FIGHT AGING! NEWSLETTER
October 6th 2014
Herein find a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress on the road to bringing aging under medical control, the prevention of age-related disease, and present understanding of what works and what doesn't when it comes to extending healthy life. Expect to see summaries of recent advances in medicine, news from the scientific community, advocacy and fundraising initiatives to help speed work on the repair and reversal of aging, links to online resources, and much more.
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- The 2014 Fight Aging! Fundraiser Starts Now: We'll Match Your Research Donations with $2 for Every $1 Given
- A Better Understanding of the Mechanisms of ALT, Alternative Lengthening of Telomeres
- Arigos Biomedical, in the Small Overlap Between Rejuvenation Biotechnology and Cryonics
- A Little Reverse Engineering of the Role of Inflammation in Age-Related Immune Dysfunction
- You Speak to the Audience You Have
- Latest Headlines from Fight Aging!
- A Novel Type of Cellular Garbage in Aging
- Coming Around to the Idea of Radical Life Extension
- More Investigation of the Choroid Plexus in Brain Aging
- A Review of What Can Be Done Today About Brain Aging
- Alzheimer's Memory Loss Turned Back with Calorie Restriction and Exercise
- Another Demonstration of Cells Taking Up Whole Mitochondria
- A Neuroprotector's Dilemma
- The "Slow Aging with Drugs" Viewpoint
- Proposing Heterochronic Parabiosis as a Way to Win Half of the Palo Alto Longevity Prize
- Young Cognitive Function Predicts Aged Pulmonary Function
THE 2014 FIGHT AGING! FUNDRAISER STARTS NOW: WE'LL MATCH YOUR RESEARCH DONATIONS WITH $2 FOR EVERY $1 GIVEN
It is that time again, and our matching fundraiser started on October 1st 2014. From now until the end of the year, December 31st 2014, we will match donations made to the SENS Research Foundation with $2 for every $1 given. These funds will help to speed progress in ongoing scientific programs conducted in US and European research centers, their ultimate aim being to repair and reverse the causes of frailty and age-related disease.
- Donate directly: http://sens.org/donate
The SENS Research Foundation is a 501(c)(3) charity and all US donations are tax-deductible. Donations from most European Union countries are also tax-deductible, though the details vary by location. Please contact the SENS Research Foundation to find out more.
The Matching Fund Founders Ask You to Join Us
Who are we? We are Christophe and Dominique Cornuejols, David Gobel of the Methuselah Foundation, Dennis Towne, Håkon Karlsen, philanthropist Jason Hope, Michael Achey, Michael Cooper, and Reason of Fight Aging! We are all long-time supporters of SENS research aimed at rejuvenation through repair of the known root causes of aging. The few types of cellular and molecular damage that accumulate in all of our tissues cause progressive dysfunction and eventual death for everyone - unless something is done to stop it. This cause is important enough for everyone to do their part, and for us that means putting up a matching fund we want you to help draw down: for every dollar you donate, we will match it with two of our own.
Even Small Donations Make a Meaningful Difference
Early stage medical biotechnology research of the sort carried out at the SENS Research Foundation costs little nowadays in comparison to the recent past. The cost of tools and techniques in biotechnology has plummeted in the past decade, even while capabilities have greatly increased. A graduate student with a few tens of thousands of dollars can accomplish in a few months what would have required a full laboratory, years, and tens of millions of dollars in the 1990s. All of the much-lamented great expense in modern medicine lies in clinical translation, the long and drawn out process of trials, retrials, marketing, and manufacturing that is required to bring a laboratory proof of concept into clinics as a widely available therapy.
The SENS Research Foundation is focused on early stage research, following a plan that leads to technology demonstrations in the laboratory. With a proof of concept rejuvenation therapy the world will beat a path to their doorstep in order to fund clinical translation. The real challenge is here and now, raising the funds to get to that step. A few tens of thousands of dollars means the difference between a significant project delayed indefinitely or that project completed.
To pick one example, last year the community raised just a few tens of thousands of dollars to fund cutting edge work in allotopic expression of mitochondrial genes, a potential cure for the issue of mitochondrial damage in aging. That was enough to have a skilled young researcher work on the process for two of the thirteen genes of interest over a period of months. It really is that cheap given an existing group like the SENS Research Foundation with diverse connections and access to established laboratories.
Your donations make a real difference.
Spread the Word, Tell Your Friends
Don't forget to tell your friends about this fundraiser. Talk to your community, online and offline. Consider running local events to help meet this fundraising goal from a grassroots community of supporters. The more people who know about the prospects for near future therapies resulting from rejuvenation research of the sort carried out by the SENS Research Foundation, the easier it becomes to raise funds and obtain institutional support for these research programs in the future.
Launched at /r/Futurology and in Conjunction with Longevity Day
Take a look at the generous spirit displayed at /r/Futurology, the futurist Reddit community, when given the chance to help. Scores of people there have already donated modest sums to the cause in response to our fundraiser: many thanks to you all!
The 1st of October marks the launch of this fundraiser, but it is also the International Day of Older Persons, and the International Longevity Alliance would like this to become an official Longevity Day. This year, just like last year, groups of futurists around the world will be holding events to mark the occasion, and this includes the scientists and advocates present at the 2014 Eurosymposium on Healthy Aging.
Download the 2014 Fundraiser Posters
The full size graphics here 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 - please help to spread the word and help this fundraiser to meet its target.
A BETTER UNDERSTANDING OF THE MECHANISMS OF ALT, ALTERNATIVE LENGTHENING OF TELOMERES
Telomeres cap the ends of chromosomes and shorten with each cell division, one part of the collection of mechanisms that limits the lifespan of somatic cells that make up the bulk of our tissues. Fresh cells with long telomeres are regularly introduced by the stem cells that support each type of tissue in the body, while old cells that have divided many times destroy themselves or lapse into a state of senescence. Average telomere length in tissues tends to shorten with ill health and aging, and this is probably a consequence of reduced stem cell activity, among other factors. This picture is then complicated by the activity of telomerase, an enzyme that lengthens telomeres in various cell types to various degrees, and further by the less well understood process known as alternative lengthening of telomeres or ALT.
