Fight Aging!

FIGHT AGING! NEWSLETTER
September 1st 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.

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

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CONTENTS

• Fight Aging! 2014 Fundraiser Poster #1
• Fight Aging! 2014 Fundraiser Poster #2
• Liver ATF4 Upregulation Common to Many of the Reliable Means of Slowing Aging in Mice
• João Pedro de Magalhães in Rejuvenation Research
• Amateur Religious Engineering and Longevity Science
• Latest Headlines from Fight Aging!
  • Growing a New Thymus From Engineered Cells
  • Inhibiting P38 MAPK Restores Proliferation in Senescent T Cells
  • Everything Looks the Same in the Distance
  • Apolipoprotein B Variants and Exceptional Human Longevity
  • Advocating Arterial Destiffening to Treat Cardiovascular Disease
  • Identifying Tissue Weakness Before Injury
  • The Cost of a Sedentary Lifestyle to Muscle and Bone
  • A Potential Source of Cardiac Stem Cells
  • Nasal Cartilage Cells Can Replace Joint Cartilage
  • The Prospects for Therapies and Enhancements via Magnetic Stimulation of the Brain

FIGHT AGING! 2014 FUNDRAISER POSTER #1
https://www.fightaging.org/archives/2014/08/fight-aging-2014-fundraiser-poster-1.php

October 1st is the start date for the Fight Aging! 2014 Fundraiser to benefit ongoing programs at the SENS Research Foundation, and the event will run through to the end of the year. While new attention and funding is swelling the longevity science community these days, it remains the case that the SENS Research Foundation is the only scientific network that meets all of my criteria for support: work is directed towards repair-based approaches to human rejuvenation rather than merely tinkering with metabolism to slow aging; there is an established non-profit organization so that average folk like you and I can make tax-deductible donations in the US and EU; and funds are spent effectively to advance the state of the art. It is a short list, but hard to fill, and it matters greatly which scientific programs we support.

In the past few months, generous donors have assembled a $100,000 Fight Aging! matching fund to encourage us all to help speed progress in rejuvenation research. Starting on October 1st we seek to raise $50,000 from the community, drawing a match of $2 from the fund for every $1 donated. Don't miss out on the chance to make every dollar you give count for three times as much! More than just a matter of donating, however, help in organization and outreach is also essential. You all know scores of people who don't read Fight Aging! and don't participate in the community, and some of them might if asked. Can you help to make this fundraiser a success by putting up flyers, organizing local events, or reaching out in your community to find new supporters?

Here is the first of two posters commissioned for the fundraiser. The full size graphics are large enough for 24 x 36 inch posters, but are also suitable for page-sized fliers. The original Photoshop files are available on request, but are a little large to put up here. Make as much use of these as you like: the purpose is to spread the word and encourage support.

FIGHT AGING! 2014 FUNDRAISER POSTER #2
https://www.fightaging.org/archives/2014/08/fight-aging-2014-fundraiser-poster-2.php

Following on from yesterday's post and poster, herein find the second commissioned piece for the Fight Aging! 2014 Fundraiser starting on October 1st, with all proceeds going to benefit the SENS Research Foundation. The Foundation organizes and funds work on near future rejuvenation treatments, ways to repair the cellular and molecular damage that causes degenerative aging. This research will ultimately lead to cures and prevention for all age-related disease. How soon can this happen? That is up to us, as funding is very much the limiting factor.

One of the exciting aspects of this era of biotechnology is that early stage research has become very cheap indeed. All of that massive expense you constantly hear about in medicine? That is spent on the road to clinical application, long after the basic research is done and finished. The cost of original research leading to a proof of concept is a drop in the bucket compared to the cost of turning that prototype into a tested, trialed, widely available, packaged, manufactured therapy. Funding for clinical application is a lot easier to raise than funding for original research, not least because you can point to something that works. Thus given a group like the SENS Research Foundation with access to existing labs and established researchers, even a few tens of thousands of dollars make the difference between successfully completing one more cutting edge project or postponing it indefinitely.

When the grassroots of this community raises money for biotechnology, it isn't just for show, and isn't just to help create an environment in which wealthier donors and larger donations are more likely to arrive: it gets things done, funds meaningful science, and makes a real difference to the pace of progress in rejuvenation research.

Here is the second of two posters commissioned for the fundraiser. The full size graphics are large enough for 24 x 36 inch posters, but are also suitable for page-sized fliers. The original Photoshop files are available on request, but are a little large to put up here. Make as much use of these as you like: the purpose is to spread the word and encourage support.

LIVER ATF4 UPREGULATION COMMON TO MANY OF THE RELIABLE MEANS OF SLOWING AGING IN MICE
https://www.fightaging.org/archives/2014/08/liver-atf4-upregulation-common-to-most-well-established-means-of-slowing-aging-in-mice.php

There are a score or more ways to reliably slow aging in mice, methods that include a few classes of drug, various single gene alterations, and calorie restriction. The most exceptional of these methods extends life by 60% or so, but most are in the much more modest 10-20% range at best. It is suspected that many of these approaches operate on a smaller overlapping set of underlying processes, but at different entry points: metabolism is a very, very complex system of interactions and feedback loops, and it is near impossible to make any change in isolation. Any given portion of our biochemistry distinct enough to be given a name and studied might consist of dozens of proteins at its core, and interact with hundreds more in ways that are important when considering the pace of aging.

