Fight Aging!

FIGHT AGING! NEWSLETTER
June 16th 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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CONTENTS

• The BAIT Project at the Buck Institute
• Aging is Not a Disease (But We Need to Treat It Anyway)
• Young Blood Reverses Age-Related Cognitive Impairment
• A Summer Update from the Methuselah Foundation
• SENS Research Foundation Newsletter for June 2014
• Latest Headlines from Fight Aging!
  • Nuclear DNA Damage Correlates With Aging
  • Quantifying Some of the Benefits of Exercise in Old Age
  • A Popular Science Article on Thymic Regeneration
  • Naked Mole Rats Maintain Cardiovascular Function in Aging
  • The Amyloid Hypothesis, Time to Move On
  • Engineering a Loss of Function PCSK9 Mutation to Reduce Cardiovascular Disease Risk
  • Progress in Growing Retinal Tissue From Stem Cells
  • Stem Cell Guided Gene Therapy of Cancer
  • RAGE is Required for Some Harm Caused by AGE Buildup
  • Physical Activity, Inflammation, and Volume of the Aging Brain

THE BAIT PROJECT AT THE BUCK INSTITUTE
https://www.fightaging.org/archives/2014/06/the-bait-project-at-the-buck-institute.php

The Interventions Testing Program has been underway at the National Institute on Aging for something like a decade now. The aim is to rigorously test all the supplements and drug-like compounds thought to modestly extend life in mice on the basis of older studies, and the results to date have largely been a demonstration that very few such items do in fact extend life in mice. Sufficient rigor was lacking in many old exploratory studies, some of which were conducted in advance of the present widespread understanding that any inadvertent reduction in calorie intake in studied mice is going to extend life. Introducing novel compounds into the diet or which might cause nausea turns out to be an excellent way to make that happen.

So it goes. A lot of these past results were simply wrong, just as a majority of results in the sciences are wrong. Research is hard and has a high failure rate, which is why we need the scientific method in order to sift the gold from the dross. It has taken until now for there to be enough of an interest in treating aging, as well as a critical mass of researchers willing to stand up and say it is possible and plausible to treat aging, for more expensive assessment programs like this to emerge. The ITP is by no means the only such effort to obtain greater rigor in data on ways to extend life in mice. I should also point out this initiative:

Historic BAIT Project Underway at the Buck Institute

With BAIT, [researchers] are building a resource for tracking how mice age, both in response to drug treatment and under normal physiological conditions. It's a "big data" project that is yielding terabytes of information on physiological markers of health including cardiac function, metabolism, bone density, body composition, activity and blood pressure, among others. "We are creating the gold standard for looking at variability in aging in mice."

"For a long time, we as an aging research community really have been focused on the survival curve. The goal had been to find treatments or genetic mutations that increase lifespan in mice, pushing the survival curve to the right. However, there have been precious few examples of understanding what the functional consequences of pushing the survival curve are. It's not necessarily a given that if you increase lifespan you will increase healthspan. Data from BAIT will provide us with numerous jumping-off points to push the research forward. We want to move therapies into the clinic; knowing how treatments impact specific functional parameters in the mice could give us a way to guide clinical trials in humans. This is the vital information that's been lacking."

The initial BAIT project involves 770 genetically identical mice that entered the study at 20 months of age (roughly equivalent to a 60-year-old human). One subset is aging normally; other subsets are being individually treated with four drugs that have already been shown to increase lifespan in simple animals such as worms and flies. BAIT is already the largest study in the world looking at functional aging in mice, and now that the pipeline is established, there is no reason not to scale up even further. [Researchers] think that, given the resources, BAIT could handle up to 50 or 60 compounds, providing a next-generation resource for drug development.

This is exciting stuff for those who feel that there is promise in working on ways to marginally slow aging through drug development, such as varied initiatives focused on calorie restriction mimetics. But a more sober assessment of what is possible and plausible suggests that this will gather a great deal of new knowledge but fail to produce ways to greatly extend life. The goals for the metabolic manipulation approach to slow aging, such as those put forward by the Longevity Dividend advocates, are to add five to ten years to healthy life by the mid-2030s. The cost of a serious attempt to achieve this goal will be stupendous: the entire research and pharmaceutical industry focused on turning a fraction of the present drug development pipeline to these efforts. We already know how much this costs and the sort of results (or lack of same) to expect, as we can just look at the past decade of sirtuin research to see in the vicinity of a billion dollars spent and very little to show for it yet.

The end result of drug development to slow aging is a treatment that is of limited use to old people even if it works, and most of us will be old by the time any such thing arrives. Aging is a process of damage accumulation, and slowing aging merely means a slower pace of that damage accumulation. Not much good if you are already so damaged that your mortality risk is high and quality of life low. The only way to make radical breakthroughs in the decades ahead, to produce methods of rejuvenation that can add decades of renewed, improved health for people already old, is to focus on - and fund - something other than the drugs and dietary compounds that so many people fixate on. Regular readers know by now that "something other" is best represented by the SENS research program, but any group working on ways to repair and reverse the underlying damage that causes aging rather than just slow it down has potentially far more promise than the mainstream approach of drugs to slow aging.

We don't have all the time in the world. If funding institutions and researchers continue to focus on scientific programs that are both inordinately expensive and very unlikely to produce therapies with meaningful effects for people who are already old, then we will miss our chance at a radical extension of healthy life far beyond present limits.

AGING IS NOT A DISEASE (BUT WE NEED TO TREAT IT ANYWAY)
https://www.fightaging.org/archives/2014/06/aging-is-not-a-disease-but-we-need-to-treat-it-anyway.php

Disease is a much abused word, and the boundaries of its varied meanings to different groups shift over time. Most of the well-known failures that occur in organs and other biological systems over the later stages of aging are referred to as diseases, but are in fact better designated as medical conditions. Medical condition is much broader term that clearly covers unpleasant things that happen to everyone, and are thus not abnormal in a given age group.

