters biochemistry to slow aging, but no unified theory as of yet. It is probably very complex. Calorie restriction is a jigsaw with many missing pieces at every level, from the biochemistry all the way up to drawing lines between the results in different species.
Still, calorie restriction is well supported as a beneficial thing to be doing as a human. Eat less and benefit. The big question is whether this is "just" the best thing you can presently do for your long-term health while paradoxically having little effect on your life expectancy, or whether it can add additional years. The present scientific consensus is that it probably won't add more than five to seven years to life, but is just as good as regular moderate exercise in many ways and considerably better in others.
As this paper shows, there are those who don't really look too far beyond simple measures over populations, such as BMI and mortality. I think they are doomed to see only paradox, and whatever resolutions exist are to be found in the lower level details. At some point there has to be a good resolution between detailed observations that show large benefits from calorie restriction, a mountain of statistical population data telling us that being overweight is bad, and a much lesser collection of statistical population data telling us that being overweight isn't bad. Meanwhile, I'll still with the compelling evidence for not eating so much and keeping the fat tissue to a minimum.
How much should we weigh for a long and healthy life span? The need to reconcile caloric restriction versus longevity with body mass index versus mortality data
A recent, very large meta-analysis has shaken the epidemiological community by showing that the lowest inflection point for the BMI-mortality curve (its nadir) lays in the overweight range. Discussion is ongoing among epidemiologists on this topic, some time referred to as the "obesity-mortality paradox." There are several confounding factors, in fact, to consider: for example, smokers tend to weigh less but have higher mortality; some chronic diseases may induce weight loss; the frail elderly with higher risk of death may also experience weight loss, etc.
An important question that gerontologists and epidemiologists should try to answer together is the following: "people who voluntarily choose a CR regimen and are already within a normal BMI range, let us say its upper half, are increasing their longevity or their mortality?" Indeed, when glancing on reports about members of the Calorie Restriction Society, or CRONies (Calorie Restriction with Optimal Nutrition) as they call themselves, we should consider their BMI. In one of the longest studies available, for example, where subject were monitored for a period of 6 years, 28 weight-stable CRONies had an average BMI of 19.7, and they were compared with 28 age-matched subjects on a typical western diet who had an average BMI of 25.6 and served as the control group. These two groups, for example, had BMI values that quite precisely spanned the normal BMI range. If these two groups of persons will keep their body weight constant for the future, what could we predict regarding their longevity? Using as guidance studies like the [the meta-analysis noted above], we should conclude that the control group should experience a lower mortality. Instead, using as guidance the generally accepted idea that CR extend laboratory animals life span together with the few available prospective studies where persons who were leaner in youth or in midlife resulted longer lived, we should conclude that the CRONies will actually experience decrease mortality and extended longevity.
Which somewhat skips over the point that the calorie restriction practitioners in that study had a longevity-associated measurement of biochemistry that was much better than the control group members. To me this is the interesting paradox regarding calorie restriction: why is it that the shifts in biochemistry are so similar between humans and mice, and yet only the mice experience a sizable extension of life as a result?
DIGGING INTO THE BIOCHEMISTRY OF LIZARD TAIL REGENERATION
Many lower species are far more proficient at regeneration than mammals. Some tiny creatures like hydra are enormously capable regenerators, and may even be so good at it that they are effectively ageless. But the simple strategy of "regenerate and replace everything, all the time" is most likely inapplicable to higher organisms that need to maintain the complex fine structure of the brain and central nervous system: a sweeping regeneration of much of the brain would most likely be equivalent to death for mammals, erasing the data of the mind and disrupting other structures and relationships necessary for moment to moment survival.
The ability of species such as salamanders, zebrafish, and lizards to regenerate inner organs, tails, fins, and limbs is much more interesting however. These animals have complex central nervous systems, yet can rebuild portions of themselves and recover from injuries that would permanently cripple or kill most mammals. A fair amount of research in recent years has focused on salamander regeneration, but at this point it is still too early to say whether it will be practical to take any of what is learned and produce a way for mammals to regenerate in the same way. Perhaps the necessary biochemical tools lie buried in the mammalian metabolism, turned off at some point in the deep evolutionary past, or perhaps they have been lost entirely.
It is clearly the case, based upon the fortuitous discovery of MRL mice capable of healing small wounds without scarring, that there are potential improvements to be made. But it is unlikely that there is much shared biochemistry to be found in the mechanisms involved in regeneration in MRL mice, salamanders, and zebrafish. Biology is complex and it is often the case that any two species found to have evolved similar capabilities actually use completely different mechanisms under the hood.