To pick one example, increased levels of the cellular housekeeping processes called autophagy show up in many ways of slowing aging in lower animals. Some of the methods of slowing aging may only work at all because they happen to influence cells into taking better care of themselves, but that influence doesn't have to be in any way direct. Some alterations to mitochondria known to extend life in nematode worms slightly raise the generated levels of damaging reactive oxygen species emitted by mitochondrial processes, and that in turn causes cells to react with greater housekeeping vigor for a net gain. Much the same net gain might also be achieved by more direct manipulations that increase levels of autophagy - but from a distance these two approaches look very different, and target quite different proteins.

Thus the challenge facing researchers interested in slowing aging is that they are in no way even close to fully understanding any of the easily replicated and studied methods of slowing aging in various laboratory animals. Decades of work lie ahead to make a serious dent in the great unknowns of how metabolism interacts with aging in detail, even with the expected increases in computing power and new tools in biotechnology. This is why researchers are not generally all that optimistic about progress in the near term via calorie restriction mimetics and other ways of altering metabolism to slow aging. It is why I favor approaches such as SENS that largely bypass expensive attempts to change metabolism in favor of repairing clearly identified age-related changes in tissues, with the expectation that lacking this damage the operation of metabolism will revert back to the known good state that exists in youth, when comparatively little of that damage is present.

Most ongoing work in the aging research community focuses on finding out more about metabolism and aging, however, with some interest in ways to slow aging. It is quite often fascinating stuff, such as the open access paper below, but bear in mind that this really isn't a path to much more than knowledge. From the practical standpoint of whether we are on the road to greatly extend healthy life and reverse aging in the near future, this is not the way forward.

ATF4 activity: a common feature shared by many kinds of slow-aging mice

ATF4 is a transcriptional factor which senses deficits in protein translation, typically related to endoplasmic reticulum stress or amino acid limitation, and in turn activates a group of target genes. The availability of multiple methods to extend mouse maximal lifespan - genetic, dietary, development, or drug-induced - provides an opportunity to test the hypothesis that augmented ATF4 action, necessary for multiple modes of lifespan extension in yeast, is also characteristic of slow aging in mice.

Data in this paper show that ATF4 levels, levels of proteins controlled by ATF4, and levels of three mRNAs regulated directly by ATF4 are elevated in liver of mice exposed to each of five interventions shown elsewhere to increase maximal longevity: the drugs acarbose and rapamycin, diets low in calories or methionine, or transient milk deprivation limited to the suckling period.

Our previous work has shown similar increases in ATF4 protein and downstream indicators of ATF4 function in liver of Snell dwarf mice and PAPP-A knock-out mice, mutations that increase maximal lifespan and health in old age by alteration of endocrine pathways connected to GH and/or IGF-1. The previous study also documented augmented ATF4 responses in fibroblast cell lines derived from skin of adult Snell and PAPP-A KO mice, suggesting that the relevant changes affect more than a single cell type and that the changes include epigenetic modifications preserved during multiple mitotic cycles in tissue culture medium. All of these data are consistent with the idea that elevation of ATF4 function may contribute to the slow aging and extended lifespan in each of these diverse varieties of mice.

You might recall that ATF4 shows up in studies of methionione restriction. It is thought that a fair fraction of the benefits of calorie restriction involve changes in the operation of metabolism triggered by mechanisms that react to low methionine levels. You might look at these past items from the Fight Aging! archives for more context:

A Report from the First International Mini-Symposium on Methionine Restriction and Lifespan

The presentations highlighted the importance of research on cysteine, growth hormone (GH), and ATF4 in the paradigm of aging. In addition, the effects of dietary restriction or MR in the kidneys, liver, bones, and the adipose tissue were discussed.

Methionine Restriction and FGF21 in Mice

Methionine restriction decreased hepatic lipogenic gene expression and caused a remodeling of lipid metabolism in white adipose tissue, alongside increased insulin-induced phosphorylation of the insulin receptor (IR) and Akt in peripheral tissues. Mice restricted of methionine exhibited increased circulating and hepatic gene expression levels of FGF21, phosphorylation of eIF2a, and expression of ATF4. Short-term 48-h MR treatment increased hepatic FGF21 expression/secretion and insulin signaling and improved whole-body glucose homeostasis without affecting body weight.

JOãO PEDRO DE MAGALHãES IN REJUVENATION RESEARCH
https://www.fightaging.org/archives/2014/08/joao-pedro-de-magalhaes-in-rejuvenation-research.php

João Pedro de Magalhães is one of the few rising notables in the aging research community who has, from day one of his career, been absolutely and openly in favor of radical life extension through progress in medical science. To his eyes, as mine, the defeat of aging and age-related disease is a goal to strive for, plausible and attainable with the right research strategies. More than ten years ago, de Magalhães penned Winning the War Against Aging, I asked permission to reprint it online, and there is still is:

Imagine that your grandmother looks like a teenager, plays soccer, parties at the clubs all night, and works as a venture capitalist. Or imagine your grandfather teaching you the latest high-tech computer software in his office, which you hate to visit because of the loud heavy metal music. Such a scenario is hard to envision because we are taught to accept aging and the resulting suffering and death as an immutable fact of life. We cannot picture our grandparents in better physical shape than we are. Nonetheless, aging may soon become nothing more than a scary bedtime story, perhaps one your grandfather will tell your grandson after a day of white-water rafting together.

