Fight Aging!

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.

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.

Link: http://dx.doi.org/10.3389/fnsys.2014.00153

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.

Link: http://wis-wander.weizmann.ac.il/scientists-identify-the-signature-of-aging-in-the-brain

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.

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.

Link: http://www.inforum.com/content/jack-zaleski-live-1000-years-no-thank-you

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."

Link: http://www.fredhutch.org/en/news/center-news/2014/09/hoarding-cellular-garbage-triggers-old-age.html

The latest news from the SENS Research Foundation turned up in my inbox today. The Foundation is perhaps the only organization in the world today that is organizing and funding serious scientific work on prevention and reversal of aging. Near every other funding organization and research group aiming to intervene in the aging process, and there are far too few of those by the way, are working on the foundation of ways to slow aging, not halt it or reverse it. Unfortunately this is the wrong path to produce results in the near term. Think in terms of metal machinery failing due to rust: the slow aging crowd wants to build an machine that rusts more slowly by altering the properties of its component parts and the metals it is made of. The prevention and reversal approach, by comparison aims at removing rust and rust-proofing - which is a much easier path, focusing on a much less complex and far better understood problem space.

To return to our biology, the rust in this analogy corresponds to the small number of types of fundamental damage to cells and molecular machinery that accumulate as a result of the ordinary operation of metabolism. The slow aging crowd are looking into the very expensive process of learning enough about altering the way in which our metabolism works in order to slow down the pace of damage. The research community has barely started on establishing the knowledge needed to do this, and even getting to the present point has required years and billions of dollars. There will be decades and tens of billions ahead before any sort of meaningful result will emerge, and even when it does it will be of no use to old people. What help is slowing down damage when you are already so damaged that you are close to death?

In comparison to metabolism, the rust - the cellular and molecular damage that causes aging - is simple. The results are only complicated because we are complicated. Further, these forms of damage are comparatively well understood and enumerated. The research community knows enough to be able to propose detailed research plans leading to repair therapies. That is far more than can be done for ways to slow aging. Repair is the better path, more cost-effective, and the end goal far more effective for patients, and yet so very few groups are working on it. This is why our support for the SENS Research Foundation is very important. Their work must receive enough funding to demonstrate its worth beyond any doubt and thus be adopted by all those other groups presently working on the slow road to nowhere.

On to the newsletter, which notes that the Foundation will be a sponsor for the forthcoming World Stem Cell Summit. You might recall that last year's meeting was where the Methuselah Foundation announced the New Organ Liver Prize.

SENS Research Foundation is proud to be a Bronze Level Sponsor of this year's World Stem Cell Summit. The World Stem Cell Summit is the largest global meeting of stem cell science and regenerative medicine stakeholders. Attendees enjoy unequaled opportunities for networking, collaboration, new partnerships, and shaping the future of this rapidly advancing field. The WSCS will be held December 3-5, 2014, at the Marriott RiverCenter, San Antonio, TX, USA. SRF CSO Dr. Aubrey de Grey will be moderating a panel at the conference.

As always the question of the month section is well worth reading. One of the present themes of the Foundation's work, illustrated by the recent Rejuvenation Biotechnology 2014 conference, is establishing the necessary relationships between research and industry that will enable a smooth transition from lab to clinic of the first prototype treatments for the causes of aging. It takes years to lay groundwork, so best to start now.

Question of the Month #6: Meeting The Challenges of the Regulatory Maze and Getting Rejuvenation Biotech Into the Clinic

Q: In response to a previous question of the month, you explained why the fact that "aging" is not recognized as a "disease" for which the FDA and other regulatory bodies license therapies should not actually pose a significant hurdle to getting rejuvenation biotechnologies licensed and into widespread use. But there was a lot of discussion at the recent Rejuvenation Biotechnology 2014 Conference about the challenges to rejuvenation biotechnology posed by current regulatory structures and some gestures toward what might be needed to advance the science into the clinic. Would you spell those out?