Why should anyone care about these fine lines in nomenclature? Why is there a perennial debate as to whether or not aging itself is a disease? The answer, as is the case in so many similar matters, involves the intersection of large amounts of money and government regulation of medical development and clinical practice. The FDA, to pick one of the worst and most intrusive of the world's regulatory bodies, only permits development and clinical use of treatments for specific named diseases. FDA bureaucrats have a list in which diseases are enumerated and painstakingly defined. If a medical condition isn't on the list, then the only way to bring potential treatment to customers within the US is to first engage in year after year of political lobbying and funding studies with no certainty of useful application. This certainly has a deadening effect on the ability to raise funds all the back up the chain, and steers allocation of resources for even fundamental research.

Nonetheless, this process grinds on for aspects of aging such as sarcopenia, the progressive loss of muscle mass and strength. Since aging isn't a disease per the FDA, the development community slowly chips away at converting small manifestations of aging into officially named diseases. People who have more of that manifestation than the average are declared diseased, and thus it becomes possible within the regulatory regime to officially start work on ways to treat them. This whole process, something that has been going on for the better part of a lifetime, is an enormous dead weight atop the natural tendency for innovation and competition. Funds are efforts are diverted from the straightest path to producing new treatments into much less effective sidelines, wherein the entire structure of research and its end goals are first and foremost shaped by regulation rather than the needs of patients.

All this being the case, the regulation of commercial clinical services will nonetheless be bypassed relatively quickly and effectively as soon as viable treatments for aging emerge. Look at what happened for stem cell therapies: they were offered everywhere in the world except the most highly regulated regions, and the regulators eventually blinked because the risk to their careers became ever greater they longer they acted as roadblocks. But this is only the case when treatments are available elsewhere, and when the public is very aware of this fact. There are any number of potential treatments that we don't see at all because of the slowing effect that regulation has on research in the wealthiest and most active scientific communities. The public is none the wiser there, and so the harmful effects of regulation continue unabated. How many lines of research languish without progress or move at a snail's pace because of this? Too many to easily count.

All of this goes some way to explain why people care as to why aging or any specific aspect of aging is a disease. It is keyed to money, pace of progress, and efforts to work within the ridiculous systems of medical regulation in wealthier countries.

Here is an open access opinion piece on this topic where I agree and disagree with varied different aspects of the author's viewpoint. The approach to aging and age-related conditions is presently terrible and inefficient, and it must change to focus more on underlying causes and less on patching over the late stage consequences. The nature of this dominant and futile approach to age-related conditions is very driven by regulation, being an extension of the incentives and regulatory barriers discussed above. Yet where this author advises abandoning work on reversing aging, I say double down on research into ways to repair the causes, to reverse the outcomes, and to create real working rejuvenation therapies.

Aging Is Not a Disease: Implications for Intervention

Aging of biological systems occurs in spite of numerous complex pathways of maintenance, repair and defense. There are no gerontogenes which have the specific evolutionary function to cause aging. Although aging is the common cause of all age-related diseases, aging in itself cannot be considered a disease. This understanding of aging as a process should transform our approach towards interventions from developing illusory anti-aging treatments to developing realistic and practical methods for maintaining health throughout the lifespan. Age-induced health problems, for which there are no other clear-cut causative agents, may be better tackled by focusing on health mechanisms and their maintenance, rather than only disease management and treatment. Continuing the disease-oriented research and treatment approaches, as opposed to health-oriented and preventive strategies, are economically, socially and psychologically unsustainable.

One's understanding of biological aging, either as a disease or as a process that increases the chances of the onset of diseases, has serious implications with respect to interventional strategies. If aging is considered as a disease, then, in an ideal condition and in principle, this could be fully treatable, and a disease-free state could be achieved. However, if aging is understood as an emergent phenomenon occurring progressively in each and every individual surviving beyond certain duration of life within the evolutionary framework, then aging cannot be considered as a disease. This latter viewpoint then transforms our approach towards aging interventions from the so-called anti-aging treatments to achieving healthy aging. This also means abandoning enemy-oriented rhetoric, such as the "war against aging", "defeating aging", and "conquering aging" etc. Instead, interventions in aging require a health-oriented approach and the use of a positive language such as maintaining health, achieving healthy aging, and having active aging. Of course, optimal treatment and management of every disease, irrespective of age, is a social and moral imperative. But considering aging as a disease that happens to everybody is an oxymoron.

YOUNG BLOOD REVERSES AGE-RELATED COGNITIVE IMPAIRMENT
https://www.fightaging.org/archives/2014/06/young-blood-reverses-age-related-cognitive-impairment.php

Heterochronic parabiosis is a process of linking the circulatory systems of an old and a young laboratory animal, such as mice. It is an investigative technique used by researchers in efforts to identify the differences in circulating proteins between old and young tissue environments, and which of these changes are important or can be altered to produce benefits in old animals. The entry point for much of this research is stem cell biology, the study of regeneration, tissue maintenance, and especially why stem cell activity declines with age, and the precise mechanisms behind this decline.

Stem cell treatments show great potential as therapies for many age-related conditions, but in order for these therapies to be as effective as they might be for the old, the problem of stem cell decline has to be solved, or at the very least worked around while a solution is created. The true solution for this, as for all aspects of aging, is to implement methods of repair that can remove the low-level cellular and molecular damage that causes aging. But in the meanwhile, it might be possible to gain some benefits and improve the outcome of stem cell treatments by overriding the protein signals in aged tissue to make native and transplanted stem cells behave as though in young tissue - at least for a while, long enough to make a difference.

Cancer is a real concern in these matters, however. The consensus position on declining stem cell activity with aging is that it is an evolved response to aging that has the effect of suppressing cancer incidence. Fewer active stem cells means less of a chance that any one of those cells gains just the wrong set of mutations to run amok as the seed of a new cancer. The cost to this is that we all suffer progressive failure of tissue maintenance and a slow, drawn out decline leading to death by organ failure. New biotechnologies mean that researchers can start to alter this balance of risk, however: perhaps it will be acceptable to put old stem cells back to work for a few months at a time in order to somewhat repair some forms of damage in portions of the aged body. Worn joints, for example, or weakened muscles. That would not be true rejuvenation, as all too much of the damage of aging has nothing to do with stem cells per se. It would be better than nothing, however, and it appears to be increasingly plausible as an option in the next decade or so.