ALT is largely studied in the context of cancer. Cancerous cells are cancerous precisely because they can replicate without limits, and to do that they must be able to lengthen their telomeres constantly. A sizable fraction of cancers use ALT for this purpose, and so a way to selectively sabotage ALT should enable researchers to shut off many forms of cancer. Indeed, the SENS Research Foundation approach to cancer is the ambitious set of proposed treatments known as WILT, or whole-body interdiction of lengthening of telomeres. This would require blocking the telomere-lengthening activity of telomerase and sabotaging ALT permanently in all tissues, which in turn would require ways to selectively lengthen telomeres in stem cell populations on a regular basis so as to preserve tissue maintenance. Of all of the lines of SENS research, this is the one where the most remains to be discovered and the least is known of how exactly to achieve this end. Nonetheless, telomere lengthening is the single known shared point of vulnerability in all cancers at this time - strike at the root, as they say.
SENS or no SENS, plenty of cancer researchers would like to interfere in the operation of ALT, and progress is being made on the understanding needed to attain that goal:
Penn Researchers Explain How Ends of Chromosomes are Maintained for Cancer Cell Immortality
Maintaining the ends of chromosomes, called telomeres, is a requisite feature of cells that are able to continuously divide and also a hallmark of human cancer. In a new study [researchers] describe a mechanism for how cancer cells take over one of the processes for telomere maintenance to gain an infinite lifespan. In general, cancer cells take over either type of telomere maintenance machinery to become immortal. Overall, approximately fifteen percent of cancers use the ALT process for telomere lengthening, but some cancer types use ALT up to 40 to 50 percent of the time.
The team showed that when DNA breaks, it triggers DNA repair proteins like the breast cancer suppressor protein BRCA2 into action, along with other helper proteins, that attach to the damaged stretch of DNA. These proteins stretch out the DNA, allowing it to search for complementary sequences of telomere DNA. "This process of repair triggers the movement and clustering of telomeres like fish being reeled toward an angler. The broken telomeres use a telomere on a different chromosome - the homologous telomere -- as a template for repair." In fact, in cancer cells that use ALT to maintain their telomeres, the team could visualize this process by imaging these clusters of telomeres coming together. The team would like to find other proteins involved in ALT and look for small molecule drugs that target this telomere maintenance mechanism in cancer cells to selectively kill cancer types that use ALT.
Interchromosomal Homology Searches Drive Directional ALT Telomere Movement and Synapsis
Telomere length maintenance is a requisite feature of cellular immortalization and a hallmark of human cancer. While most human cancers express telomerase activity, ∼10%-15% employ a recombination-dependent telomere maintenance pathway known as alternative lengthening of telomeres (ALT) that is characterized by multitelomere clusters and associated promyelocytic leukemia protein bodies.
Here, we show that a DNA double-strand break (DSB) response at ALT telomeres triggers long-range movement and clustering between chromosome termini, resulting in homology-directed telomere synthesis. Damaged telomeres initiate increased random surveillance of nuclear space before displaying rapid directional movement and association with recipient telomeres over micron-range distances.
This phenomenon required Rad51 and the Hop2-Mnd1 heterodimer, which are essential for homologous chromosome synapsis during meiosis. These findings implicate a specialized homology searching mechanism in ALT-dependent telomere maintenance and provide a molecular basis underlying the preference for recombination between nonsister telomeres during ALT.
ARIGOS BIOMEDICAL, IN THE SMALL OVERLAP BETWEEN REJUVENATION BIOTECHNOLOGY AND CRYONICS
The small industry of cryonics is the destination for the few visionary survivors who can see the golden future ahead, but who will die before the advent of working rejuvenation biotechnology, ways to repair the old, turn back age-related disease, and restore their health. The therapies necessary to attain this goal can be envisaged today in great detail: removing metabolic waste; repairing mitochondrial DNA damage; restoring declining stem cell activity to youthful function; and so forth. But tens of millions of lives are lost to aging with each passing year, and widespread, reliable, cost-effective rejuvenation treatments are as yet decades ahead of us even in the best of plausible futures.
There is only only one fallback plan at the moment, and that is cryonics: to be vitrified and put into low-temperature storage, knowing that if you can wait, the pattern of your mind preserved indefinitely in the fine structure of your brain, then the upward curve of science and technology will lead to future restoration. The molecular nanotechnologies needed to restore a vitrified brain to active life can also be envisaged in some detail, for all that they are much more complex and distant than mere near-perfect control over disease, cells, and all other aspects of our biology. If a future society can restore a cryopreserved person to life, then repairing the damage of age and crafting a new body to order should be a simple task in comparison.
Throughout the past two decades of growth in the modern community of longevity advocates and researchers there has been an overlap between interest in cryonics and interest in treating aging. In the matter of goals, they are both approaches to reduce the odds of dying, an admirable target and something the rest of society should give more than the lip service it does. On the side of science there is an overlap between cryonics and the tissue engineering infrastructure that will be needed in the decades ahead: when building tissues to order is a routine undertaking, it also becomes necessary to efficiently and effectively store tissues. The ability to indefinitely warehouse tissue products will make all the difference to prices at the clinic, and the only candidate approach is vitrification and low-temperature storage, exactly the same technologies used in cryopreservation.