A decade on and my online efforts have become Fight Aging!, while de Magalhães now heads a research group investigating the molecular biology of aging at Liverpool University. He also runs the senescence.info website and associated databases, which are collectively an excellent resource on the science of aging for laypeople and scientists alike. I in no way suggest equivalence in our efforts: he is doing far more than I to advance this cause. Great things lie ahead in this field, and I have the greatest of admiration for people who plant a flag in the ground, set a target, and then stride forth to do what they say they were going do. The world could use more people of this ilk.

On that note, allow me to draw your attention to a position paper by de Magalhães in the pending publication queue of the Rejuvenation Research journal. In it he recapitulates his long-standing views on aging, radical life extension, and medical science - which is to say that the defeat of aging is possible and plausible, but efforts to that end remain woefully underfunded in comparison to their importance.

The scientific quest for lasting youth: prospects for curing aging

People have always sought eternal life and everlasting youth. Recent technological breakthroughs and our growing understanding of aging have given strength to the idea that a cure for human aging can eventually be developed. As such, it is crucial to debate the long-term goals and potential impact of the field. Here, I discuss the scientific prospect of eradicating human aging. I argue that curing aging is scientifically possible and not even the most challenging enterprise in the biosciences. Developing the means to abolish aging is also an ethical endeavor since the goal of biomedical research is to allow people to be as healthy as possible for as long as possible.

There is no evidence, however, that we are near developing the technologies permitting radical life-extension. One major difficulty in aging research is the time and costs it takes to do experiments and test interventions. I argue that unraveling the functioning of the genome and developing predictive computer models of human biology and disease are essential to increase the accuracy of medical interventions, including in context of life-extension, and exponential growth in informatics and genomics capacity might lead to rapid progress.

Nonetheless, developing the tools for significantly modifying human biology is crucial to intervene in a complex process like aging, yet in spite of advances in areas like regenerative medicine and gene therapy, the development of clinical applications has been slow and this remains a key hurdle for achieving radical life-extension in the foreseeable future.

You'll note from the abstract above, and from the work of his research group, that de Magalhães has a position on the best path forward that is fairly close to that of the present focus on genetics and longevity in the US research and development community. For my part, I ascribe the failure of past efforts to produce progress as being due to the fact that next to no work has been focused on repair of root causes in the SENS model. I predict that we will see significant progress when that state of affairs finally changes, which is something that we can help along by funding SENS or other similar disruptive approaches, pushing them closer to providing ever more convincing results that pull in other researchers as allies and supporters.

AMATEUR RELIGIOUS ENGINEERING AND LONGEVITY SCIENCE
https://www.fightaging.org/archives/2014/08/amateur-religious-engineering-and-longevity-science.php

There exists a very long history of people starting explicitly religious movements to achieve secular goals in the mundane world. A very broad range of such ventures can be found even in recent history, in this apostate age of comparatively weak and apolitical mainstream religious institutions. For every group who set out to achieve their ends through political advocacy, such as by starting a single issue political party, you'll find another who choose to start a church. Those who do this outside the established religious mainstream are looked at askance, and often deservedly so, but really you're just as likely to be taken for a ride on either side of the fence. The accumulation of worldly wealth and privilege at the expense of a gullible flock is almost a tradition in certain segments of the modern religious landscape.

For the purposes of this post, I want to glance at a very narrow thread of religious ventures, fictional and otherwise, that winds its way from the science fiction of the golden age and later through satire and art of the 70s and 80s and then into the online transhumanist community of the 90s and its present descendant organizations. At all these points in time, someone thought it a plausible idea that a religious movement should exist for the purpose of preserving and propagating secular technological goals, in particular the extension of healthy life spans through progress in medical science.

As an aside, I should mention that when I'm out there talking to people about longevity science and the need for funding, you can be certain that I'm not bringing any sort of religion to the table. In fact I'd be happier if religious movements started for the purpose of promoting the secular goal of life extension didn't exist, and for many of the same reasons that I'd rather the more vocal "anti-aging" supplement sellers and snake-oil salesmen went away. To the extent that these people succeed in gaining attention for themselves, they make life harder for the rest of us. Nonetheless, these initiatives exist, they are a part of the extended community of supporters, there is a fascinating history bubbling behind it all, and therefore this is worthy of at least a short post to note all of the above.

If you are widely read in science fiction, you will have no doubt encountered numerous tales in which the principals are engaged in what might be called religious engineering: attempting to change the world by means of exploiting the religious impulse as a lever, with varying degrees of cynicism and spiritualism involved. Stranger in a Strange Land and Neverness are two works that spring to mind. It is not an uncommon concept in fiction spanning the last decades of the last century, probably helped along by the fact that a former figure in that space was off doing something of the sort in the real world, with results we're all familiar with by now. That aside, science fiction serves a purpose in the evolution of technology and culture by virtue of being an idea hothouse. What exists today in the sciences and technology was usually chewed over speculatively and in increasingly accurate detail by numerous authors of the past century. Ideas don't stay stuck in their books: they take wing when they are found attractive.