As researchers continue in their investigations of parabiosis, they are cataloging the various systems and cell populations that benefit from the youthful blood of the younger partner in the pairing. Here is an interesting example:

In Revival of Parabiosis, Young Blood Rejuvenates Aging Microglia, Cognition

Aging brings with it not only a decline in cognition but also a smoldering inflammation within the innate immune system. In the brain, this manifests as an abnormal state of that organ's main resident immune cell, the microglia. To see whether this is an internal affair of the aging brain or influenced by the periphery, [researchers]returned to a blood-sharing experiment called parabiosis. [They had] previously used it to show that a young systemic environment can essentially rejuvenate neurogenesis and other aspects of the aging brain.

[Researchers] said that pairing an 18-month-old with a 3-month-old mouse, and letting them live together for five weeks, reversed microglial aging. Microglial activation as measured by CD68 expression was down in the brains of old mice exposed to young blood. In the electron microscope, the old mice's microglia looked like those of young mice. [The team compared] the microglial transcriptome from old mice paired with other old mice to that from old mice paired with young mice. They saw that blood supplied by a young mouse did indeed largely reverse the gene expression phenotype of microglial aging.

Whether these changes at the molecular and cellular level amount to better function is difficult to assess in parabiotic mice. The pairs run the rotarod together, but rigorous behavior assays are not possible. Instead, the [scientists] decided to model parabiosis by transferring young plasma into an old mouse once every three days for three weeks. In this study, old mice injected with plasma from young mice outperformed untreated old mice in the radial arm water maze and a fear-conditioning test. The treated mice also recapitulate other previously shown parabiosis phenotypes, including more neurogenesis, synaptic plasticity, spine density, and less neuroinflammation.

A SUMMER UPDATE FROM THE METHUSELAH FOUNDATION
https://www.fightaging.org/archives/2014/06/a-summer-update-from-the-methuselah-foundation.php

The email quoted below recently arrived in my in-box from the Methuselah Foundation. The Foundation is now more than ten years old, an organization whose staff, volunteers, and supporters have had a hand in most of the best changes to occur in the aging and longevity science community over that time. The Methuselah Foundation was the original home of SENS research into the repair of aging, prior to spinning off the dedicated SENS Research Foundation, but is now primarily focused on advancing the state of the art in tissue engineering, so as to accelerate progress towards the creation of organs to order. Beyond that all of the networking and advocacy behind the scenes in the research community continues just as it has for a decade. It isn't enough to just suggest things to researchers every now and again or educate the public, though both of these activities are certainly helpful. The world turns on the basis of networking: alliances must be formed, and connections made between funding sources and promising research groups who had no idea the other side existed. In this matter the Foundation has made great strides over the years.

Dear Friends,

We hope you've been having a productive and satisfying 2014.

If you haven't seen it yet, definitely visit our new Methuselah Foundation blog and let us know what you think. We've been publishing weekly posts, including a primer on the science of organ regeneration and a regenerative medicine news roundup from around the web during April and May.

We've also posted several recent interviews there, with Dr. Alan Russell of Carnegie Mellon, Dr. Takanori Takebe of Yokohama City University, Dr. Eric Lagasse of the University of Pittsburgh, and Brock Reeve of the Harvard Stem Cell Institute. In the weeks ahead, look out for part 2 of the Brock Reeve piece, a new interview with MIT's Dr. Robert Langer, and more.

Congratulations to Dr. Huber Warner

On May 30th, at the 43rd Annual Meeting of the American Aging Association in San Antonio, Texas, we awarded a $10,000 Methuselah Prize to Dr. Huber Warner for founding the National Institute on Aging's Intervention Testing Program (ITP), a "multi-institutional study investigating treatments with the potential to extend lifespan and delay disease and dysfunction in mice." Dr. Warner is a former program director for the NIA Biology of Aging Program and former Associate Dean of Research for the College of Biological Sciences at the University of Minnesota.

According to Kevin Perrott, Executive Director of the Methuselah Prize, "The vision Dr. Warner showed, and his persistence over years of resistance to establish the ITP, is truly worthy of recognition. This program is going to provide not only potential near-term interventions in the aging process, but hard data to support claims of health benefits in a statistically significant manner. Science needs solid foundations on which to base further investigations, and the ITP provides the highest level of confidence yet established."

"I saw lots of papers from grantees of the NIA about slowing down aging and extending lifespan," said Dr. Warner, "but they were rarely backed up and given credibility through testing. Research over the last 25 years has been characterized by great success in identifying genes that play some role in extending the late-life health and longevity of several useful animal models of aging, such as yeast, fruit flies, and mice. The next challenging step is to demonstrate how this information might be used to increase the health of older members of our human populations around the world as they age."

Other News

With New Organ, we've been busy growing our partner alliance, garnering endorsements (for example, from the Founding Fellows of the Tissue Engineering and Regenerative Medicine International Society), defining criteria for our upcoming heart prize, and working toward an official announcement of our first group of teams participating in the liver prize. We've had good initial interest, with five teams committed so far, and we're currently in dialogue with many more.

The pre-release construction phase of our beautiful marble and granite monument installation in the U.S. Virgin Islands, to honor all of the major donors who are part of the Methuselah 300, will be completed by August. We've got some cool surprises in store, and our goal is to formally dedicate the monument in the first quarter of 2015, during the peak tourist season - with as many of you in attendance as are able!

Finally, don't miss the SENS Research Foundation's upcoming Rejuvenation Biotechnology Conference, taking place on August 21-23 in Santa Clara, CA.

Warm regards,

Dave Gobel

It is good to hear that the New Organ prize initiative continues to gather support and interest. Like many initiatives in the research community it is often hard to see what is actually going on, as much of the important action happens behind the scenes.