The folk at 21st Century Medicine have been working to bridge that gap for years, but it isn't the only such venture. A few years back some of the people also involved in the rejuvenation research side of the industry founded Arigos Biomedical to work on a better method of vitrification for organ preservation. The company was one of the first recipients of venture funding from Breakout Labs, presented some of their work at the SENS6 conference, and quite recently the SENS Research Foundation extended a bridge loan on the occasion of Tanya Jones transitioning from the SRF to full time work at Arigos:
SENS Research Foundation is pleased to announce that its Board has authorized a bridge loan to Arigos Biomedical, Inc. Arigos's work in the long-term preservation of organs for the transplant industry - an intrinsic, necessary infrastructure component for the development of a tissue engineering industry - is supportive of SRF's overall mission to advance rejuvenation biotechnology. Our Chief Operating Officer, Tanya Jones, began this company with another co-founder three years ago, and she will be leaving SRF to be Arigos's full-time CEO. Tanya's work has had an indelible impact on SRF, where her efforts included establishing our first Bay area research facility, and our expansion into our current research center. SRF is proud to have this opportunity to support the work that Arigos is doing, and the great progress that it promises.
The SENS Research Foundation has a fine tradition of graduating researchers and employees out to other cutting edge ventures in the Bay Area, and Jones is far from the first to go on to other interesting work in a related field. Networking is everything in this world, and this is an example of how that works. Both Breakout Labs and the SENS Research Foundation are within Peter Thiel's network, which in turn is an active part of the Bay Area venture community, where everyone of note is at most two steps removed from everyone else of note. A bridge loan is a fairly common practice when raising funds for a young company, given that (a) the process always takes more time and effort than you think it is going to, and (b) funding sources are often quite happy to draw things out in order to gain more favorable terms from an operating business with ongoing expenses. Demonstrating the ability to produce bridge loans from thin air is an effective counter to that ploy.
Thus one can assume that Arigos Biomedical is doing well enough to be raising funds in this up market and pulling in more time and effort from those involved. We shall see how that all goes, but the signs in recent years have all been pointing to the start of meaningful progress in organ preservation. The company follows the long-standing tradition in early stage medical and biotech startups of having no web presence at all - it isn't unusual, for all that it makes life just a little more challenging for those of us who do use the internet for everything. To find out more about what the company is doing requires some digging, such as turning up this article from last year:
When a person dies, doctors often have mere hours - or in the case of kidneys, just over a day - to find a recipient before the organ degrades. "This precludes any chance of banking organs and makes every transplant an emergency procedure, often in the dead of night... when patients aren't ready," says Stephen van Sickle of Arigos Biomedical in Mountain View, California.
Nearly 1 in 5 donor kidneys is discarded in the US each year, because a suitable recipient or clinic cannot be found in time. But what if these organs could be frozen? Standard freezing creates damaging ice crystals. An alternative is vitrification. This process is often used to store human eggs or embryos for years and involves infusing the tissue with an antifreeze-like liquid and rapidly cooling it to create a glassy state. Doing this with large organs such as hearts and kidneys is harder, as more antifreeze can be toxic and the glassy organ can crack.
To tackle this problem, van Sickle combined vitrification with persufflation, in which blood is replaced with a gas - helium in this case. The organ cools more quickly, less antifreeze is needed and pockets of tissue are separated by gas, protecting against shattering. So far, van Sickle, who outlined his work at the Strategies for Engineered Negligible Senescence meeting in Cambridge, UK, has frozen pig kidneys. CT scans revealed a lot less fracturing than with vitrification alone. The next stage is to rewarm the organs to see if they remain viable.
A LITTLE REVERSE ENGINEERING OF THE ROLE OF INFLAMMATION IN AGE-RELATED IMMUNE DYSFUNCTION
Short term inflammation is a vital part of the immune response, necessary to keep us healthy in the face of life's many slings and arrows. Chronic inflammation is a different story, however, as it is a potent source of damage to tissues and bodily systems over the course of a lifetime. Numerous research groups are focused on developing a better understanding of how and why rising levels of chronic inflammation goes hand in hand with aging and dysfunction of the immune system. They see this as a characteristic process of degenerative aging, and in recent years have taken to calling it inflammaging.
To pick one example of the mechanisms involved in inflammaging, chronic inflammation is one important factor in the correlation between more visceral fat tissue, shorter life expectancy, and higher risk of suffering all of the common age-related diseases. Visceral fat is metabolically active and its interaction with immune cells is unhealthy, causing inflammation. That has meaningful consequences for health and mortality if you happen to carry a lot of fat tissue around with you.
Fat or no fat, the immune system becomes steadily more dysfunctional with age, however. The fat just makes it worse. An aged immune system is less effective at its tasks of defense and elimination of potentially dangerous damaged cells, but also overactive at the same time, fallen into a state of chronic inflammation in its disarray. The recently published research quoted below suggests that increased inflammation is such an important component of this degenerative process that even very crude tools that suppress inflammation can provide benefits. This suggests that more sophisticated approaches may also be worth pursuing even through they would most likely be only stepping stones on the way to real immune rejuvenation. Present means of suppressing age-related chronic inflammation don't address the root causes, the damage and misconfiguration of the aged immune system. Future treatments that tackle root causes should be far more effective.
Making Old Lungs Look New Again
The researchers compared lung cells from old and young mice and found that in the old mice, genes that make three classic pro-inflammatory proteins, called cytokines, were more active in the lungs of old mice. The cytokines are interleukin-1 (IL-1), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-a). In addition, immune system cells called macrophages in the lungs from old mice were in an advanced state of readiness to fight an infection - a status that signals inflammation. Macrophages in young mouse lungs were in a normal, resting state.
In test tubes, the scientists exposed mouse lung macrophages to tuberculosis (TB) bacteria. The macrophages from old mouse lungs were quicker to absorb the bacteria than were immune cells from young mice, but that initial robust immune response from the cells of old mice could not be sustained. "A primed macrophage in an old mouse has lots of receptors on its surface that can bind to TB, taking it up and trying to kill it. But what it lacks is the ability to increase the response further. A resting macrophage in a young mouse takes up TB and then can be activated to do something even more effective at killing the bacteria."