A: Rejuvenation biotechnologies are a new approach to preventing and treating the diseases and disabilities of aging, based on the repair and maintenance of the cellular and molecular structures that become damaged over time. Degenerative aging processes occur all across our bodies as this damage accumulates in particular tissues; the "diseases" that emerge in our bodies late in life are simply the recognizable impairment of organ-specific function resulting from the gradual build-up of this damage.

This approach is so new that it is not very well-served by current regulatory structures, which mostly assume the presence of an existing disease, and that drugs will either alleviate current symptoms, or will intervene in metabolic pathways that perpetuate aspects of abnormal function without having any effect on the underlying damage that causes it.

Several regulatory changes would help to bring rejuvenation biotechnologies into clinical trials and then into widespread use. One is to reverse the sequence in which rejuvenation biotechnologies are tested.

First, there are several states of ill health driven by the degenerative aging process that are clearly extremely disabling and deadly, but that are not yet recognized as "diseases" by the FDA. The most glaring of these is sarcopenia (or, some have argued, "dynapenia"): the age-related loss of muscular strength that results from the combination of loss of muscle mass, and the degradation of the cellular and molecular integrity of what muscle remains. Sarcopenia is highly disabling, restricts people's ability to take care of themselves, increases the risk of accidents and fractures, and is strongly linked to increased risk of death - but it is not yet a licensed "disease" indication.

Fortunately, the FDA seems to be open to the idea of developing a new indication for therapies that combat sarcopenia, and several pharmaceutical companies are working in the field. There have now been several scientific conferences and high-level summit meetings in which senior FDA officials, sarcopenia researchers, and major pharmaceutical companies have worked toward defining diagnostic criteria and suitable outcomes for licensing anti-sarcopenia drugs. The sooner they succeed, the better.

Second: today, new drugs are usually first tested in patients with existing disease. Regulatory approval depends on the drug showing a clear impact on clearly-defined, hard clinical outcomes such as heart attacks or progression to dialysis. Over time, many therapies initially approved on this basis later come to be used in a more preventive approach in high-risk patients without overt disease, through a mixture of informal practice and clinical trials. This occurred, for example, with statins, antihypertensives, and antidiabetics.

Unfortunately, this progression begins to yield useful data too late in the pathological process to optimally test rejuvenation biotechnologies. Our goal is to develop therapies that will keep people's tissues sufficiently healthy and functional that such late-stage pathologies do not occur. Thus, we will want to test these therapies in patients not yet exhibiting overt disease, with minimal or no symptoms and no near-term risk of death or disability from the disease.

Instead, it would be preferable for regulators to accept the removal, repair, or replacement of cellular and molecular damage itself as an initial goal of clinical trials. The prevention of particular diseases' emergence would then be incorporated in a kind of "conditional licensing" a longer-term goal, perhaps to be monitored in a robust system of postmarket surveillance. This, again, reverses the usual practice in today's regulatory system, where the endpoint is initially a catastrophic patient outcome such as heart attack or stroke, and only later are surrogate outcomes on mediating metabolic factors (such as lowering LDL cholesterol or blood glucose) accepted.

Finally, it would be of tremendous benefit to test rejuvenation biotechnologies in combination with each other from the outset. The normal approval path for a candidate drug entails that it first be tested for effectiveness and safety on its own, or as an add-on to drugs that are already the standard of care. But many specific, diagnosed diseases of aging are actually the clustering together of several forms of aging damage in one or more tissues. Additionally, it is often the case (as with the beta-amyloid protein and aberrant tau species in Alzheimer's disease) that the contributing kinds of aging damage are intertwined with one another in complex causal chains.

In such cases, the removal of only one form of aging damage may not be enough to demonstrate a positive effect on tissue function or disease-related outcomes. If researchers are forced to test individual rejuvenation therapies that each remove only one of these contributing forms of damage in isolation, they may well fail to show any meaningful effect, and be kept out of the hands of doctors and patients - even though they would have indefinitely postponed the disease if tested together.

This potential dilemma could be resolved if complementary rejuvenation biotechnologies - each targeting one of the key lesions driving such a disease state - could be tested in combination from the outset, following the collection of basic safety data, without first having to prove their individual effectiveness in averting catastrophic outcomes.