For me this email is a reminder that we're halfway through the year already, and so the next time I look up from a keyboard it will likely be nearly a year since the last SENS Research Foundation grassroots fundraising initiative. That was a very spur of the moment affair for me, but nonetheless the community rallied round and raised $100,000 in the last two months of 2013 and January 2014. I would like to do better this year, on matters of organization at least, given that no-one I know has unexpected become stupendously wealthy since January. We may not be millionaires, or at least most of us are not, but our support is nonetheless important and our donations fund real, meaningful projects at the cutting edge of medical biotechnology.

So all things considered it is probably time to start thinking about plans for a round of rejuvenation biotechnology research fundraising starting just a few short months from now.

SENS RESEARCH FOUNDATION NEWSLETTER FOR JUNE 2014
https://www.fightaging.org/archives/2014/06/sens-research-foundation-newsletter-for-june-2014.php

The latest SENS Research Foundation newsletter arrived in my in-box today, with an update on what is new in the Foundation's programs of research into the foundations of future rejuvenation treatments. There is a conference coming up later this year, a new crop of young scientists interning at various research centers to help advance the state of the art, and recently published research directed at the removal of a form of amyloid implicated in the death of those who live the longest and survive everything else that aging throws at us.

The Foundation staff have set themselves an aggressive mid-year fundraising goal of $250,000 before the end of August. Your home town will burn that much on their next game night, but here this is enough to fund numerous sophisticated projects that advance the state of knowledge in areas of medical science most relevant to treating and reversing the underlying processes that cause aging. There is always a balance between saving for the future and spending now to build better options in the future, but no society in history has ever come close to funding enough work on building better medicine. More is always better. Now we have a golden chance to eliminate the suffering and death caused by age-related disease in just a few short decades of work, and the price to achieve this goal is falling dramatically as biotechnologies improve.

As I mentioned yesterday, we might not be millionaires, but we are the ones with vision enough to band together and help to fund the early work on rejuvenation treatments, the necessary foundations for the proof of concept in mice that will exist in years to come. The big donors always turn up late to the party to pick up the sure thing and carry proven, demonstrated work the last few yard into the clinics. Without us, there would be no party.

At the end of last year the grassroots community raised $100,000 for SENS research, and I'm pleased to have played a modest role in helping that to happen. That was an investment in ensuring that later in our lives we will not be left helpless in the face of age-related disease. I would like to think that we can do just as well this year: more than just money, it is a matter of showing that there are thousands of people who support this work and the goal of an end to the suffering that comes with advancing age. That support attracts attention, and makes it ever more possible for the Foundation to open doors to traditional and more conservative funding sources.

Help Us Meet Our Mid-Year Fundraising Goal

SENS Research Foundation would like to thank all of you for your ongoing support. hanks to your generous donations of time, money, and encouragement, we have been able to continue advancing our work to cure - not just treat, but cure - the diseases of aging. We are accomplishing this goal in 2014 by:

1) Funding promising new research: SRF currently has 3 internal and 15 extramural research projects taking place at universities and research institutes around the world. In March 2014, SENS Research Foundation secured its highest-profile academic publication to date, with the publication by J. Biological Chemistry of a report of SRF-funded work at the University of Texas at Houston. In this study, Dr. Sudhir Paul and colleagues report the isolation of catabodies selective for the type of amyloid that underpins the number one cause of death in the oldest of the old - those who reach the age of 110. A catabody is an unusual type of antibody, on which Dr. Paul is the world leader; rather than just attaching to their target, they actually cut it up. By this means, we can destroy this amyloid and eliminate a major component of aging.

2) Building a strong, collaborative community: We are bringing together leading scientists, regulators, venture capitalists and the general public together at our upcoming Rejuvenation Biotechnology Conference, August 21-23, 2014, in Santa Clara CA.

3) Training the next generation of bright, young scientists: Currently, 17 interns are hard at work contributing to our funded research projects. These students will be presenting in the Poster Session at the Rejuvenation Biotechnology Conference.

However, in order to continue advancing the field of regenerative medicine, we need your help. Simply put, your funding will help us continue our research, support our interns and bring the community together. We've set a funding challenge to raise at least $250,000 between today and August 31, 2014. If you would like to help these programs continue to grow, please show your support by making your tax deductible donation today.

SRF Education: 2014 Summer Scholars Program Is In Session

SENS Research Foundation is pleased to announce the start of the 2014 Summer Scholars Program. Fifteen students were selected to participate this year at the Buck Institute for Research on Aging, the Harvard Stem Cell Institute / Harvard Medical School, University College London, the University of Oxford, the Wake Forest Institute for Regenerative Medicine, and our very own SRF Research Center. Over the next month, SRF will be posting profiles on the SRF Education blog for each of our summer scholars to give you the opportunity to learn more about each scholar and the research he or she will be conducting.

SRF's Thomas Hunt Awarded 2014 Thiel Foundation Fellowship

SENS Research Foundation would like to congratulate Thomas Hunt, who has been awarded one of the 20 Thiel Fellowships granted in 2014. Thomas, 17, began volunteering in our Research Center three years ago and now works alongside our intramural team studying Alternative Lengthening of Telomeres (ALT), a mechanism that may play a key role in the development of cancer. He has a particular interest in automated high-throughput drug screening to find compounds that reduce ALT activity.

As is usually the case, the best part of the newsletter is the question of the month section, in which Michael Rae answers queries from supporters. This month's topic is something I recall discussing once or twice with folk myself, and certainly in past Fight Aging! posts on unusual lower animals such as possibly ageless hydra and rejuvenating microbes. Why can't researchers just investigate the details of the indefatigable regeneration of the hydra and port the underlying mechanisms into our biology? As it turns out there are very good reasons as why we can't do this, much of which stems from the fact that we are more structurally complex. Our lives and our very selves depend on the fine structural details of our tissues, especially the brain and nervous system, remaining intact without being recycled, rebuilt, or otherwise majorly altered.

Question Of The Month #4: Can Medicine Take a Cue from 'Natural' Negligible Senescence?

Q: Amongst the "Strategies for Engineered Negligible Senescence" (SENS), have you considered the original negligibly-senescing organisms as sources for strategies? Organisms like bristlecone pine, lobsters, and the "immortal jellyfish" Turritopsis dohrnii seem to live indefinitely without suffering age-related ill-health or loss of function, so maybe we could learn their tricks and incorporate them into the human genome.