So to the green anole lizard, which like the salamander is capable of tail regeneration. As it turns out, the way in which that regeneration happens is very different in these two species. This somewhat strengthens the case for tempering any optimism regarding limb and organ regeneration in humans achieved via this means. If researchers are in fact examining a range of independently evolved mechanisms in these various species, it renders it less likely that there is a shared heritage dormant in mammals, and more likely that it will be very hard to recreate these forms of regeneration in humans - no shortcuts here. But again, it really is far too early to have more than suspicions about where this will all go. This group of researchers seem optimistic about the study of lizard regeneration, however:
How lizards regenerate their tails: researchers discover genetic 'recipe'
"Lizards basically share the same toolbox of genes as humans. Lizards are the most closely-related animals to humans that can regenerate entire appendages. We discovered that they turn on at least 326 genes in specific regions of the regenerating tail, including genes involved in embryonic development, response to hormonal signals and wound healing. Regeneration is not an instant process. In fact, it takes lizards more than 60 days to regenerate a functional tail. Lizards form a complex regenerating structure with cells growing into tissues at a number of sites along the tail."
Other animals, such as salamanders, frog tadpoles and fish, can also regenerate their tails, with growth mostly at the tip. During tail regeneration, they all turn on genes in what is called the 'Wnt pathway' - a process that is required to control stem cells in many organs, such as the brain, hair follicles and blood vessels. However, lizards have a unique pattern of tissue growth that is distributed throughout the tail.
"We have identified one type of cell that is important for tissue regeneration. Just like in mice and humans, lizards have satellite cells that can grow and develop into skeletal muscle and other tissues. Using next-generation technologies to sequence all the genes expressed during regeneration, we have unlocked the mystery of what genes are needed to regrow the lizard tail. By following the genetic recipe for regeneration that is found in lizards, and then harnessing those same genes in human cells, it may be possible to regrow new cartilage, muscle or even spinal cord in the future."
Transcriptomic Analysis of Tail Regeneration in the Lizard Anolis carolinensis Reveals Activation of Conserved Vertebrate Developmental and Repair Mechanisms
We have carried out the first transcriptomic analysis of tail regeneration in a lizard, the green anole Anolis carolinensis, which revealed 326 differentially expressed genes activating multiple developmental and repair mechanisms. Specifically, genes involved in wound response, hormonal regulation, musculoskeletal development, and the Wnt and MAPK/FGF pathways were differentially expressed along the regenerating tail axis.
However, high levels of progenitor/stem cell markers were not observed in any region of the regenerating tail. Furthermore, we observed multiple tissue-type specific clusters of proliferating cells along the regenerating tail, not localized to the tail tip. These findings predict a different mechanism of regeneration in the lizard than the blastema model described in the salamander and the zebrafish. Thus, lizard tail regrowth involves the activation of conserved developmental and wound response pathways, which are potential targets for regenerative medical therapies.
WITHOUT NEW MEDICAL TECHNOLOGIES YOUR ODDS OF LIVING TO 100 ARE EXTREMELY POOR
Very few people become centenarians, making it to the old age of 100 years. As you pass 80 and 90 years of age your past and current lifestyle choices start to diminish in significance, while genetic variations gain a growing influence on your survival as an increasingly damaged and frail individual. At age 90 something like 75% of your age-matched peers are dead, and that includes a majority of everyone who made the best choices throughout life in health and lifestyle. You can't reliably exercise your way to living to 100, as illustrated by the numbers quoted below: between age 90 and age 100 there is a precipitous fall in survival.
Becoming Centenarians: Disease and Functioning Trajectories of Older U.S. Adults as They Survive to 100
Little is known about the health and functioning of individuals who become centenarians in the years prior to reaching age 100. We examined long-term trajectories of disease, disability, and cognitive function in a sample of U.S. centenarians to determine how their aging experience differs from their nonsurviving cohort counterparts, and if there is heterogeneity in the aging experience of centenarians.
Data are from the 1993-2010 waves of the nationally representative Health and Retirement Study. Among those who had the potential to become centenarians, we identified 1,045 respondents who died before reaching age 100 and 96 who survived to their 100th birthday. Respondents, or their proxies, reported on diagnosis of six major diseases (hypertension, heart disease, lung disease, stroke, cancer, and diabetes), limitations in activities of daily living, and cognitive function.
As they age to 100, centenarians are generally healthier than nonsurviving members of their cohort, and a number of individuals who become centenarians reach 100 with no self-reported diseases or functional impairments. About 23% of centenarians reached age 100 with no major chronic disease and approximately the same number had no disability (18%). Over half (55%) reached 100 without cognitive impairment. Disease and functioning trajectories of centenarians differ by sex, education, and marital status.