Starting a religious movement for reasons that are openly secular, as opposed to keeping your secular goals hidden behind a veneer of faith, has come and gone as a fashion over recently decades. You might look at Discordianism, the Church of the Subgenius, and even Pastafarianism as examples of openly secular religions. The degree to which people do take these things religiously is a matter for debate, but it is hard to argue against their success as cultural movements in their time. These are the children and the siblings of science fictional religious engineering, ideas for advocacy escaped and made real.

So given this promiscuously inventive history, and not even touching on the ever-changing fringes of mainstream Christianity in countries like the US, we shouldn't be entirely surprised to discover small religious movements and proposals for the same associated with the support of longevity science. Any community of a meaningful size will produce such initiatives, and the modern community supportive of radical life extension achieved through advances in medicine is now several generations old, spanning a time of great invention in religious engineering, both inside and outside the mainstream. One of the first examples of this sort of thing that I recall encountering via the transhumanist community was the Church of Virus, a clear descendant of numerous science fiction concepts. That, perhaps appropriately, is little more than an idea:

Virus was created to compete with the traditional (irrational) religions in the human ideosphere with the idea that it would introduce and propagate memes which would ensure the survival and evolution of our species. The main advantage conferred upon adherents is Virus provides a conceptual framework for leading a truly meaningful life and attaining immortality without resorting to mystical delusions.

There are also populated groups, however, such as the Society for Venturism that has been a co-traveler with the cryonics community for some time now:

For those not familiar with it, Venturism is a 'secular religion' in the sense that the Praxis might be considered one, but very minimalistic and targeted specifically to the needs of the cryonics community. One of the things it does is to help cryonicists optimize their suspensions, by giving them "religious" grounds to object to autopsy (which would greatly harm their chances of repair and reanimation). Another thing it has done is fundraising for cases where last-minute funding was needed for a terminal patient who could not obtain life insurance.

Similarly, and of a more recent origin, there is apparently a Church of Perpetual Life which has the sound of Unitarianism for supporters of radical life extension and cryonics:

Perpetual Life is a science-based church that is open to people of all faiths. We are non-denominational and non-judgmental. We are also a central gathering place for Humanists, atheists, agnostics and Transhumanists. We hope that you also will find this church to be welcoming and inspiring. Our Mission is to assist all people in the radical extension of healthy human life, and to provide fellowship for longevity enthusiasts through regular, holiday and memorial services.

As it becomes increasingly known among the public that new approaches to treating aging and extending healthy life spans are on the way, I can only imagine that we'll see more of this. The sphere of religion as it evolves in practice works much like the intersection of politics and business: in particular there is disruption, revolution of ideas, movement of customers, and change. The large mainstream is always slow-moving and conservative, and as a consequence its leaders will find themselves challenged on the topic of extended healthy life spans, just as they have been challenged on medical advances in the past. They will fight a little, and then smaller and more nimble challengers espousing more sympathetic theologies will gain adherents, and ultimately the mainstream will accommodate them or be replaced: the same brand, but different bishops running the show. I'm sure it will be interesting to watch, for all that it has little relevance to presently important goals and challenges in advocacy for longevity science.

LATEST HEADLINES FROM FIGHT AGING!

GROWING A NEW THYMUS FROM ENGINEERED CELLS
Monday, August 25, 2014
https://www.fightaging.org/archives/2014/08/growing-a-new-thymus-from-engineered-cells.php

The thymus is vital to generation of new immune cells, and the fact that it atrophies early in life, turning a river of new cells into a trickle, is one of the factors placing an effective cap on the adult immune cell population. In part because of this limit in later life competent immune cells capable of dealing with new threats are crowded out by other immune cell types. Solutions to this issue include restoration of a larger supply of new cells by restoring the thymus or targeted destruction of the excess cells to free up space and spur the body to generate replacement immune cells that are capable of doing their jobs.

Earlier this year researchers published a demonstration of a short cut to rejuvenate the aged thymus simply by manipulating levels of FOXN1 to boost the population of certain important progenitor cells responsible for maintaining the thymus. It is rare to find such short cuts in tissue engineering, and this one most likely only exists for the thymus because of its unusual early decline in adults - a course very different from most organs, and which may have a comparatively simple set of triggers. Here the same research group shows off the next stage in their work, which is the generation of a complete new thymus in vivo by much the same set of mechanisms:

[Scientists] started with cells from a mouse embryo. These cells were genetically "reprogrammed" and started to transform into a type of cell found in the thymus. These were mixed with other support-role cells and placed inside mice. Once inside, the bunch of cells developed into a functional thymus. Structurally it contained the two main regions - the cortex and medulla - and it also produced T-cells. "This was a complete surprise to us, that we were really being able to generate a fully functional and fully organised organ starting with reprogrammed cells in really a very straightforward way. This is a very exciting advance and it's also very tantalising in terms of the wider field of regenerative medicine."

Here, we show that enforced ​Foxn1 expression is sufficient to reprogramme fibroblasts into functional thymic epithelial cells (TECs), an unrelated cell type across a germ-layer boundary. On transplantation, iTECs established a complete, fully organized and functional thymus, that contained all of the TEC subtypes required to support T-cell differentiation and populated the recipient immune system with T cells. iTECs thus demonstrate that cellular reprogramming approaches can be used to generate an entire organ, and open the possibility of widespread use of thymus transplantation to boost immune function in patients.