All of these moves are dramatic departures from the ways that medical therapies are currently tested, approved, and regulated for use. Fortunately, substantial moves in these directions are already afoot in the testing of rejuvenation biotechnologies for Alzheimer's disease and other neurological disorders. We believe that these moves can be supported and normalized, and then used as a template for the testing of rejuvenation biotechnologies generally.

One of the discoveries of past years in Alzheimer's disease research is that the β-amyloid accumulating between cells is less harmful to neurons than other associated proteins involved in the creation of that amyloid. Here is a paper that suggests much the same sort of thing for neurofibillary tangles, the other characteristic form of protein deposit associated with Alzheimer's:

Pathological aggregation of the microtubule-associated protein tau and subsequent accumulation of neurofibrillary tangles (NFTs) or other tau-containing inclusions are defining histopathological features of many neurodegenerative diseases, which are collectively known as tauopathies. Due to conflicting results regarding a correlation between the presence of NFTs and disease progression, the mechanism linking pathological tau aggregation with cell death is poorly understood.

An emerging view is that NFTs are not the toxic entity in tauopathies; rather, tau intermediates between monomers and NFTs are pathogenic. Several proteins associated with neurodegenerative diseases, such as β-amyloid (Aβ) and α-synuclein, have the tendency to form pore-like amyloid structures (annular protofibrils, APFs) that mimic the membrane-disrupting properties of pore-forming protein toxins.

The present study examined the similarities of tau APFs with other tau amyloid species and showed for the first time the presence of tau APFs in brain tissue from patients with progressive supranuclear palsy (PSP) and dementia with Lewy bodies (DLB), as well as in the P301L mouse model, which overexpresses mutated tau. Furthermore, we found that APFs are preceded by tau oligomers and do not go on to form NFTs, evading fibrillar fate. Collectively, our results demonstrate that in vivo APF formation depends on mutations in tau, phosphorylation levels, and cell type. These findings establish the pathological significance of tau APFs in vivo and highlight their suitability as therapeutic targets for several neurodegenerative tauopathies.

Link: http://dx.doi.org/10.1186/2051-5960-2-56

Growing amounts of amyloid-β (Aβ) between cells forms one part of the pathology of Alzheimer's disease. This is a dynamic process, as much a matter of reduced clearance rates as increased production or simple accumulation: there are systems in the body capable of clearing out this amyloid and which can in theory be altered to increase clearance rates. One part of the puzzle of what makes Alzheimer's disease an age-related condition is why exactly these clearance mechanisms fail with advancing aging: which of the known forms of cellular and molecular damage associated with aging cause this to happen? These researchers are working with microglia, supporting cells of the innate immune system present in the brain, with an eye to producing therapies to enhance amyloid clearance:

Alzheimer's disease (AD) is characterized by extracellular amyloid-β (Aβ) deposits and microglia-dominated inflammatory activation. Innate immune signaling controls microglial inflammatory activities and Aβ clearance. However, studies examining innate immunity in Aβ pathology and neuronal degeneration have produced conflicting results.

In this study, we investigated the pathogenic role of innate immunity in AD by ablating a key signaling molecule, IKKβ, specifically in the myeloid cells of [a mouse model of Alzheimer's disease]. Deficiency of IKKβ in myeloid cells, especially microglia, simultaneously reduced inflammatory activation and Aβ load in the brain and these effects were associated with reduction of cognitive deficits and preservation of synaptic structure proteins. IKKβ deficiency enhanced microglial recruitment to Aβ deposits and facilitated Aβ internalization, perhaps by inhibiting TGF-β-SMAD2/3 signaling, but did not affect Aβ production and efflux.

Therefore, inhibition of IKKβ signaling in myeloid cells improves cognitive functions in AD mice by reducing inflammatory activation and enhancing Aβ clearance. These results contribute to a better understanding of AD pathogenesis and could offer a new therapeutic option for delaying AD progression.