It's a great idea to exercise regularly and practice calorie restriction. Research demonstrates that it will make your later life much more tolerable, healthy, and likely a few years longer besides. But don't think that this will produce enormous changes in the end result in and of itself: don't buy into that story. If medical technology fails to advance significantly by the time you are old, then regardless of what you do and have done then you will die on roughly the same schedule as your parents and grandparents. Similarly, your later life will see you much reduced: sick, frail, and in pain, no matter what path you took to get there. You can tilt the scales to make it less terrible, but it is still going to be terrible.
There is only one way to break out of this box, and that is for today's body of medicine to expand and progress to include rejuvenation treatments. The nature of these treatments can presently be envisaged in great detail, such as in the SENS research programs or the noted Hallmarks of Aging paper. There is a short laundry list of forms of damage that accumulate in and around cells, and to reverse and prevent the ravages of age-related disease and frailty all that has to be accomplished is to repair this damage.
I say "all" and of course it is a tall order, but this goal is nonetheless a lot less challenging than continuing along the present path in which researchers try to intervene in the enormously complex late stages of aging. Aging is like rust: simple root causes spiral out into very complex patterns based on the details of random chance and because their surroundings are very complex. Yet much of the research community focuses on proximate causes in age-related disease, trying to decipher details of a process at the very point at which it is most complicated and hardest to understand. The treatments they produce ignoring root causes, and are in essence attempts to adapt a very complicated system to work less poorly when it is damaged. Can you imagine doing this with a car? Rebuilding it to work slightly less poorly while dangerously rusted rather than fixing the rust problem at the source? This approach guarantees that the work of most medical researchers will produce at best marginal, expensive results that do little more than delay the inevitable.
We want to do better than that, and produce meaningful cures for aging - to bring aging under medical control by directly and effectively addressing its causes. That is the only way that most of us will see a hundredth birthday. But if it does happen, if sufficient funding and support arrives, then we will be in far better health at age 100 than any centenarian in history has been, as the causes of aging will be stripped from us, leaving vigor and health in their place.
REPORTS FROM REJUVENATION BIOTECHNOLOGY 2014
If things are comparatively quiet at the moment, it is because a lot of people are attending Rejuvenation Biotechnology 2014 in California. The event is hosted by the SENS Research Foundation in an effort to hasten some of the organization and relationship building needed to speed the clinical development of near future rejuvenation treatments. The basic science for those treatments is in some cases just a few years away from practical utility if funding continues to grow, so some foresight and preparation is called for with regard to the long path ahead. There are many steps on the road leading from limited technology demonstration in the laboratory to widely available therapy in the clinic, and while not all of them need planning at this stage, it is certainly the case that a smooth transition from laboratory research to clinical development doesn't happen without planning and effort.
Some of the folk attending the Rejuvenation Biotechnology 2014 conference are posting on the topic, and many thanks to them for doing so. You might browse the links below:
Live from SENS Rejuvenation Biotechnology Conference
Opening remarks by Mike Kope, CEO of SENS Research Foundation, remind us of how much progress has been made in the field in the last several years, yet also reminds us we still have a way to go. Jerri Riley, VP of Outreach, outlines the agenda for the day, and thanks the audience, sponsors and exhibitors before introducing the keynote speaker, Dr. George Church, a pioneer in genomics and synthetic biology.
Molecular and Cellular Damage as the Cause of the Diseases of Aging
On the stage sits an all-star panel including Aubrey de Grey, Jeff Karp, Caleb Finch, Stephen Minger and Richard Baker, discussing the idea that diseases of aging may stem from molecular and cellular damage that accrues with age. I am trying to not think about the sheer brainpower and knowledge that sits just a few feet away.
SENS Rejuvenation Biotechnology Conference - Toward a New Investment Paradigm
Jim O'Neil is a partner at Mithril Capital Management, which invests in transformative and durable technologies. With a background in as a Regulator at DHHS, he quickly realized that too much regulation is counterproductive. Jim talks about Breakout Labs, which funds emerging technology start ups. He states Mithril wants to right "backwards industries," those which desperately need to be examined and changed to become more efficient. One example he uses is health care, which I can certainly attest to, having worked and consulted in the field for over 20 years.
SENS Rejuvenation Biotechnology - Economic Impact of an Aging Population on the Healthcare System
If this helps people live longer, albeit not necessarily without disease, what are the economic effects we can expect to see? Enter Peter Nakada. Well, if you can model it, you can insure it, right? With a background in Risk Management, Peter tell us that statistical models are not the way to go, as they do not capture "regime shifts", such as advancing technology. For example, mortality rates went up during the Industrial Revolution, due to more dangerous jobs using machinery, increased pollution, etc. These are examples of the "regime shifts" that are not accounted for in statistical models. Yet another reason how you measure is just as important as what you measure.