A: As beautifully illustrated in Rachel Sussman's recent book, The Oldest Living Things in the World, the example of these organisms is inspiring and imaginatively appealing. Among other things, they put the lie to the idea that degenerative aging is simply an ineluctable part of being alive, against which nothing can be done. Still, trying to adapt their specific metabolic and structural mechanisms to human use is not likely to help us achieve our goal of preventing and arresting age-related ill health.

While we don't yet know all the metabolic and molecular details, we do have a pretty good idea of why these organisms don't meaningfully age, and unfortunately those reasons aren't compatible with human biology. For instance, bristlecone pines can be said to "live" for thousands of years, but only the outermost layers of the tree are actually still alive: the wood in the middle of a tree is composed of dead 'husks' of cells. The tree is "alive" because the outer layers surrounding the "dead" inner core continues to carry out the business of life, performing photosynthesis and dividing, allowing the composite structure of the tree to keep growing. There is no plausible way to adapt this as a bulwark against the problems of human aging.

The situation is less extreme in the case of most negligibly-senescing animals - but still, it's difficult to see how their tricks could be applied to us without harm. Most such organisms never stop growing, allowing their continuously-dividing cells to literally dilute aging damage away. Rockfish and lobster, for instance, will continue to grow and grow as long as they are fed and not killed by causes unrelated to aging. Aside from the alarming or ridiculous vision of humans that continued to grow and grow year in and year out for centuries, a major problem with adopting this trick is that some of our most of our most important organs are composed of nondividing cells: heart, brain, and skeletal muscle. (That's why major mitochondrial mutations, for instance, build up in these organs and not (for instance) in the skin or liver). We're rather attached to having these cells stay in place and intact, especially when it comes to the way that our neurons arrange themselves; we wouldn't want to tamper with them by triggering them to begin dividing again.

The jellyfish example is even less compatible with the human life cycle (and with our aims biomedically): their "immortality" comes from the fact that they aren't really even single organisms, but colonies of cooperating unicellular organisms that transiently adopt particular functions within the "meta-organism" of the polyp. The individual cells that comprise the polyp potentially divide indefinitely, and can differentiate and re-differentiate to adopt different functions. When a given polyp is irreversibly damaged, this flexibility allows its constituent cells to disperse, regroup, and create a new polyp, with each constituent of the old polyp transforming itself into a different kind of cell to perform a function that is needed by the newly-formed "daughter" polyp. It is not that these abilities allow T. dohrnii cells to indefinitely preserve the healthy function of a single, identifiable organism over time, in other words, but that it allows them to form new polyps when a given polyp-form can no longer be sustained.

These incompatibilities probably mean that the only way to take advantage of these tricks would be to engineer a completely new human-like organism, starting from the embryo and growing it out. Whether or not the life of such an organism is feasible or desirable, it isn't something that we can do to help humans that are alive today to avert a future of age-related disease and disability.

Instead of starting over from scratch and fundamentally reshaping our bodies and brains and way of being alive in the world, the strategy under pursuit by SENS Research Foundation is to repair and renew the bodies that we already have at the cellular and molecular level over time. Organisms that are naturally negligibly-senescent are able to dilute away the cellular and molecular damage that drives degenerative aging. By developing rejuvenation biotechnologies that remove, repair, replace, and render harmless this damage as it accumulates in our own cells and tissues, we can return our bodies to their youthful structural integrity. Through regular applications of this "cellular surgery," we cam restore the structural and functional youth of our bodies to a state of health, vigor, and vitality, keeping the degenerative aging process and its many diseases and disabilities at bay.

LATEST HEADLINES FROM FIGHT AGING!

NUCLEAR DNA DAMAGE CORRELATES WITH AGING
Monday, June 9, 2014
https://www.fightaging.org/archives/2014/06/nuclear-dna-damage-correlates-with-aging.php

The overwhelming balance of scientific evidence shows that damage to nuclear DNA increases with age. This is one of the reasons why cancer is an age-related condition: as time goes by there is an ever greater chance of some cell somewhere in the body suffering just the right combination of mutations to become cancerous. The mainstream position is that this damage also provides a meaningful contribution to the broader aging process by causing disarray in the processes of cells where it occurs, although this point is debated. It may be that beyond cancer incidence the level of nuclear DNA damage suffered over the present human life span is not large enough to provide a significant contribution to age-related disease, frailty, and death.

Here is a review of the literature that confirms the correlation between nuclear DNA damage and age. It is necessary in the scientific process to continually anchor every concept with ever more evidence, especially when the matter at hand is a complex system only partially understood:

Although DNA is not the only target changed with aging, taking account of the major role of this macromolecule in the regulation of all cellular structures and its own cell cycle, DNA damage has been studied with particular attention. The alterations could have several consequences for genome stability with repercussions on cellular component synthesis, cell cycle machinery and signaling pathways that control cell cycle arrest, and programmed cell death or apoptosis. The consequences of DNA damage will depend on the type of damage, genes affected and type of cell and tissue damaged.

The prevailing view is that there is a tendency for an age-related DNA damage accumulation. However, on examination, results of studies show inconsistency; it is possible that confounding factors influence this relation and explain some of the inconsistency. Factors such as diet, lifestyle, exposure to radiation and genotoxic chemicals seem to have a significant influence on the relationship between cumulative DNA damage and age. Methodological factors might have also influenced the observed results. Indeed, different assays may be used to measure DNA damage. Furthermore, the measured DNA damage could reflect changes in the causative factors, and/or changes in DNA protection and/or changes in DNA repair capacity. It must also be noted that the type of cell and tissue used could reflect different aging rates within the organism.

Although there are several excellent narrative reviews on age-related nuclear DNA damage, they usually refer to individual animal and humans studies and, as far as we know, no meta-analytic technique has been used to estimate the extent of effect of potential moderators on age-related DNA damage in humans. Thus, the overall goal of this paper is to address this important gap in the literature.