Though some elements of the elderly response to TB remain a mystery, this finding suggested that the inflammation in the lungs of elderly mice had the direct effect of reducing the long-term effectiveness of their immune response to TB infection. The researchers gave old and young mice ibuprofen in their food for two weeks and then examined their lung cells. After this diet modification, several pro-inflammatory cytokines in the lungs of old mice had been reduced to levels identical to those in the lungs of young mice, and the macrophages in old mouse lungs were no longer in a primed state. "There's a trend toward reduced inflammation. Essentially, ibuprofen made the lungs of old mice look young. Putting young mice on ibuprofen had no effect because they had no lung inflammation, which implies the ibuprofen reduced the inflammation and changed the immune response in the old mice."
Characterization of lung inflammation and its impact on macrophage function in aging
Systemic inflammation that occurs with increasing age (inflammaging) is thought to contribute to the increased susceptibility of the elderly to several disease states. The elderly are at significant risk for developing pulmonary disorders and infectious diseases, but the contribution of inflammation in the pulmonary environment has received little attention.
In this study, we demonstrate that the lungs of old mice have elevated levels of proinflammatory cytokines and a resident population of highly activated pulmonary macrophages that are refractory to further activation by IFN-γ. The impact of this inflammatory state on macrophage function was determined in vitro in response to infection with Mycobacterium tuberculosis (M.tb). Macrophages from the lungs of old mice secreted more proinflammatory cytokines in response to M.tb infection than similar cells from young mice and also demonstrated enhanced M.tb uptake and P-L fusion.
Supplementation of mouse chow with the NSAID ibuprofen led to a reversal of lung and macrophage inflammatory signatures. These data indicate that the pulmonary environment becomes inflammatory with increasing age and that this inflammatory environment can be reversed with ibuprofen.
YOU SPEAK TO THE AUDIENCE YOU HAVE
Steve Aoki is a successful musician, but also, of late at least, an advocate for transhumanist goals for the near future that include rejuvenation research after the SENS model. This scientific paradigm is a path towards radical life extension: not just a mere few years gained, but decades at first and soon thereafter indefinite healthy life spans, as the ability of medical technologies to repair us overtakes the ability of aging to damage us.
Advocacy is not a profession. It isn't something you plan on, go to school for, follow a laid-out career. When it hits you that a particular goal is important enough to talk about, to take the people of the world by the shoulders and shake them - and it still amazes me that the slow and painful death of everyone you know is a non-issue to most people - then you speak to the audience you have and with the tools you have to hand. For my part, I'm a technologist. Whatever I chose to do in life was probably going to involve web sites: it's hard to avoid being swept up by the biggest wave in your field. So here I am, and here you are, reading what I write.
In Aoki's case, there is a much flashier platform and an entirely different audience: electronic music and young club-goers. I think this is a good thing, and I'm encouraged by the existence of individuals who choose to speak about rejuvenation research in ways and to listeners entirely unrelated to whatever I, the online futurist community, the aging research establishment, and others are ever likely come up with. Many approaches means many chances to reach more people, and thus persuade more people to materially support the cause of defeating all age-related disease. That's really all any grand and sweeping change requires: just a little persuasion, and each mention of the subject raises the water level just a little more, leading to a more receptive public. Many quarters of the science fiction community, for example, have for decades forged a path to set down the seeds that later grew into early support for the defeat of aging. All of this has value to my eyes, though of course it is very hard to directly measure the results of any particular instance of a spread of ideas through popular culture. The more that people talk about using medicine to directly tackle aging the better off we all, I say, and if that message is first seen in fiction or music, what does it matter for so long as it still leads some people in the right direction?
An Interview With Steve Aoki
Although Steve Aoki is best known for his shameless EDM anthems and unusual habit of covering his fans with cake, the L.A. DJ is also a cunning label head and enthusiastic techno-futurist. His latest album [is] a 10-song journey into a world when humans merge with technology, live forever and party even harder than they do now. Google engineer and The Age of Spiritual Machines author Ray Kurzweil speaks on the intro and Ending Aging wiz Aubrey de Grey riffs over the New Age closer.
"I started reading books on singularity and the progress of science and technology, and that was all really exciting to me because, being a science-fiction nut growing up and reading comic books. When you start seeing that some of the science-fiction - some of these ideas are actually real trajectories that are going to happen in our lifetime - at least notable writers and people doing research that you trust and respect, then my interest starts lighting up. Then when you start finding information all you want to do is share that information.
"Extending our lives, extending our creativity, opening up the mysteries of the brain. All those things that are really exciting - that's kind of the basis of [the album], and that's why I interviewed Ray Kurzweil and Aubrey de Grey. I'm also doing a companion set [where] I'm interviewing different scientists, authors, writers - interesting people who have written books that have inspired me."
In the years ahead we'll be seeing ever more of this sort of thing as the tipping point of public support for longevity science comes closer. More people are persuaded, more people are thinking on the topic, and ever more of them will work in fields and communities that are very distant from the audiences of today's supporters and advocates.
LATEST HEADLINES FROM FIGHT AGING!
A NOVEL TYPE OF CELLULAR GARBAGE IN AGING
Monday, September 29, 2014
A variety of forms of cellular garbage accumulate with aging, and in some cases it is up for debate as to whether the garbage is a primary cause of aging or secondary effect of other damage that degrades cell maintenance. The origins of degenerative aging in single-celled organisms lie in the way in which they handle garbage when dividing: one option is for a mother cell to consistently retain garbage and split off pristine daughter cells. The mother cells is thus aging and will eventually die. This doesn't directly relate to the much more complex process of aging in multicellular organisms, however, but rather informs the cell dynamics of tissue maintenance over time. It is perhaps most relevant in long-lived cells, such as those of the central nervous system, that might be with us for our entire lifetime.