Studying regenerative medicine, amount of improvement was calculated, along with types of diseases that can be treated by stem cell therapy. It is up to this community to probabalize the benefits of developments such as new organ growth and stem cell treatments. In essence, we need to start thinking about the implications of longevity now, to ensure a better future tomorrow.
SENS Rejuvenation Biotechnology Conference - Cancer Session
We learn that senescent cells drive aging and age related diseases, but why? Apparently, these cells secrete molecules that can act at a distance, affecting multiple neighboring cells, which causes failure of tissue function. [This is] noted to increase inflammation, which is single factor common in all diseases, including cancer. Senescent cells disrupt normal cellular function and structure. For example, premalignant cells injected into mice are activated and turn cancerous with the addition of senescent cells, while injection of non-senescent cells did not result in development of cancerous tumors. How can we fix this? One strategy includes medication which stop cells from secreting [these molecules] yet it needs to be present at all times.
LATEST HEADLINES FROM FIGHT AGING!
WE JUSTIFY WHAT WE HAVE NO CHOICE IN, TO OUR DETRIMENT
Monday, August 18, 2014
People are good at building a belief that whatever cannot be changed in life is in fact a good situation. It is a lie, but it helps keep us sane in the face of miserable situations that we can do nothing about. So while matters are improving with the advance of technology, the world remains packed wall to wall with pain and suffering, and with people who tell us that it is all good. The pain and suffering of aging is the focus here at Fight Aging!, as it is the greatest cause of death and disease. Even here where the cost is so clear and so high positive change driven by progress in medical science is resisted by those who tell us that aging, a terrible degenerative condition that ends in death, is in fact a good thing:
Buddha believed the way to end human suffering was the regular practice of meditation and introspection. But Buddha didn't have biotech. As far as we know, humans are the only species conscious of their own mortality. The theme has dominated human thought for ages untold. Philosophy and religion, built brick by brick over millennia, aim to ease our anxiety over death and impermanence.
Much of our musing has focused on how best to deal with or justify death and suffering because, of all our problems, they look the most unassailable, the least likely to yield to technology. Our mortality motivates us to do great works, we say. Suffering informs deep insights about ourselves. Pleasure is only pleasurable relative to pain.
Above all, it's often said that because death and suffering are a natural part of life, we should resign ourselves to them. In Meditations, Roman emperor and stoic philosopher Marcus Aurelius said, "Despise not death, but welcome it, for nature wills it like all else." But biotechnology wasn't even the hint of a mote in the eye of Marcus Aurelius. And it's fascinating that the modern mind simultaneously rebels against its own mortality and at the thought of abolishing death and suffering.
DEATH IS WRONG, FREE PDF VERSION
Monday, August 18, 2014
Fresh from the success of a fundraiser to distribute copies of the children's book Death is Wrong, the PDF version is now freely available. Grassroots advocacy for longevity science is made up of many such small projects, all of which are collectively necessary as a foundation for attracting greater support from more conservative institutions and high net worth individuals. Large donations only reliably arrive for fields in which public support is active and involved in this way:
At least 1,029 children in at least 14 countries will be taught that death is wrong as a result of the successful provision of Death is Wrong books to 50 longevity activists throughout the world. On August 7, 2014, the last book shipment, free for all recipients, was made, paid for by the funds raised through the Indiegogo campaign I ran in coordination with the Movement for Indefinite Life Extension (MILE). (Read Eric Schulke's earlier article about the success of the fundraiser and the tremendous efforts and publicity that made it possible.) While some of my critics, such as Slate's Joelle Renstrom, preemptively proclaimed that the funds raised would fall well short of the goal, we actually not only reached the goal in time but even exceeded it - and we have already spent all the money raised on providing free books to children.
Now that my campaign to spread over 1,000 Death is Wrong books to children has succeeded, I have asked myself what I could do to spread the book and its message even further. In an effort to increase the readership of the book, I have made the Second Edition available for free download as a PDF file. Perhaps, in this way, the book could reach tens or even hundreds of thousands of readers. Thus far, PDF versions are available in English, Russian, and Spanish.
INCREMENTAL PROGRESS TOWARDS XENOTRANSPLANTATION
Tuesday, August 19, 2014
In between today and a future in which cell therapies are advanced enough to repair organs in situ a range of sophisticated transplant treatments will emerge to address organ failure. Among the present contenders are decellularization of donor organs, artificial organs of various types, including bioprinted tissues, and xenotransplantation, the use of animal organs. The latter is moving towards practicality, step by step:
[Researchers] have successfully transplanted hearts from genetically engineered piglets into baboons' abdomens and had the hearts survive for more than one year, twice as long as previously reported. This was achieved by using genetically engineered porcine donors and a more focused immunosuppression regimen in the baboon recipients. "Until we learn to grow organs via tissue engineering, which is unlikely in the near future, xenotransplantation seems to be a valid approach to supplement human organ availability. Despite many setbacks over the years, recent genetic and immunologic advancements have helped revitalized progress in the xenotransplantation field."