Electronic databases and bibliographies for studies published since 2004 were searched. A total of 76 correlations from 36 studies with 4676 participants were included. Based on our analysis, a correlation between age and DNA damage was found. The test for heterogeneity of variance indicates that the study's results are significantly high. Moderator variables such as smoking habits, technique used, and the tissue/sample analyzed, are shown to influence age-related DNA damage. Nevertheless, sex did not show any influence on this relation.

In conclusion, this meta-analysis showed an association between age and DNA damage in humans. It was also found that smoking habits, the technique used, and tissue/sample analyzed, are important moderator variables in age-related DNA damage.

QUANTIFYING SOME OF THE BENEFITS OF EXERCISE IN OLD AGE
Monday, June 9, 2014
https://www.fightaging.org/archives/2014/06/quantifying-some-of-the-benefits-of-exercise-in-old-age.php

Most older people undertake far less exercise than they might, and there is a cost in health and life expectancy associated with the choice to live a sedentary life. Studies like this one help to quantify the difference between exercise and no exercise, and therefore the health benefits that are either obtained or lost:

Our previous studies have shown that 70-year-old men with lifelong participation in football possess a postural balance and rapid muscle force that is comparable to that of 30-year-old untrained men. This time we have gone one step further by evaluating the intensity of football training as well as the health and fitness effects of football for untrained elderly men with little experience of football.

The study revealed that inactive elderly men improved their maximum oxygen uptake by 15% and their performance during interval exercise by as much as 50% by playing football for 1 hour two times per week over 4 months. Moreover, muscle function was improved by 30% and bone mineralization in the femoral neck increased by 2%.

The results provide strong evidence that football is an intense, versatile and effective form of training, including for untrained elderly men. It is definitely never too late to start playing football. Football boosts physical capacity and heart health, and minimizes the risk of falls and fractures in elderly, men who have never played football before or have not played for decades.

Our study shows that intense training such as football can change the lives of elderly men. The remarkable improvements in aerobic fitness and muscle strength make it easier for the players to live an active life and overcome the physical challenges of everyday life such as climbing stairs, shopping, cycling and gardening.

A POPULAR SCIENCE ARTICLE ON THYMIC REGENERATION
Tuesday, June 10, 2014
https://www.fightaging.org/archives/2014/06/a-popular-science-article-on-thymic-regeneration.php

The thymus is the gateway for immune cell creation, but it is only highly active in the first two decades of life. After that it atrophies. This effectively places a cap on the number of immune cells supported by the body, which is a limit we'd like to work around in order to better maintain immune function in the old. One approach is to rebuild the thymus, such as via tissue engineering or some form of treatment that alters cell signaling to convince existing cells in the body that they are young and thus should be recreating a large and active thymus.

It is as big as an apple in children, but shrinks to peanut size in later life. A quirk of evolution had transformed a "raging torrent", which pumps out [a large number of] T-cells a day in the young, into a "dripping tap" in adults. "The human body was programmed to live for two quick generations in the jungle. Nowadays we all live much longer. We're dealing with an ageing population sitting there without a thymus."

Now [scientists] say they have created the "seeds" to regrow the organ which produces the immune system's soldier cells. [The researchers] have found a way of fashioning stem cells that can develop into the thymus, a pyramid-shaped organ near the heart. The breakthrough [is] the first step in rewiring humans' immune systems to keep pace with their longer life expectancy. The study, which took three years, converted human embryonic stem cells into "thymic" stem cells capable of sprouting a full-sized thymus. The cells could be injected into adult thymuses, triggering renewed growth, or used to grow another thymus from scratch elsewhere in the body.

The next step is to convert the cells into a three-dimensional structure, by cultivating a cluster of the cells around a framework of microscopic fibres in a test tube, and transplanting it under a fold of skin or a membrane around the kidney. The budding thymus is then "logged on" to blood vessels so that it can attract the blood stem cells it converts into T-cells. Last year [scientists] succeeded in doing this in mice. While clinical trials on humans are about five years away, [the] approach could be a major boost for AIDS sufferers or people with depleted immunity. They include cancer patients on chemotherapy or radiation therapy, transplant recipients on anti-immunity drugs, and elderly people who have become so run down that ordinary viruses pose a significant threat.

NAKED MOLE RATS MAINTAIN CARDIOVASCULAR FUNCTION IN AGING
Tuesday, June 10, 2014
https://www.fightaging.org/archives/2014/06/naked-mole-rats-maintain-cardiovascular-function-in-aging.php

Naked mole rats live up to nine times longer than other similarly sized rodent species, and display little in the way of evident signs of aging across much of this span. Researchers, being thorough, are working their way through specific organs and systems of the body to see whether this holds generally for all of them - a part of the process of determining exactly why naked mole rats are so long-lived. Here the focus is the cardiovascular system:

The naked mole-rat (NMR) is the longest-lived rodent known, with a maximum lifespan potential (MLSP) of more than 31 years. Despite such extreme longevity, these animals display attenuation of many age-associated diseases and functional changes until the last quartile of their MLSP.

We questioned if such abilities would extend to cardiovascular function and structure in this species. To test this, we assessed cardiac functional reserve, ventricular morphology, and arterial stiffening in NMRs ranging from 2 to 24 years of age. Dobutamine echocardiography revealed no age-associated changes in left ventricular (LV) function either at baseline or with exercise-like stress. Baseline and dobutamine-induced LV pressure parameters also did not change. Thus the NMR, unlike other mammals, maintains cardiac reserve with age.

NMRs showed no cardiac hypertrophy, evidenced by no increase in cardiomyocyte cross-sectional area or LV dimensions with age. Age-associated arterial stiffening did not occur as there were no changes in aortic blood pressures or pulse-wave velocity. Only LV interstitial collagen deposition increased 2.5-fold from young to old NMRs. However, its effect on LV diastolic function is likely minor since NMRs experience attenuated age-related changes in diastolic dysfunction in comparison to other species.

Overall, these findings conform to the negligible senescence phenotype, as NMRs largely stave off cardiovascular changes for at least 75% of their MLSP. This suggests that using a comparative strategy to find factors that change with age in other mammals but not NMRs could provide novel targets to slow or prevent cardiovascular aging in humans.