Patients who need a bone marrow transplant and children who are born without a functioning thymus could all benefit. Ways of boosting the thymus could also help elderly people. The organ shrinks with age and leads to a weaker immune system. However, there are a number of obstacles to overcome before this research moves from animal studies to hospital therapies. The current technique uses embryos. This means the developing thymus would not be a tissue match for the patient. Researchers also need to be sure that the transplant cells do not pose a cancer risk by growing uncontrollably.

INHIBITING P38 MAPK RESTORES PROLIFERATION IN SENESCENT T CELLS
Monday, August 25, 2014
https://www.fightaging.org/archives/2014/08/inhibiting-p38-mapk-restores-proliferation-in-senescent-t-cells.php

Senescent non-dividing cells of all types accumulate in various tissues. This is probably an adaptation that acts to suppress cancer risk, but these cells secrete damaging compounds that degrade nearby tissue function and cause surrounding cells to also tend towards senescence. The most straightforward approach to removing this contribution to degenerative aging is some form of targeted destruction of senescent cells, perhaps via adaptation of any one of the numerous cell killer technologies under development in the cancer research community.

In recent years some progress has been made in another direction, that of reversing the senescent state of cells. Ultimately the research community will be able to reprogram any cell into any desired state, but that lies a way into the future yet. Reversing senescence will undoubtedly prove complicated and tissue-specific, and there is the open question of whether this will increase cancer risk. Here is an example of one small step on this road, but note that it is only restoring the ability of one type of senescent cell to divide once more. It may or may not be adequately addressing the other undesirable behaviors of the cells, and may or may not turn out to be the best approach.

As we age our immune systems decline. Older people suffer from increased incidence and severity of both infections and cancer. In addition, vaccination becomes less efficient with age. In previous [work, researchers] showed that ageing in immune system cells known as T lymphocytes was controlled by a molecule called p38 MAPK that acts as a brake to prevent certain cellular functions. They found that this braking action could be reversed by using a p38 MAPK inhibitor, suggesting the possibility of rejuvenating old T cells using drug treatment.

In a new study [the] group shows that p38 MAPK is activated by low nutrient levels, coupled with signals associated with age, or senescence, within the cell. It has been suspected for a long time that nutrition, metabolism and immunity are linked and this paper provides a prototype mechanism of how nutrient and senescence signals converge to regulate the function of T lymphocytes. The study also suggests that the function of old T lymphocytes could be reconstituted by blocking one of several molecules involved in the process.

"Our life expectancy at birth is now twice as long as it was 150 years ago and our lifespans are on the increase. Healthcare costs associated with ageing are immense and there will be an increasing number of older people in our population who will have a lower quality of life due in part to immune decline. It is therefore essential to understand reasons why immunity decreases and whether it is possible to counteract some of these changes. An important question is whether this knowledge can be used to enhance immunity during ageing. Many drug companies have already developed p38 inhibitors in attempts to treat inflammatory diseases. One new possibility for their use is that these compounds could be used to enhance immunity in older subjects. Another possibility is that dietary instead of drug intervention could be used to enhance immunity since metabolism and senescence are two sides of the same coin."

EVERYTHING LOOKS THE SAME IN THE DISTANCE
Tuesday, August 26, 2014
https://www.fightaging.org/archives/2014/08/everything-looks-the-same-in-the-distance.php

One of the challenges we face in directing fund and attention to the most promising research into human longevity, rather than efforts that are doomed from the start to achieve no meaningful near term gains, is that from the distance of unfamiliarity everything looks the same. The average journalist or person in the street can't tell the difference between SENS rejuvenation research, metabolic alterations with a poor chance of slightly slowing aging after the Longevity Dividend model, research into genetics of longevity and personalized medicine, and opportunists who cloak their old-fashioned health businesses with the mere appearance of modern longevity science. From the perspective of people at a distance it all looks the same, equally valid. Which is far from being the case.

This article is an example of the phenomenon, in which it is a matter of accident and publicity as to whom the author discusses, rather than whether or not their efforts are relevant or effective. Thus what is intended to be a discussion of Silicon Valley initiatives targeting aging and longevity manages to omit the SENS Research Foundation, despite the organization being headquartered there, and spends many of its words on the next generation of self-deluding snake oil salespeople, pushing the quantified self rather than pills this time around.

Asprey is trying to stop individual bodies from aging - starting with his own - and investment is pouring into a growing number of companies whose stated goal is to increase human longevity and, in some cases, even cure death. Asprey freely admits that these are grandiose, quixotic endeavors. But in a place where geeks have changed the world with previously unthinkable breakthroughs in science, nothing seems impossible. "When you're young and you've just created something amazing that makes you a ton of a money, you do egotistical things. And I'm not saying that's a bad thing: I want to swing for the fences. What is all of this cool technology we're creating compared to getting an extra hundred years of life?"