In this research scientists uncover a novel form of garbage in yeast cells, but for the reasons noted above much more work is needed to fully understand its relevance and role in mammalian tissues:
In two recently published studies, [researchers] reported that certain proteins stick around for the entire lifespan of cells, which could be the cause of cellular old age. Using baker's yeast, a single-celled fungus that shares certain characteristics with human stem cells, the scientists identified several ways these proteins could cause cellular aging, from changing the acidity of cells to creating stockpiles of molecular "garbage" that build up over time.
Long-lasting proteins in the eyes, brain and joints are unique because they exist outside of cells or inside cells that don't divide. Stem cells grow and divide over our lifetimes but eventually give out; one theory of human aging suggests that a dwindling pool of stem cells may drive old age as fewer cells are available to repair or regenerate failing body parts. Both stem cells and yeast divide asymmetrically, with aging "mother" cells giving birth to newborn "daughter" cells. Yeast mothers can generate 30 to 35 daughter cells before dying; their normal lifespan when dividing lasts less than two days. [The new] discoveries point to the reason mother cells age and die and how their daughter cells are able to start their life anew after budding.
To look for long-lived proteins in yeast, the scientists used a special protein-labeling technique to track molecules from a mother cell's birth to her death. They found a collection of 135 proteins present only in mother cells that don't turn over during the cell's lifespan. To the scientists' surprise, all but 21 of these proteins were non-functional fragments. Although the scientists don't yet understand what the individual protein fragments do in the cell or how they might initiate aging, these fragments are not good news. Because of the specific pieces present and their sheer number, they are likely to interfere with normal proteins and cellular functions. "With the number of different fragments, we think they're going to cause trouble in the cell."
COMING AROUND TO THE IDEA OF RADICAL LIFE EXTENSION
Monday, September 29, 2014
One of the reasons that most people reject the idea of living longer through new medical technologies is that they believe, incorrectly, that it will result in being aged, frail, and in pain for longer. This is not the goal, and probably not even possible, but it has proven to be very hard to convince people that the result of success in this field of research will be years of extended youth and health. Ultimately the goal is indefinite postponement of aging by periodic repair of its causes, a state of medicine that would lead to accident-limited lifespans of thousands of years.
This goal requires support and funding, however. Progress today is much slower than it might be given large-scale funding and thousands of scientists hard at work. Very little happens on the large scale in this world without widespread discussion and the backing of a sizable fraction of the public, however, and few are at present in favor or even aware of this work. So it is always pleasant to see small signs of progress in the process of advocacy, in the form of pundits who understand and respond to the idea of restored health and youthful vigor:
Nodding off the other night, I caught a piece of a public radio program that featured a scientist/lecturer/philosopher who said there is someone living on the planet today who will reach the age of 1,000 years old. As I shifted in the recliner to ease the reliable late-night achy tightness in my back, the promise of new body parts sounded good. As I realized I couldn't see the clock because my glasses had slipped off while I dozed, the prospect of sharp, young eyes again - that might last for hundreds of years - was intoxicating.
It's no longer just about organ transplantation and knee replacement but rather about molecular manipulations that "create" tissues and organs. It no longer is merely about treating disease and injury with drugs and devices but rather applying a mind-boggling array of therapies that actually re-create the body as it ages or when it suffers trauma.
Still, I could not grasp the notion of living for 1,000 years. Nothing in human experience - other than sci-fi rumination and phantasy - anticipates such longevity. Yet, it's not that long ago that living 100 years was rare. Today, centenarians are as common as 60-year-olds were in the 1950s. If the prognosticator on the radio was right, it will be my 8-year-old granddaughters who benefit from a new age in medicine, health and longevity in ways we aging boomers can't imagine. But then again, our parents could not have fathomed the advances in medicine and pharmaceuticals that have extended lifespans and enhanced the quality of life for their children.
Can you imagine? One thousand years old. I'm not ready for it. Fact is, at my age I've about had it up to my gills with a lot of people, and they have had it with me. We'd not want to hang together for 500 years (which would be the new middle age), let alone 1,000. But, if I could do something permanent for a contrary lower back, the click-pain-click of that left knee, the slight hearing fade in the right ear - well, I'd go for it right now.
MORE INVESTIGATION OF THE CHOROID PLEXUS IN BRAIN AGING
Tuesday, September 30, 2014
A fair amount of research over the years has pointed to dysfunction of the choroid plexus as a contributing factor to degeneration in the brain. This structure generates and filters cerebrospinal fluid, and is thus its decline is a candidate reason as to why metabolic wastes such as the amyloid involved in Alzheimer's disease are found in growing amounts in the aging brain. Here researchers may have found a way to partially compensate for one aspect of this decline:
Until a decade ago, scientific dogma held that the blood-brain barrier prevents the blood-borne immune cells from attacking and destroying brain tissue. [However] the immune system actually plays an important role both in healing the brain after injury and in maintaining the brain's normal functioning. They have found that this brain-immune interaction occurs across a barrier that is actually a unique interface within the brain's territory. This interface, known as the choroid plexus, is found in each of the brain's four ventricles, and it separates the blood from the cerebrospinal fluid. "The choroid plexus acts as a 'remote control' for the immune system to affect brain activity. Biochemical 'danger' signals released from the brain are sensed through this interface; in turn, blood-borne immune cells assist by communicating with the choroid plexus. This cross-talk is important for preserving cognitive abilities and promoting the generation of new brain cells."
[Researchers] suggest that cognitive decline over the years may be connected not only to one's "chronological age" but also to one's "immunological age," that is, changes in immune function over time might contribute to changes in brain function - not necessarily in step with the count of one's years. To test this theory, [the] researchers used next-generation sequencing technology to map changes in gene expression in 11 different organs, including the choroid plexus, in both young and aged mice, to identify and compare pathways involved in the aging process.