[Reseachers] developed techniques on two fronts to overcome some of the roadblocks that previously hindered successful xenotransplantation. The first advance was the ability to produce genetically engineered pigs as a source of donor organs. The pigs had the genes that cause adverse immunologic reactions in humans "knocked out" and human genes that make the organ more compatible with human physiology were inserted. The second advance was the use of target-specific immunosuppression, which limits rejection of the transplanted organ rather than the usual generalized immunosuppression, which is more toxic.
In this study, researchers compared the survival of hearts from genetically engineered piglets that were organized into different experimental groups based on the genetic modifications introduced. The gene that synthesizes the enzyme alpha 1-3 galactosidase transferase was "knocked out" in all piglets, thus eliminating one immunologic rejection target. The pig hearts also expressed one or two human transgenes to prevent blood from clotting. This longest-surviving group was the only one that had the human thrombomodulin gene added to the pigs' genome. Thrombomodulin expression helps avoid some of the microvascular clotting problems that were previously associated with organ transplantation.
AN EXAMPLE OF A TARGETED VIRAL CANCER THERAPY
Tuesday, August 19, 2014
The present standards for cancer treatment are poorly targeted in comparison to prototype work taking place in the labs and clinical trials. Chemotherapy, radiotherapy, and the like have a detrimental impact on the rest of the body, and their effectiveness is limited by the degree to which they hurt the patient in the process of impacting cancer cells. Their days are numbered, however. A broad range of next generation targeted treatments have been demonstrated in recent years, with few side-effects because they affect only cancer cells and their nearest neighbors. A number of these therapies use existing biological systems as a means of targeting cancer cells, such as viruses:
The patient suffered from multiple myeloma, a cancer of the bone marrow. Last June, [doctors] injected her bloodstream with a form of measles that was genetically re-engineered to attack myeloma cells. The measles therapy followed a decade of unsuccessful treatments from numerous courses of chemotherapy to two stem cell transplants. But the cancer returned time and time again - until now. A year after the measles injections, she's still cancer-free. The idea of using viruses to defeat cancer - called oncolytic virotherapy - is not a new idea. [But] her case is the "first well-documented instance of a patient who has received an intravenously administered virus that has caused complete remission of disseminating cancer. We've known for a long time that this is possible in mice, but we had not known that it's possible in people. We now know it's possible and this should energize the field - but we have a lot of work to do."
Oncolytic virotherapy works by exploiting the fact that cancer cells usually have weak ability to fight off infections. Viruses can infect normal cells, but it's a self-limiting infection, so normal cells can easily overpower these viruses and get rid of the infection. But in the weakened cancer cells, the virus can replicate, destroy cancer cells [and] make more new virus, which can then go and kill more cancer cells around it. [The] treatment is different from a vaccine. "When you administer a vaccine, you give the minimum dose you can give in order to alert the immune system. We are using the virus as a weapon. We give it into a vein and we ask those viruses to seek and destroy the cancer cells. There are a large number of cancer cells in the body, so you need to give a massive dose of virus."
The [researchers] used a strain of the measles virus that has been used in vaccinations since 1954 and "taught it to grow on human cancer cells ... That's how it became specific for cancer." [Researchers] have given this treatment to six patients, but only one of them had a complete response to the treatment. One had a partial response and the others no response at all. One of the barriers to successful virotherapy treatment is the body's own immune system. If an antibody to a virus is present in the patient's blood stream, it will negate the benefit of giving the virus. [The] hope is to have a variety of viruses to use so that doctors can always find ones patients aren't already immune to.
ELITE ATHLETES LIVE LONGER
Wednesday, August 20, 2014
It remains an open question as to why top-level athletes live notably longer than the rest of us. The point of interest is to what degree the longevity difference is produced by exercise and training versus a population bias among successful athletes to more robust individuals who would live longer regardless of their profession. That's hard to answer at this point, and is a part of broader research regarding exercise, in that while moderate regular exercise is clearly beneficial, it is unknown as to whether anything more than merely moderate regular exercise is more beneficial over the long term.