He's far from the only one dreaming of a home run. Last year Google launched Calico Labs, a medical company whose goal is to tackle aging and illness. While so far Calico is remaining fairly secretive about its projects (my requests for an interview were politely declined), experts believe its objective is to go beyond solving individual diseases the way most medical researchers have done until now. Earlier this year, Calico hired Cynthia Kenyon [who] has been experimenting with tweaking genes in animals to slow aging. By disabling a gene called daf-2, she has doubled the life-span of roundworms, fruit flies, and mice. In her new role as VP of aging research at Calico, she will ostensibly be attempting to re-create these results in humans.

This year, another company, Human Longevity, joined the anti-aging quest. Founded by J. Craig Venter, another millionaire entrepreneur, it's central goal involves understanding DNA. [In] some ways, the goals of Human Longevity are in line with what medicine has been trying to do all along: cure illness, improve life quality, and extend the human life-span. The difference is that his company applies big-data tools to process vast quantities of information we now have about the human body. The organization will sequence 2 million human genomes in five years, gathering unparalleled insights into the causes of disease. Rather than tackling problems incrementally, he says it is possible to work on a bigger scale, yielding more dramatic results. One of them could be cheating death.

I brought many of these questions to Laura Deming, one of the youngest people in the anti-aging movement. She's just 20, but she's already been working on the problem for close to a decade. "I was taken by this idea that if you have a vision of what you want to make, you can just build it," she tells me. Deming immediately began trying to fix the problem. At 12 she started work at a lab and enrolled at MIT at the age of 14. Three years later, she dropped out to become a Thiel fellow to continue her research. She has recently started the Longevity Fund, a company that seeks to attract investors to startups working on aging and life extension. Deming points out that people's views tend to change when they move away from big existential questions to imagining individual people instead. While ending death is one part of the story, a more tangible part is curing the diseases that cause death. She believes almost everyone would cure cancer or arthritis or dementia if they could.

APOLIPOPROTEIN B VARIANTS AND EXCEPTIONAL HUMAN LONGEVITY
Tuesday, August 26, 2014
https://www.fightaging.org/archives/2014/08/apolipoprotein-b-variants-and-exceptional-human-longevity.php

Studies of human longevity-associated genes produce results that tend to be hard to replicate. The effects are individually tiny and vary widely between study populations, indicating a complex web of influences. Only a few genes stand out as having small and consistent rather than tiny and varying associations with longevity, such as APOE variants involved in the operation of cholesterol metabolism among other things. So on the one hand expect the results of this study to be hard to replicate, especially given the small sample size, but on the other hand it is somewhat connected to APOE so we shall see:

Exceptional longevity (EL) is a rare phenotype that can cluster in families, and co-segregation of genetic variation in these families may point to candidate genes that could contribute to extended lifespan. In this study, for the first time, we have sequenced a total of seven exomes from exceptionally long-lived siblings (probands of more than 103 years and at least one sibling of more than 97 years) that come from three separate families. We have focused on rare functional variants (RFVs) which have ≤ 1% minor allele frequency according to databases and that are likely to alter gene product function.

Based on this, we have identified one candidate longevity gene carrying RFVs in all three families, APOB. Interestingly, APOB is a component of lipoprotein particles together with APOE, and variants in the genes encoding these two proteins have been previously associated with human longevity. Analysis of nonfamilial EL cases showed a trend, without reaching statistical significance, toward enrichment of APOB RFVs. We have also identified candidate longevity genes shared between two families (5 - 13) or within individual families (66 - 156 genes). Some of these genes have been previously linked to longevity in model organisms, such as PPARGC1A, NRG1, RAD52, RAD51, NCOR1, and ADCY5 genes. This work provides an initial catalog of genes that could contribute to exceptional familial longevity.

ADVOCATING ARTERIAL DESTIFFENING TO TREAT CARDIOVASCULAR DISEASE
Wednesday, August 27, 2014
https://www.fightaging.org/archives/2014/08/advocating-arterial-destiffening-to-treat-cardiovascular-disease.php

It is always good to see more scientists come around to the SENS viewpoint of damage repair as the best treatment for age-related disease. Addressing root causes is a much better approach than the current prevalent paradigm of trying to adapt failing biological systems to work less poorly when damaged, while failing to make a dent in the damage itself. Tackling the root causes should be much more cost-effective and simply much more effective overall, and in many cases the root causes for specific age-related conditions are known rather than merely surmised.

Cardiovascular risk factors (CVRFs) have been shown to induce end organ damage. Until now, the main approach to reduce CVRF-induced end organ damage was by normalization of CVRFs; this approach was found effective to reduce damage and cardiovascular (CV) events. However, a residual risk always remained even when CVRFs were optimally balanced. An additional risk factor which has an immense effect on the progression of end organ damage is aging. Aging is accompanied by gradual stiffening of the arteries which finally leads to CV events. Until recently, the process of arterial aging was considered as unmodifiable, but this has changed.

Arterial stiffening caused by the aging process is similar to the changes seen as a result of CVRF-induced arterial damage. Actually, the presence of CVRFs causes faster arterial stiffening, and the extent of damage is proportional to the severity of the CVRF, the length of its existence, the patient's genetic factors, etc. Conventional treatments of osteoporosis and of hormonal decline at menopause are potential additional approaches to positively affect progression of arterial stiffening.