That is how they identified a strikingly unique "signature of aging" that exists solely in the choroid plexus - not in the other organs. They discovered that one of the main elements of this signature was interferon beta - a protein that the body normally produces to fight viral infection. This protein appears to have a negative effect on the brain: When the researchers injected an antibody that blocks interferon beta activity into the cerebrospinal fluid of the older mice, their cognitive abilities were restored, as was their ability to form new brain cells. The scientists were also able to identify this unique signature in elderly human brains. The scientists hope that this finding may, in the future, help prevent or reverse cognitive decline in old age, by finding ways to rejuvenate the "immunological age" of the brain.
A REVIEW OF WHAT CAN BE DONE TODAY ABOUT BRAIN AGING
Tuesday, September 30, 2014
Little can be done today to stem the tide of age-related degeneration, at least in comparison to the potential rejuvenation treatments of tomorrow. It remains the case that regular moderate exercise and calorie restriction have more solid, proven effectiveness over the long term than any available treatment or enhancement technologies for basically healthy people. Hence you find them right at the top of this open access review on the subject of present methods used to somewhat slow age-related cognitive decline. To see any greater impact than this, we will need new and more effective medical technologies that treat the root causes of aging, and the sooner these treatments are developed the better:
Brain aging and aging-related neurodegenerative disorders are major health challenges faced by modern societies. Brain aging is associated with cognitive and functional decline and represents the favourable background for the onset and development of dementia. Brain aging is associated with early and subtle anatomo-functional physiological changes that often precede the appearance of clinical signs of cognitive decline. Neuroimaging approaches unveiled the functional correlates of these alterations and helped in the identification of therapeutic targets that can be potentially useful in counteracting age-dependent cognitive decline.
Advancements in fluorescent microscopy, molecular biology, and electrophysiological techniques have helped to unravel many molecular determinants of neuronal plasticity. These technical advancements, along with the notion that the aging brain retains the capacity to reorganize its morphological and functional architecture, have promoted strong interest and leaps forward in the knowledge of the physiology of the aging brain and aging-related cognitive processes as well as in the exploration of strategies aimed at enhancing or maintaining cognitive skills in the elderly.
A growing body of evidence supports the notion that cognitive stimulation and aerobic training can preserve and enhance operational skills in elderly individuals as well as reduce the incidence of dementia. This review aims at providing an extensive and critical overview of the most recent data that support the efficacy of non-pharmacological and pharmacological interventions aimed at enhancing cognition and brain plasticity in healthy elderly individuals as well as delaying the cognitive decline associated with dementia.
ALZHEIMER'S MEMORY LOSS TURNED BACK WITH CALORIE RESTRICTION AND EXERCISE
Wednesday, October 1, 2014
There is primary aging and there is secondary aging. The former is a side-effect of the operation of metabolism, an accumulation of damage about which little is done at present. The latter is the consequence of an unhealthy lifestyle, which at the most obvious end of the spectrum includes the metabolic syndrome and type 2 diabetes caused by becoming sedentary and fat. Over the years numerous studies have shown that some of the declines of aging taken as inevitable are in fact self-inflicted by our own indulgences in this age of comparative leisure and low-cost calories. There is a modest difference to be made here, it is true, but you can't do much about primary aging. That requires new medical technologies capable of repairing the cellular and molecular damage that causes primary aging.
Here researchers demonstrate that the modest difference of a good lifestyle extends to the progression of early stage Alzheimer's disease, which is probably not surprising given the established risk factors for this condition include lack of exercise and being overweight. The methodology employed in this study included mild calorie restriction and exercise, which have been shown to improve pretty much anyone's general health at even advanced ages. Given the size of the effects of those two items demonstrated in past studies of health, I suspect the rest of the regimen is all window dressing. I'd like to see this run again with just the exercise and calorie restriction, and I'd wager the results would be much the same.
Overall this should be taken as a reminder that letting health maintenance slip in later years has a measurable cost, and in an era so close to the development of ways to treat primary aging, every year counts:
In the first, small study of a novel, personalized and comprehensive program to reverse memory loss, nine of 10 participants, including the ones above, displayed subjective or objective improvement in their memories beginning within 3-to-6 months after the program's start. Of the six patients who had to discontinue working or were struggling with their jobs at the time they joined the study, all were able to return to work or continue working with improved performance. Improvements have been sustained, and as of this writing the longest patient follow-up is two and one-half years from initial treatment. These first ten included patients with memory loss associated with Alzheimer's disease (AD), amnestic mild cognitive impairment (aMCI), or subjective cognitive impairment (SCI; when a patient reports cognitive problems). One patient, diagnosed with late stage Alzheimer's, did not improve.
[The] approach is personalized to the patient, based on extensive testing to determine what is affecting the plasticity signaling network of the brain. As one example, in the case of the patient with the demanding job who was forgetting her way home, her therapeutic program consisted of some, but not all of the components involved with [the] therapeutic program, and included:
(1) eliminating all simple carbohydrates, leading to a weight loss of 20 pounds; (2) eliminating gluten and processed food from her diet, with increased vegetables, fruits, and non-farmed fish; (3) to reduce stress, she began yoga; (4) as a second measure to reduce the stress of her job, she began to meditate for 20 minutes twice per day; (5) she took melatonin each night; (6) she increased her sleep from 4-5 hours per night to 7-8 hours per night; (7) she took methylcobalamin each day; (8) she took vitamin D3 each day; (9) fish oil each day; (10) CoQ10 each day; (11) she optimized her oral hygiene using an electric flosser and electric toothbrush; (12) following discussion with her primary care provider, she reinstated hormone replacement therapy that had been discontinued; (13) she fasted for a minimum of 12 hours between dinner and breakfast, and for a minimum of three hours between dinner and bedtime; (14) she exercised for a minimum of 30 minutes, 4-6 days per week.