Link: http://dx.doi.org/10.1523/JNEUROSCI.1348-14.2014

There are three classes of aging research, in order of decreasing size and funding: firstly the work that only investigates and catalogs aging, with no attempt to intervene; secondly work on ways to slow aging through metabolic and genetic alteration, which is doomed to very expensive and very slow progress to a marginal end result; and lastly work on repairing the cellular and molecular damage that causes aging. The latter is the only practical path forward to greatly extending healthy life and defeating age-related disease soon enough to matter for those of use reading this today. After a decade of advocacy to get to the present point of the existence of multiple labs and organizations such as the SENS Research Foundation explicitly funding work on rejuvenation biotechnology, if it has 1% of the funding of work on slowing aging, I'd be surprised. Work on slowing aging might in turn have 1% of the funding directed to merely studying aging. It is a frustrating situation, and must change.

The mainstream of modern research is steered by regulation into the inefficient process of examining late-stage mechanisms in disease and then working backwards. Since commercial development is only permitted to treat named diseases, and since putting potential treatments through the regulatory process generally requires demonstration of a comprehensive understanding of the relevant underlying biological mechanisms, the whole pipeline all the way back to funding for fundamental research is geared towards producing marginal impact on late stage disease in the most difficult way possible. Researchers struggle to understand the very complicated final stages of the disease process, with all its attendant confusion and interacting mechanisms of degeneration, and pull out some way to try to make our biological machinery work better while horribly damaged.

This is of course far from the best way to proceed for any machine, biological or not. The best way is to start with the much simpler roots of dysfunction, the damage that accumulates initially as a consequence of the ordinary operations of biological machinery, and block it before it spirals out into all sorts of different forms of dysfunction. Researchers know what that damage is - a list exists, well supported by evidence - and most of the arguments over how important it is and how exactly it connects to age-related disease could be settled by simply repairing that damage and observing the consequences. Working forwards in this way is a much, much cheaper prospect than trying to work backwards in the way forced by present regulation. Yet of course it is not the mainstream.

In fact, the approach of repairing the damage that causes aging is so very much not the mainstream that summary reviews of the state of the field such as the one quoted below can omit it entirely, focusing only on ways to alter metabolism to maybe slow down aging just a little bit. This is the real fight in the field of aging research now and for the next decade or two, the only important battle to my eyes: whether the research community (a) keeps on spending vast sums to better understand the fine details of how aging progresses while at the same time failing to do much of anything to actually help people, or whether (b) more than the present small minority of researchers wake up and turn to the better course of repairing damage, the course that offers a real chance of defeating degenerative aging and preventing the suffering and illness of old age.

Thus this review is not really a review of aging research; it is a review of work on slowing aging only, which is not all but rather only near all of the work presently aimed at intervening in the aging process. It is my believe that slowing aging is ultimately destined to be a dead end, producing only knowledge and no treatments of real value: it is most likely so very much harder and less productive than the repair approach that it will be displaced, but the repair approach is so much earlier in its development and funded to a fraction of the same level that it is taking time for this to become self-evident. So this is a review written from the position that repair of the causes of aging is not an option and that all we can really do is alter metabolism to slow the onset of damage. This is simply not the case, but those who hold to that position are right to assume that, by their metric and on their road, progress in the future will be hard, slow, and produce only marginal benefits.

Aging Research - Where Do We Stand and Where Are We Going?

The magnitude of the challenge is illustrated by considering known causes of aging. The good news is that many mechanisms causing aging, as well as pathways that can mitigate effects of aging, have been identified. This is also the bad news - aging processes and pathways offering an ability to modify their effects are extremely complex. It is widely assumed that aging is a major risk factor for most late-onset diseases (cancer, cardiovascular disease, diabetes, neurodegenerative diseases, etc.), and therefore interventions directed at aging offer an opportunity to ameliorate all these diseases at once. Although this idea has attracted much attention, we must also consider that the complexities of aging processes likely exceed those of specific diseases, and the challenge of reigning in the global decline of cellular processes across many tissues will be large.