To determine whether the health benefits of exercise are actually confined (or not) to noncompetitive, moderate (or recreational) practice is of broad medical interest and might help clinicians have more evidence-based data on exercise benefits. Thus, we conducted a meta-analysis of cohort studies comparing mortality in elite athletes with mortality in the general population. We hypothesized that the overall health benefits of competitive exercise would counteract any potential detrimental effect, resulting in higher longevity and lower disease risk in elite athletes than in the general population.
Ten studies, including data from a total of 42,807 athletes (707 women), met all inclusion criteria. The all-cause pooled standard mortality ratio (SMR) was 0.67 with no evidence of publication bias but with significant heterogeneity among studies. Six studies provided data on cardiovascular disease (CVD) and 5 on cancer (in a total of 35,920 and 12,119 athletes, respectively). When only CVD was considered as a cause of mortality, the pooled SMR was 0.73 with no evidence of bias or heterogenity among studies. The SMR for cancer was 0.60 with no evidence of bias despite a significant heterogeneity.
The evidence available indicates that top-level athletes live longer than the general population and have a lower risk of 2 major causes of mortality, namely, CVD and cancer. [This] suggests that the beneficial health effects of exercise, particularly in decreasing CVD and cancer risk, are not necessarily confined to moderate doses. Future studies might elucidate whether the present high demands of professional sports participation also translate into an actual longevity and health benefit.
MAPPING BLOOD VESSEL ELASTICITY IN THE BRAIN
Wednesday, August 20, 2014
Loss of elasticity in blood vessels occurs for a number of reasons, including the rising level of persistent cross-links that glue together important structural proteins, effects of chronic inflammation on mechanisms needed for blood vessel elasticity, and so forth. This form of structural failure has material consequences, raising the risk of life-threatening events such as stroke.
Exercise has been shown to slow the progression of blood vessel stiffening, and here a new technique for assessing blood vessel stiffness in the brain adds more data in support of that view. More importantly, this sort of technology will be very useful as a means of rapidly assessing the effectiveness of near future rejuvenation treatments, such as means to break glucosepane cross-links presently funded by the SENS Research Foundation:
[Researchers] have developed a new technique that can noninvasively image the pulse pressure and elasticity of the arteries of the brain, revealing correlations between arterial health and aging. The [researchers] routinely record optical imaging data by shining near-infrared light into the brain to measure neural activity. Their idea to measure pulse pressure through optical imaging came from observing in previous studies that the arterial pulse produced strong signals in the optical data, which they normally do not use to study brain function. Realizing the value in this overlooked data, they launched a new study that focused on data from 53 participants aged 55-87 years.
"When we image the brain using our optical methods, we usually remove the pulse as an artifact - we take it out in order to get to other signals from the brain. But we are interested in aging and how the brain changes with other bodily systems, like the cardiovascular system. When thinking about this, we realized it would be useful to measure the cerebrovascular system as we worry about cognition and brain physiology."
The initial results using this new technique find that arterial stiffness is directly correlated with cardiorespiratory fitness: the more fit people are, the more elastic their arteries. Because arterial stiffening is a cause of reduced brain blood flow, stiff arteries can lead to a faster rate of cognitive decline and an increased chance of stroke, especially in older adults. "Noninvasive optical methods can provide estimates of arterial elasticity and brain pulse pressure in different regions of the brain, which can give us clues about the how different regions of the brain contribute to our overall health. For example, if we found that a particular artery was stiff and causing decreased blood flow to and loss of brain cells in a specific area, we might find that the damage to this area is also associated with an increased likelihood of certain psychological and cognitive issues."
HUMAN TRIALS OF YOUNG BLOOD TRANSFUSED INTO OLD INDIVIDUALS
Thursday, August 21, 2014
Studies of parabiosis, in which a young and an old mouse have their blood systems joined, show that altering the balance of circulating proteins in old tissue can restore stem cells to action and revert a range of measures that change with age. It is thought that frequent blood transfusions should capture at least some of this outcome, although it is unclear as to the degree to which the relevant proteins are short-lived in circulation, and transfusions are really just a stand-in for some yet to be established but more effective way of directly altering levels of the proteins of interest.
Stem cells decline and protein levels change as a reaction to rising levels of cellular damage, or at least that is the dominant view of aging as a process in the research community. In the case of stem cells this may be an evolved mechanism to suppress cancer risk, a balance between death by failing tissue maintenance versus death due to damaged cells running amok. Thus there is some concern that crude changes intended to bring stem cells back into a youthful mode of activity will produce high rates of cancer, but it is entirely possible that this can be avoided while still retaining benefits. First generation stem cell treatments came attached to much the same concern, and where that concern was professionally addressed these therapies are clearly producing meaningful benefits in older people.