THE AMYLOID HYPOTHESIS, TIME TO MOVE ON
Wednesday, June 11, 2014
https://www.fightaging.org/archives/2014/06/the-amyloid-hypothesis-time-to-move-on.php

This paper is one example of numerous varied critiques of the mainstream consensus view that accumulating amyloid in the brain is the proximate cause of Alzheimer's disease pathology. No current consensus in science ever goes unchallenged, especially when working therapies are slow to emerge as a result of that consensus:

The "amyloid hypothesis" has dominated Alzheimer research for more than 20 years, and proposes that amyloid is the toxic cause of neural/synaptic damage and dementia. If correct, decreasing the formation or removing amyloid should be therapeutic. Despite discrepancies in the proposed mechanism, and failed clinical trials, amyloid continues to be considered the cause of a degenerative cascade.

Alternative hypotheses must explain three features: (i) why amyloid toxicity is not the etiology of Alzheimer's disease (AD), (ii) what alternative mechanisms cause the degeneration and dementia of AD, and (iii) why increased amyloid accumulates in the brain in AD. We propose that AD, which occurs in elderly, already vulnerable brains, with multiple age-related changes, is precipitated by impaired microvascular function, resulting primarily from decreased Notch-related angiogenesis. With impaired microvasculature, a lack of vascular endothelial-derived trophic factors and decreased cerebral blood flow cause the atrophy of neural structures. Therapeutic strategies should focus on supporting normal angiogenesis.

ENGINEERING A LOSS OF FUNCTION PCSK9 MUTATION TO REDUCE CARDIOVASCULAR DISEASE RISK
Wednesday, June 11, 2014
https://www.fightaging.org/archives/2014/06/engineering-a-loss-of-function-pcsk9-mutation-to-reduce-cardiovascular-disease-risk.php

The advent of efficient techniques for gene editing such as CRISPR is moving us into an era in which all sorts of beneficial enhancements to human biology become possible. The regulatory establishment is exceedingly conservative with regard to genetic alterations and will vigorously resist all such treatments, of course, but gene therapies with good evidence of beneficial effects will become available via medical tourism in the same way as stem cell treatments did more than a decade ago. Myostatin knockout is a good example of a possible target of benefit to basically healthy people as well as those suffering age-related frailty, as it induces greater muscle mass and growth. But there are many other possible targets for gene therapies, such as the example here:

Individuals with naturally occurring loss-of-function PCSK9 mutations experience reduced blood low-density lipoprotein cholesterol (LDL-C) levels and protection against cardiovascular disease. The goal of this study was to assess whether genome editing using a clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated (Cas) system can efficiently introduce loss-of-function mutations into the endogenous PCSK9 gene in vivo.

We used adenovirus to express Cas9 and a CRISPR guide RNA targeting Pcsk9 in mouse liver, where the gene is specifically expressed. We found that within three to four days of administration of the virus, the mutagenesis rate of Pcsk9 in the liver was as high as 50% or more. This resulted in decreased plasma PCSK9 levels, increased hepatic LDL receptor levels, and decreased plasma cholesterol levels (by 35%-40%) in the blood. No off-target mutagenesis was detected in 10 selected sites.

Genome editing with the CRISPR-Cas9 system disrupts the Pcsk9 gene in vivo with high efficiency and reduces blood cholesterol levels in mice. This approach may have therapeutic potential for the prevention of cardiovascular disease in humans.

PROGRESS IN GROWING RETINAL TISSUE FROM STEM CELLS
Thursday, June 12, 2014
https://www.fightaging.org/archives/2014/06/progress-in-growing-retinal-tissue-from-stem-cells.php

Tissue engineered replacement retinal tissue lies somewhere in the future, and researchers are making progress towards that goal. Retinal degeneration spurred by the accumulation of metabolic waste products in long-lived retinal cells causes a number of common forms of age-relative blindness, and replacing retinal tissue is one potential approach to repairing these conditions. Here induced pluripotent stem cells are used to generate tissue that somewhat resembles that of a real retina:

Previous studies showed that an early-stage retina, including photoreceptors with primary cilia and parts of the inner segment structure, can be generated in culture from induced human pluripotent stem cells (iPSCs). Now [researchers] demonstrate the ability to grow the most mature retinal tissue from iPSCs yet: the in vitro product was able to develop functional photoreceptor cells. "The major advance here is the ability to make retinal cells that can respond to light and that form into what appears to be remarkably proper orientation."

The miniature human retinal tissue was able to form the outer-segment discs that are essential for light-sensing and contained all seven retinal cell types, including the four types of photoreceptor cells that express opsins, the transmembrane proteins that transfer captured photons into a physiological sensory response to light. While others have also developed systems to study the human retina in the lab, the current study extends these capabilities.

"Outer segments, which are the business end of photoreceptors, have not been previously shown to form from scratch in culture. This study is important as it demonstrated the extent to which we can study the retina in a culture dish. The stem cells could build up the retinal structure almost autonomously. Somehow the cells knew what to do and we just needed to give them time to do it. This was really surprising. The major lessons that [such] stem cell studies are leading us towards is that there are intrinsic instructions within the stem cells themselves to build tissue. We really don't know about these yet, but they are revealing themselves - if we are careful enough to observe them. It makes our jobs as tissue engineers much more doable, if we are working with cells that have these intrinsic emergent properties to build tissues."

STEM CELL GUIDED GENE THERAPY OF CANCER
Thursday, June 12, 2014
https://www.fightaging.org/archives/2014/06/stem-cell-guided-gene-therapy-of-cancer.php

This open access review outlines an interesting basis for the development of targeted cancer treatments in which stem cells are used as the vector to deliver modified genes. This is apparently well underway, progressing at least as well as other targeted cell killing approaches to treating cancer that are currently in laboratory studies and clinical trials. The breadth of different technology platforms forming the next generation of cancer treatments is one of the reasons why I am optimistic about progress towards robust, highly effective therapies for near all forms of cancer.