ANOTHER DEMONSTRATION OF CELLS TAKING UP WHOLE MITOCHONDRIA
Wednesday, October 1, 2014
One of the several possible approaches to address the important issue of mitochondrial damage in aging, wherein cells are overtaken by malfunctioning mitochondria and cause harm to surrounding tissues as a result, is some combination of destroying the damaged mitochondria and replacing them with whole new mitochondria infused into the body. Conveniently, it turns out that cells will of their own initiative take up and adopt new mitochondria introduced into the nearby environment. A number of demonstrations of this process have been carried out in recent years, and here is another one:
In eukaryotic cells, mitochondrial dysfunction is associated with a variety of human diseases. Delivery of exogenous functional mitochondria into damaged cells has been proposed as a mechanism of cell transplant and physiological repair for damaged tissue.
We here demonstrated that isolated mitochondria can be transferred into homogeneic and xenogeneic cells by simple co-incubation using genetically labelled mitochondria, and elucidated the mechanism and the effect of direct mitochondrial transfer. Isolated homogeneic mitochondria were transferred into human uterine endometrial gland-derived mesenchymal cells in a dose-dependent manner. Moreover, mitochondrial transfer rescued the mitochondrial respiratory function and improved the cellular viability in mitochondrial DNA-depleted cells and these effects lasted several days.
Finally, we discovered that mitochondrial internalization involves macropinocytosis. In conclusion, these data support direct transfer of exogenous mitochondria as a promising approach for the treatment of various diseases.
A NEUROPROTECTOR'S DILEMMA
Thursday, October 2, 2014
Here is a recent article from the SENS Research Foundation, a review of recent work in the broader research community relating to the development of neuroprotective drugs and proteins, ways to help brain cells resist the damage of aging:
The aging brain is characterized by the accumulation of a variety of proteinaceous aggregates, high levels of which constitute the distinctive neuropathological hallmarks and (in the consensus view) the underlying drivers of the neurodegenerative diseases of aging. Removal of these aggregates from the brain is therefore a central damage-repair strategy to prevent and arrest the course of "normal" cognitive aging and its diagnostically-specified extreme manifestations. Happily, this subfield of rejuvenation research has been advanced further toward medical availability than any other, with new strategically-positioned trials of Aβ immunotherapies and of a first-in-class α-synuclein vaccine.
Another pillar of comprehensive neurorejuvenation is cell therapy for the aging brain. However, cell therapy to preserve and restore the neuronal circuitry underlying higher-order cognitive functions in the aging brain is a much more formidable undertaking. Unlike with other major organs such as the heart or kidneys - or even the repair of dopaminergic brain circuitry as exhibited prominently in Parkinson's disease - wholesale replacement of brain functional units is undesirable, due to the structural basis of memory and identity. Thus, a more sophisticated and gradualist approach is required, in which existing circuits are rebuilt and reinforced by ongoing integration of transplanted neurons and precursors, in such a way as to maintaining their existing architecture.
Neuroprotective agents offer a potential stopgap, to hold the therapeutic window open in the period between the availability of aggregate-clearing immunotherapies and the development of neuronal replacement techniques. From first principles, one might anticipate that in a scenario in which therapeutic clearance of some aggregate had been achieved, the most effective neuroprotective agents would be those that target mechanisms of neurodegeneration that are not directly downstream of these aggregates. However, it is also likely that in the earliest iterations of these therapies, their specificity, range of action, therapeutic index, pharmacokinetics, or other properties may limit the scope and magnitude of clearance that can be achieved in a given round of application, so that even agents that allow vulnerable neurons to survive the downstream effects of these aggregates may yet deliver some neuroprotective benefit.
THE "SLOW AGING WITH DRUGS" VIEWPOINT
Thursday, October 2, 2014
Most of that portion of the aging research community interested in intervening in the aging process to extend healthy life focus on near term drug discovery and reuse. They recognize that the gains here will be small and the process, like all drug development, will be enormously expensive. They are trying to alter the operation of metabolism in order to slow down the pace at which it damages itself, but the ongoing interactions of metabolism and aging form an enormously complex and still poorly understood system. Researchers still don't have a full understanding of the easily replicated and widely studied life extension produced by calorie restriction in most species, for example. Even if drugs can be produced to recapture some of this alteration without meaningful side-effects, that will result in only a small gain in human life span, and it will do little to help the old. What use is a drug to slightly slow down the damage of aging when you are already so damaged as to be near death?
In short, the traditional approach of drug development to alter the operation of our biochemistry is a terrible way forward to extend healthy life. It is an expensive path to a mediocre result, and the research community is doing the worst thing that it could do: aiming very low and digging through drugs that already exist rather than building new technologies. But this is the mainstream today, and that is something that must change. The need for change is why I support disruptive next-generation research programs such as those of the SENS Research Foundation, where the focus is on evading the complexities of metabolism to focus on repair of clearly understood damage. Clean up the damage in the machinery, rather than try to change the whole machine to slow down the pace of damage. It's a much better path forward, and the only one likely to produce actual rejuvenation in the old.
Millions of people are taking anti-ageing drugs every day - they just don't know it. Drugs to slow ageing sound futuristic but they already exist in the form of relatively cheap medicines that have been used for other purposes for decades. Now that their promise is emerging, some scientists have started using them off-label in the hope of extending lifespan - and healthspan. "We are already treating ageing. We have been doing ageing research all along but we didn't know it. We can develop effective combinations for life extension right now using available drugs."