In both mice and humans, GDF11 falls with age. We don't know why it declines, but we know it is involved in several mechanisms that control growth. It is also thought to mediate some age-related effects on the brain, in part by activation of another protein that is involved in neuronal growth and long-term memory. So the billion-dollar question is: would a GDF11 boost have the same effect in humans? [Researchers think] it will, having taken the next step of injecting young human blood plasma into old mice. His preliminary results suggest that human blood has similar rejuvenating benefits for old mice as young mouse blood does. "We saw these astounding effects. The human blood had beneficial effects on every organ we've studied so far."
Now, the final step - giving young human blood plasma to older people with a medical condition - is about to begin. Getting approval to perform the experiment in humans has been relatively simple, thanks to the long safety record of blood transfusions. So in early October, a [team] will give a transfusion of blood plasma donated by people under 30 to older volunteers with mild to moderate Alzheimer's. Following the impressive results in animal experiments, the team hopes to see immediate improvements in cognition, [but] cautions that it is still very experimental. "We will assess cognitive function immediately before and for several days after the transfusion, as well as tracking each person for a few months to see if any of their family or carers report any positive effects. The effects might be transient, but even if it's just for a day it is a proof of concept that is worth pursuing."
All researchers involved in the work agree that GDF11 is unlikely to be the only factor that keeps organs youthful. "It's too optimistic to think there would be just one factor. It's much more likely to be several factors that exert these effects in combination."
MEDIA BABBLE ON GREATLY EXTENDED HUMAN LONGEVITY IS DRIFTING IN A POSITIVE DIRECTION
Thursday, August 21, 2014
Radical life extension is the now somewhat dated term for the process of adding decades and then centuries to healthy life spans through near future rejuvenation therapies. The media has a quota system, I think, for turning out articles on this topic that are little better than babble. A stream of consciousness is committed to the page and sent forth into the world. In past years this typically consisted entirely of knee-jerk objections and assertions that death by aging was a wonderful thing: that we live in the best of all worlds in which we are privileged to suffer and die to a schedule not our own, and besides the whole idea of living longer is impossible, as any sensible individual should see, and now let us stop dwelling upon fantasies of a world in which medicine improves and get back to something important, such as the latest celebrity gossip.
It is hopefully not just an illusion in my eyes, but I do believe I see some drift in a positive direction in the babble of late. Babble it may be, but it is still a signal of sorts. There is more of an acceptance of radical life extension as an inevitability, and something of a balancing of views. The same old knee-jerk objections remain in force, but there are also wistful glances at the possibility of a life that is longer and better in all aspects. The times are changing, and the average media figure bends with the wind when it comes to any field in which large and very public investments are now happening. Take this piece from NPR, for example:
Even if we don't spend the day thinking about it (and who could bear it?), pretty much most of what we do is connected in one way or another with the certainty of death. To lose this certainty, to have a vast, unchallenged expanse of time ahead, would certainly change our psyche in very essential ways. The word "legacy" would need to be redefined. Immortality could be quite boring, a life without a sense of pace. An immortal being would be an aberration, opposite to everything that we see around us, a world where transformation and decay is the rule.
Thomas Nagel, [counters] by arguing that, perhaps, an immortal life could still be "composed of an endless sequence of quests, undertakings and discoveries, including successes and failures. ... I am not convinced that the essential role of mortality in shaping the meaning we find in our actual lives implies that earthly immortality would not be a good thing."
Is immortality scientifically viable? We don't know, although many researchers think of aging as an illness that can be treated. It's hard to imagine that science will not be going that way. But here is the key question: If you could extend your life by another 50 or 100 healthy years, would you? Quite possibly, we will be moving toward a "soft immortality" in the next decades. The question of how a very long life will affect our minds will then become an experiment.
Whatever the many debates the topic incites, there is one good consequence of it, as Ed Regis and George Church noted in an essay from 2012: A race of soft immortals would have plenty of motivation to preserve the planet. After all, without Earth, what's the point of pursuing a long life?
SUPPORTING EVIDENCE FOR MITOCHONDRIAL TRANSFER AS THERAPY
Friday, August 22, 2014
Bacteria-like mitochondria are the cell's power plants, and they become damaged with age. This damage spirals out to create a small but significant population of cells that export harmful reactive compounds into surrounding tissues and the circulatory system, contributing to a range of age-related conditions. One possible approach to address this issue involves destroying existing damaged mitochondria and replacing them with undamaged versions. Simply introducing new undamaged mitochondria is an easier proposition but probably not sufficient, as the damaged versions overtake cells because they have an advantage in replication: diluting their numbers won't last very long.