For practicing clinicians, who treat patients suffering from advanced cancers with contemporary systemic therapies, the challenge is to attain therapeutic efficacy, while minimizing side effects. Unfortunately, all systemic therapies, including chemotherapy, radiation therapy, and radio-immunotherapy, affect to some extent also healthy cells; thus cause side effects. Therefore, there is an urgent need for the patients' personalized and the cancers' targeted therapies.

Stem cells have the unique potential for self renewal and differentiation. This potential is the primary reason for introducing them into medicine to regenerate injured or degenerated organs, as well as to rejuvenate aging tissues. Recent advances in genetic engineering and stem cell research have created the foundations for genetic engineering of stem cells as the vectors for delivery of therapeutic transgenes. One of the most advanced approaches is based on introduction into tumor cells of genes capable for converting a non-toxic pro-drug into a cytotoxic agent. Specifically in oncology, the stem cells are genetically engineered to deliver the cell suicide inducing genes selectively to the cancer cells only. Expression of the transgenes kills the cancer cells, while leaving healthy cells unaffected.

Herein, we present various strategies to bioengineer suicide inducing genes and stem cell vectors. Moreover, we review results of the main preclinical studies and clinical trials. However, the main risk for therapeutic use of stem cells is their cancerous transformation. Therefore, we discuss various strategies to safeguard stem cell guided gene therapy against [this outcome].

RAGE IS REQUIRED FOR SOME HARM CAUSED BY AGE BUILDUP
Friday, June 13, 2014
https://www.fightaging.org/archives/2014/06/rage-is-required-for-some-harm-caused-by-age-buildup.php

Advanced glycation endproducts, AGEs, build up in tissues over time as a natural consequence of the operation of metabolism. The detrimental effects that AGEs have on tissue integrity and cellular behavior contribute to degenerative aging - their presence is a form of damage. Some attempts have been made in past years to develop drugs to safely break down AGEs, but little progress has been made. The types of AGE important in humans are quite different from those that matter in rodents, and so promising animal studies went nowhere. At the present time the research community lacks the tools to work with the most common AGE in humans, glucosepane, and the SENS Research Foundation is one of the very few groups trying to do something about this.

This research group shows some of the harm caused by AGEs in brain tissue, and notes that it depends on the presence of the receptor for AGEs, RAGE, which is much as expected. They then take the expected route for mainstream science, proposing an alteration to the operation of cells to block or remove RAGE so as to reduce the impact of AGEs, rather than proposing removal of the AGEs. This sort of inefficient focus on consequences and proximate causes rather than root causes is very common in modern medical research, and it needs to change.

Synaptic dysfunction and degeneration is an early pathological feature of aging and age-related diseases, including Alzheimer's disease (AD). Aging is associated with increased generation and deposition of advanced glycation endproducts (AGEs), resulting from nonenzymatic glycation (or oxidation) of proteins and lipids. AGE formation is accelerated in diabetes and AD-affected brain, contributing to cellular perturbation.

In addition to its ability to directly alter the structure and function of targeted proteins within cells that causes cell or tissue damage, emerging evidence has also demonstrated AGEs as a signaling ligand, interacting with RAGE; AGEs elicit signal transduction changes that adversely affect numerous peripheral organs. Although AGE accumulation is increased in cortical neurons, hippocampal pyramidal neurons, astrocytes, and other glial cells in aging and AD brain, the direct effect of AGEs-RAGE interaction on brain function, in particular on changes in synaptic structure and function, remains largely unknown.

Using our novel transgenic mouse model with neuronal expression of RAGE signaling and lacking neuronal RAGE in the forebrain for evaluation of synaptic transmission and plasticity (almost every brain function relays on synaptic transmission), we provide convincing evidence to support a pivotal role of neuronal AGEs-RAGE interaction on MAPK P38 activation, hippocampal plasticity deficit, and synaptic injury. Addition of AGEs to brain slices impaired hippocampal long-term potentiation (LTP). Similarly, treatment of hippocampal neurons with AGEs significantly decreases synaptic density. Such detrimental effects are largely reversed by genetic RAGE depletion. Notably, brain slices from mice with neuronal RAGE deficiency or DN-RAGE are resistant to AGE-induced LTP deficit.

Taken together, these data show that neuronal RAGE functions as a signal transducer for AGE-induced synaptic dysfunction, thereby providing new insights into a mechanism by which the AGEs-RAGE-dependent signaling cascade contributes to synaptic injury via the p38 MAP kinase signal transduction pathway. Thus, RAGE blockade may be a target for development of interventions aimed at preventing the progression of cognitive decline in aging and age-related neurodegenerative diseases.

PHYSICAL ACTIVITY, INFLAMMATION, AND VOLUME OF THE AGING BRAIN
Friday, June 13, 2014
https://www.fightaging.org/archives/2014/06/physical-activity-inflammation-and-volume-of-the-aging-brain.php

The vast, overwhelming majority of people should undertake regular moderate exercise - just as their physicians no doubt advise, supported by a mountain of evidence for the benefits of exercise. The relationship between physical activity and some specific measures of health is complex, however, because our biology is complex. All sorts of different internal and environmental factors interact and influence one another to arrive at any one specific outcome, though this paper is quite clear that if you want to better retain brain volume as you age, then you should be exercising:

Physical activity influences inflammation, and both affect brain structure and Alzheimer's disease (AD) risk. We hypothesized that older adults with greater reported physical activity intensity and lower serum levels of the inflammatory marker tumor necrosis factor α (TNFα) would have larger regional brain volumes on subsequent magnetic resonance imaging (MRI) scans.

In 43 cognitively intact older adults (79.3 ± 4.8 years) and 39 patients with AD (81.9 ± 5.1 years at the time of MRI) participating in the Cardiovascular Health Study, we examined year-1 reported physical activity intensity, year-5 blood serum TNFα measures, and year-9 volumetric brain MRI scans. We examined how prior physical activity intensity and TNFα related to subsequent total and regional brain volumes. Physical activity intensity was measured using the modified Minnesota Leisure Time Physical Activities questionnaire at year 1 of the study, when all subjects included here were cognitively intact.

Stabil