One of the most promising groups of drugs is based on a compound called rapamycin. It was first used to suppress the immune system in organ transplant recipients, then later found to extend lifespan in yeast and worms. In 2009, mice were added to the list. This led to an explosion of research into whether other structurally similar compounds - called rapalogs - might be more potent. Now the first evidence has emerged of one such drug having an apparent anti-ageing effect in humans. A drug called everolimus, used to treat certain cancers, partially reversed the immune deterioration that normally occurs with age in a pilot trial in people over 65 years old.
Other familiar drugs might also fit the bill. Low-dose aspirin and statins are widely taken by healthy people to reduce their risk of heart disease. Both extend lifespan in animals and seem to have anti-inflammatory effects. Inflammation is one of the proposed mechanisms behind ageing, so aspirin and statins could be effective heart drugs in part because they slow ageing.
The fact that common mechanisms seem to be behind the major diseases of ageing, like heart disease, stroke and dementia, is good news, as it suggests we should be able to extend our lifespan while also extending healthspan. Indeed, it would be difficult to imagine an effective longevity agent that worked without alleviating or delaying such conditions. Rapamycin, for instance, has been found to reduce the cognitive decline that accompanies ageing in animals.
PROPOSING HETEROCHRONIC PARABIOSIS AS A WAY TO WIN HALF OF THE PALO ALTO LONGEVITY PRIZE
Friday, October 3, 2014
The recently announced Palo Alto Longevity Prize is split into two parts, with the second to be awarded for a demonstration that restores metabolic homeostasis in an aging mammal to that of a young mammal. The prize administrators picked heart rate variability as the surrogate measure of homeostasis, which is an interesting choice.
Here one of the longevity science advocates from the Russian aging research community suggests that heterochronic parabiosis could be a winning approach for this portion of the prize. This involves linking the circulatory systems of two animals, usually mice, one old and one young. In recent years this has been used to identify some of the changes in circulating proteins that are key to the behavior of stem cells and other aspects of our biology that change with age.
One of the most productive paradigms of aging suppression is based on rejuvenation of blood-borne systemic regulatory factors. Parabiosis, which is characterized by a shared blood supply between two surgically connected animals, may provide such experimental paradigm. We propose to use heterochronic parabiosis, the parabiotic pairing of two animals of different ages, for old mouse rejuvenation. Heterochronic parabiosis also provides an experimental system to identify systemic factors influencing the aging process of the old mouse and promoting its longevity. The probability of the proposed study to demonstrate significant improvement of the heart rate variability marker is extremely high, because parabiosis was already shown to promote functional parameters of the nervous and cardiovascular systems.
The optimum rejuvenation effect of heterochronic parabiosis can be achieved using genetically identical animals. Genetically identical non-model organisms of different age can only be obtained by cloning. Interestingly, that there are no investigations of heterochronic parabiosis of cloned animals. Heterochronic parabiosis experiments indicate that blood-borne signals from a young circulation can significantly impact the function of aging tissues. The implication of these findings is that old tissues might make their function almost as well as young tissues if, by means of systemic influences, the molecular pathways could be 'rejuvenated' from an old state to a young state.
At first we will perform cloning of adult (1-year-old) mice using technique for improved success cloning rate. The parabiosis will be established at the age of 18 months for old partners and 2 month for the young ones. The detailed life span assay will reveal the influence of heterochronic parabiosis with the young clone on cardiovascular, nervous, respiratory, skeletal and muscular systems. The lifespan assay will how the young clone parabiosis impact on longevity of older partner. In addition, systemic factors, which influence the aging process of the old mouse and promote its longevity and rejuvenation, will be revealed.
YOUNG COGNITIVE FUNCTION PREDICTS AGED PULMONARY FUNCTION
Friday, October 3, 2014
Many measurable differences in human ability and life course correlate with long-term health, age-related dysfunction, and mortality. Intelligence, social standing, and wealth are some of the more easily measured line items, but the reasons why these things correlate with better health and life expectancy remain to be proven. We can all suggest that more intelligent people will obtain access to and make better use of medical resources, as well as take better care of their general health, but demonstrating that this is in fact the mechanism using data from human populations is a whole different story. The issue is confounded by the fact that intelligence, social standing, and wealth all correlate strongly with one another as well, and there is even some evidence to suggest that greater intelligence and a more robust metabolism might have a biological connection in mechanisms of stress resistance.
On this subject, here is an interesting correlation pulled from historical epidemiological records, showing that young cognitive ability predicts future function of the respiratory system:
Poor pulmonary function is associated with mortality and age-related diseases, and can affect cognitive performance. However, extant longitudinal studies indicate that early cognitive ability also affects later pulmonary function. Despite the multifaceted nature of pulmonary function, most longitudinal studies were limited to a single index of pulmonary function: forced expiratory volume in 1 s (FEV1). In this study, we examined whether early adult cognitive ability predicted five different indices of pulmonary function in mid-life.
Mixed modelling tested the association between young adult general cognitive ability (mean age=20), measured by the Armed Forces Qualification Test (AFQT), and mid-life pulmonary function (mean age=55), in 1019 men from the Vietnam Era Twin Study of Aging. Pulmonary function was indexed by per cent predicted values for forced vital capacity (FVC%p), FEV1%p, maximum forced expiratory flow (FEFmax%p), and maximal voluntary ventilation (MVV%p), and by the ratio of FEV1 to FVC (FEV1/FVC), an index of lung obstruction.
After adjusting for smoking, pulmonary disease, occupation, income and education, age 20 AFQT was significantly associated with mid-life FVC%p, FEV1%p, FEFmax%p, and MVV%p, but was not significantly associated with FEV1/FVC. [Thus], early adult cognitive ability is a predictor of multiple indices of aging-related pulmonary function 35 years later, including lung volume, airflow and ventilator capacity. Cognitive deficits associated with impaired aging-related lung function may, thus, be partly pre-existing. However, results also highlight that early life risk factors may be differentially related to different metrics of later-life pulmonary health.