The new approach to further decrease progression of arteriosclerosis, thus preventing events, is the prevention of age-associated arterial structural changes. This approach should further decrease age-associated arterial stiffening. A totally new promising approach is to study the possibility of affecting collagen, elastin, and other components of connective tissue that participate in the process of arterial stiffening. Reduction of pulse pressure by intervention in arterial stiffening process by novel methods as breaking collagen cross-links or preventing their formation is an example of future directions in treatment. This field is of enormous potential that might be revolutionary in inducing further significant reduction of cardiovascular events.

IDENTIFYING TISSUE WEAKNESS BEFORE INJURY
Wednesday, August 27, 2014
https://www.fightaging.org/archives/2014/08/identifying-tissue-weakness-before-injury.php

This is an interesting technology demonstration that suggests an obvious pairing with regenerative treatments based on the use of stem cells or similar means to spur tissue repair. With regular scans it might be possible to preempt many instances of muscle and bone injury caused by use and stress, preventing them from ever developing by repairing tissue weak spots before they develop into injuries.

[Researchers] have developed algorithms to identify weak spots in tendons, muscles and bones prone to tearing or breaking. The technology, which needs to be refined before it is used in patients, one day may help pinpoint minor strains and tiny injuries in the body's tissues long before bigger problems occur. "Tendons are constantly stretching as muscles pull on them, and bones also bend or compress as we carry out everyday activities. Small cracks or tears can result from these loads and lead to major injuries. Understanding how these tears and cracks develop over time therefore is important for diagnosing and tracking injuries."

[The researchers] developed a way to visualize and even predict spots where tissues are weakened. To accomplish this, they stretched tissues and tracked what happened as their shapes changed or became distorted. [They] combined mechanical engineering fundamentals with image-analysis techniques to create the algorithms, which were tested in different materials and in animal models. "The new algorithm allowed us to find the places where the tears were beginning to form and to track them as they extended. Older algorithms are not as good at finding and tracking localized strains as the material stretches."

In fact, one of the two new algorithms is 1,000 times more accurate than older methods at quantifying very large stretches near tiny cracks and tears, the research showed. And a second algorithm has the ability to predict where cracks and failures are likely to form. "This extra accuracy is critical for quantifying large strains. Commercial algorithms that estimate strain often are much less sensitive, and they are prone to detecting noise that can arise from the algorithm itself rather than from the material being examined. The new algorithms can distinguish the noise from true regions of large strains."

THE COST OF A SEDENTARY LIFESTYLE TO MUSCLE AND BONE
Thursday, August 28, 2014
https://www.fightaging.org/archives/2014/08/the-cost-of-a-sedentary-lifestyle-to-muscle-and-bone.php

A mountain of evidence exists to demonstrate that being sedentary will lead to greater ill health and a shorter life expectancy. As we inch closer towards the implementation of rejuvenation treatments at some uncertain point in the decades ahead, every year of health and life gained counts, raising the odds of living long enough to benefit from proposed ways to repair the damage of aging.

Being physically active may significantly improve musculoskeletal and overall health, and minimize or delay the effects of aging, according to a review of the latest research. It long has been assumed that aging causes an inevitable deterioration of the body and its ability to function, as well as increased rates of related injuries such as sprains, strains and fractures; diseases, such as obesity and diabetes; and osteoarthritis and other bone and joint conditions. However, recent research on senior, elite athletes suggests usage of comprehensive fitness and nutrition routines helps minimize bone and joint health decline and maintain overall physical health.

"An increasing amount of evidence demonstrates that we can modulate age-related decline in the musculoskeletal system. A lot of the deterioration we see with aging can be attributed to a more sedentary lifestyle instead of aging itself." The positive effects of physical activity on maintaining bone density, muscle mass, ligament and tendon function, and cartilage volume are keys to optimal physical function and health. "Regimens must be individualized for older adults according to their baseline level of conditioning and disability, and be instituted gradually and safely, particularly for elderly and poorly conditioned adults." To improve fitness levels and minimize bone and joint health decline, when safely allowable, patients should be encouraged to continually exceed the minimum exercise recommendations.

A POTENTIAL SOURCE OF CARDIAC STEM CELLS
Thursday, August 28, 2014
https://www.fightaging.org/archives/2014/08/a-potential-source-of-cardiac-stem-cells.php

Many research groups in the stem cell field are engaged in a search for sources of useful tissue-specific cells in the body, developing means of identification and isolation. This runs in parallel with efforts to reprogram more easily obtained cells, such as from skin samples, into a range of different types for therapy and research. Both approaches add value in the near term, expanding the range of tissues in which regeneration might be greatly enhanced. The heart is of particular interest as it normally has little capacity for repair, and is of course the cause of a great many fatal problems as we age. Here is an example of progress in identifying existing cell populations that support heart tissue:

Endothelial cells residing in the coronary arteries can function as cardiac stem cells to produce new heart muscle tissue. The findings [offer] insights into how the heart maintains itself and could lead to new strategies for repairing the heart when it fails after a heart attack. The heart has long been considered to be an organ without regenerative potential. Recent findings, however, have demonstrated that new heart muscle cells are generated at a low rate, suggesting the presence of cardiac stem cells. The source of these cells was unknown.