Here researchers provide more evidence to show that simply introducing new mitochondria into a tissue environment is probably sufficient to see them taken up into cells and used. This is great news for work on inherited genetic mitochondrial disorders, where supplying new unmutated mitochondria should be a cure, but it is only a part of any potential treatment for the mitochondrial damage of aging based on mitochondrial replacement:
Mitochondria play an essential role in eukaryotes, and mitochondrial dysfunction is implicated in several diseases. Therefore, intercellular mitochondrial transfer has been proposed as a mechanism for cell-based therapy. In addition, internalization of isolated mitochondria cells by simple coincubation was reported to improve mitochondrial function in the recipient cells. However, substantial evidence for internalization of isolated mitochondria is still lacking, and its precise mechanism remains elusive.
We tested whether enriched mitochondria can be internalized into cultured human cells by simple coincubation using fluorescence microscopy and flow cytometry. Mitochondria were isolated from endometrial gland-derived mesenchymal cells (EMCs) or EMCs stably expressing mitochondrial-targeted red fluorescent protein (EMCs-DsRed-mito), and enriched by anti-mitochondrial antibody-conjugated microbeads. They were coincubated with isogeneic EMCs stably expressing green fluorescent protein (GFP).
Live fluorescence imaging clearly showed that DsRed-labeled mitochondria accumulated in the cytoplasm of EMCs stably expressing GFP around the nucleus. Flow cytometry confirmed the presence of a distinct population of GFP and DsRed double-positive cells within the recipient cells. In addition, transfer efficiency depended on mitochondrial concentration, indicating that human cells may possess the inherent ability to internalize mitochondria. Therefore, this study supports the application of direct transfer of isogeneic mitochondria as a novel approach for the treatment of diseases associated with mitochondrial dysfunction.
CRYOPRESERVATION AT ALCOR
Friday, August 22, 2014
Cryonics is the process of vitrifying the body and brain at death, preserving as much of the fine tissue structure as possible to enable the possibility of future restoration to life. There's no fundamental barrier to achieving that revival other than the fact that the necessary technology doesn't yet exist, and subject to the continuation of storage facilities the vitrified cryopreservees can wait for that time to arrive. A small cryonics industry has existed for some four decades now, with the most established non-profit groups being Alcor and the Cryonics Institute in the US. Several hundred people are presently preserved. It is an undertaking with an unknown timeline and chance of success, but these are the best odds offered to those who will age to death prior to the development of rejuvenation treatments.
Like most popular press articles on cryonics, the piece quoted below confuses low-temperature vitrification with freezing. They are in fact two very different things with very different outcomes on tissue viability: vitrification minimizes ice crystal formation, for example, which is the cause of much of the damage to frozen tissues.
Cryopreservation is a darling of the futurist community. The general premise is simple: medicine is continually getting better. Those who die today could be cured tomorrow. Cryonics is a way to bridge the gap between today's medicine and tomorrow's. "We see it as an extension of emergency medicine. We're just taking over when today's medicine gives up on a patient. Think of it this way: 50 years ago if you were walking along the street and someone keeled over in front of you and stopped breathing you would have checked them out and said they were dead and disposed of them. Today we don't do that, instead we do CPR and all kinds of things. People we thought were dead 50 years ago we now know were not. Cryonics is the same thing, we just have to stop them from getting worse and let a more advanced technology in the future fix that problem."
Alcor's members come from all over the world. Ideally the company will have an idea of when their members are going to die. Alcor maintains a watch list of members in failing health, and when it seems as though the time has come they send what they call a "standby team" to do just that - stand by the person's bed until they die. "It could be hours, days, we've gone as long as three weeks on standby." Once the person in question is declared legally dead, the process of preserving them can begin, and it's an intense one. First, the standby team transfers the patient from the hospital bed into an ice bed and covers them with an icy slurry. Then Alcor uses a "heart-lung resuscitator" to get the blood moving through the body again. They then administer 16 different medications meant to protect the cells from deteriorating after death. Once the patient is iced up and medicated, they move them to a place for surgery.
The next step includes draining as much blood and bodily fluids as possible from the person, replacing them with a solution that won't form ice crystals - essentially the same kind of antifreeze solution used in organ preservation during transplants. Once the patient's veins are full of this antifreeze, Alcor can begin to cool them down by about one degree Celsius every hour, eventually bringing the body down to -196C after about two weeks. Eventually the body finds its final home for the foreseeable future: upside down in a freezer, often alongside three others.
Most members are somewhat squeamish about the actual process of cryopreservation - but they see it as a means to an end. "We don't want to be cryopreserved - we hate the idea in fact. The idea of sitting in a tank of liquid nitrogen not able to control our own destinies is not appealing. But it's a lot more appealing than the alternative, to be digested by worms or incinerated - that doesn't appeal to us at all."