[Researchers] postulated that the endothelial cells that line blood vessels might have the potential to generate new heart cells. They knew that endothelial cells give rise to other cell types, including blood cells, during development. Now, using sophisticated technologies to "track" cells in a mouse model, they have demonstrated that endothelial cells in the coronary arteries generate new cardiac muscle cells in healthy hearts. They found two populations of cardiac stem cells in the coronary arteries - a quiescent population in the media layer and a proliferative population in the adventitia (outer) layer.

The finding that coronary arteries house a cardiac stem cell niche has interesting implications. Coronary artery disease would impact this niche. "Our study suggests that coronary artery disease could lead to heart failure not only by blocking the arteries and causing heart attacks, but also by affecting the way the heart is maintained and regenerated."

NASAL CARTILAGE CELLS CAN REPLACE JOINT CARTILAGE
Friday, August 29, 2014
https://www.fightaging.org/archives/2014/08/nasal-cartilage-cells-can-replace-joint-cartilage.php

Cartilage regeneration and tissue engineering has proven more difficult than initially expected. It is a tissue with a deceptively complex structure, in which important mechanical properties necessary to its load-bearing role are derived from the details of that structure. Simply culturing cartilage cells is far from enough to produce a useful end result, and researchers have only recently made inroads into producing tissue engineered cartilage that is somewhat like the real thing. In this work a novel approach is taken to produce grafts for injured joint cartilage:

Cartilage lesions in joints often appear in older people as a result of degenerative processes. However, they also regularly affect younger people after injuries and accidents. Such defects are difficult to repair and often require complicated surgery and long rehabilitation times. A new treatment option has now been presented by a research team: nasal cartilage cells can replace cartilage cells in joints.

[Scientists] were especially surprised by the fact that in the animal model with goats, the implanted nasal cartilage cells were compatible with the knee joint profile; even though, the two cell types have different origins. During the embryonic development, nasal septum cells develop from the neuroectodermal germ layer, which also forms the nervous system; their self-renewal capacity is attributed to their lack of expression of some homeobox (HOX) genes. In contrast, these HOX genes are expressed in articular cartilage cells that are formed in the mesodermal germ layer of the embryo.

Cartilage cells from the nasal septum (nasal chondrocytes) have a distinct capacity to generate a new cartilage tissue after their expansion in culture. In an ongoing clinical study, the researchers have so far taken small biopsies (6 millimeters in diameter) from the nasal septum from seven out of 25 patients below the age of 55 years and then isolated the cartilage cells. They cultured and multiplied the cells and then applied them to a scaffold in order to engineer a cartilage graft the size of 30 x 40 millimeters. A few weeks later they removed the damaged cartilage tissue of the patients' knees and replaced it with the engineered and tailored tissue from the nose.

THE PROSPECTS FOR THERAPIES AND ENHANCEMENTS VIA MAGNETIC STIMULATION OF THE BRAIN
Friday, August 29, 2014
https://www.fightaging.org/archives/2014/08/the-prospects-for-therapies-and-enhancements-via-magnetic-stimulation-of-the-brain.php

Transcranial magnetic stimulation (TMS) is a fascinating field of study in which it is clearly possible to affect the brain, but researchers are still in the comparatively early stages of finding out how to reliably produce and measure useful end results. The research noted here is an example of one of the more positive findings, a way to enhance memory function. It doesn't address underlying causes of dysfunction in aging, unfortunately, rather being a possible methodology to compensate somewhat for losses. This isn't the preferred direction for medicine if we seek true prevention and cure of age-related loss of function, but as for many such things, one has to ask "why not see whether or not this can be applied all the time, for everyone?"

In the past, TMS has been used in a limited way to temporarily change brain function to improve performance during a test, for example, making someone push a button slightly faster while the brain is being stimulated. The study shows that TMS can be used to improve memory for events at least 24 hours after the stimulation is given.

It isn't possible to directly stimulate the hippocampus with TMS because it's too deep in the brain for the magnetic fields to penetrate. So, using an MRI scan, [researchers] identified a superficial brain region a mere centimeter from the surface of the skull with high connectivity to the hippocampus. [They] wanted to see if directing the stimulation to this spot would in turn stimulate the hippocampus. It did. When TMS was used to stimulate this spot, regions in the brain involved with the hippocampus became more synchronized with each other, as indicated by data taken while subjects were inside an MRI machine, which records the blood flow in the brain as an indirect measure of neuronal activity. The more those regions worked together due to the stimulation, the better people were able to learn new information.

Scientists recruited 16 healthy adults ages 21 to 40. Each had a detailed anatomical image taken of his or her brain as well as 10 minutes of recording brain activity while lying quietly inside an MRI scanner. Doing this allowed the researchers to identify each person's network of brain structures that are involved in memory and well connected to the hippocampus. The structures are slightly different in each person and may vary in location by as much as a few centimeters. Each participant then underwent a memory test, consisting of a set of arbitrary associations between faces and words that they were asked to learn and remember. After establishing their baseline ability to perform on this memory task, participants received brain stimulation 20 minutes a day for five consecutive days. Then, at least 24 hours after the final stimulation, they were tested again. Both groups performed better on memory tests as a result of the brain stimulation. It took three days of stimulation before they improved.

In an upcoming trial, [researchers] will study the electrical stimulation's effect on people with early-stage memory loss, [but] cautioned that years of research are needed to determine whether this approach is safe or effective for patients with Alzheimer's disease or similar disorders of memory.