We may have but scratched the surface of what bioinformatics can provide in identifying new genes and pathways important in human aging, as well as allowing for the knowledge we have already gained to be applied in a more effective, personalized way. Analysis of the transcriptome, epigenome, and proteome of individuals spanning a wide age range will provide the most detailed phenotyping of human aging so far.

If the genes and pathways that seem to correlate with slow or fast aging can be thus identified by big data analysis, resulting hypotheses about brain aging may be tested by conducting field studies. Possible treasure troves are the various long-term human longitudinal studies, which provide a cornucopia of health information spanning decades and, in some cases, provide access to genotyping. This may potentiate testing whether genetic haplotypes that correlate with slow or rapid aging identified bioinformatically exert predictable effects in a human population over the course of a lifetime. For example, one might test whether haplotypes correlating with slow molecular brain aging protect against cognitive decline or neurodegenerative diseases in these longitudinal studies.

The past two centuries have witnessed advances at many levels that allow people to live longer and more productive lives. I have attempted to place current research on the biology of aging into this context and have arrived at a few predictions. First, it will be more achievable and desirable to extend human health span rather than life span per se. Changes in maximum human life span will, in my opinion, be quite difficult to achieve and will take many years to even assess. From the point of view of economic and societal benefits, striving to make people healthier longer without necessarily extending their maximum life span may be the wisest course. Put another way, the nightmare scenario would be to extend maximum human life span without extending health span.

Second, bioinformatics will play a substantial role in the progress of aging research, especially as it applies to humans. There may already be buried in the sea of ever-increasing human genomic data novel clues about genes and pathways that govern aging in different tissues. In this regard, it remains to be seen how much of aging will prove to be systemic and affect all tissues simultaneously emanating from brain signals, for example, and how much will be tissue autonomous.

Third, aging and the genes and pathways that govern its effects are complex. It is not likely that there will be a silver bullet for aging any more than there will be a silver bullet for cancer. However, there will likely be novel pharmaceutical interventions for the effects of aging emerging directly from aging research. These interventions may need to be tissue specific, taking into account the personalized way aging impacts an individual tissue-by-tissue. Overall, it is an exciting, albeit uncertain, time to speculate how human health will be impacted in the decades to come by research on the biology of aging.

One approach to scaffolding for tissue engineering is to deliver a dissolving material along with transplanted cells that provides just enough support for those cells to get them past the point of generating their own extracellular matrix scaffold to replace the artificial material. Here researchers test that approach in tissue patches that can restore function to damaged heart tissue:

Researchers have coaxed stem cells to develop into heart cells called cardiomyocytes and then transplanted them into animals. However, these cells can't make it alone. Half of them die right after injection, and the survival rate is as low as 10% after one week. A second ingredient is necessary - some kind of biological mortar to hold them in place and support their development and integration into the body.

[Researchers] developed a self-assembling nanogel made up of two peptides. The peptides each have a hydrophobic and a hydrophilic part; this drives them to form a nanostructured gel when mixed in water. The gel mimics the structure and mechanical properties of the natural extracellular matrix. One peptide acts like a natural protein that adheres to cells and promotes cell survival. The second peptide is readily broken down by a protease. The team designed the gel so that when it is implanted, it begins to degrade a bit, allowing cells from the body to migrate in. Eventually the gel should disintegrate completely as the heart tissue builds its own extracellular matrix. This particular gel has already performed well as a support for other kinds of cells grown from stem cells, including pancreatic and muscle cells.

[Researchers] mixed the gel with cardiomyocytes derived from embryonic stem cells and injected this mixture into the hearts of mice with injuries simulating the damage caused by a heart attack. They compared the health and survival of the cells transplanted naked with the health of cells transplanted in the nanogel. As a further control, they also monitored mice that had been injected with a salt solution. After two weeks, mice treated with cells, whether in the gel or not, had better heart function on an echocardiogram than untreated mice. Animals injected with the cells in the nanogel continued to have strong cardiac function through the end of the 12-week experiment. But the health of mice treated with cells alone began to deteriorate after three weeks. Examining the mice's hearts under the microscope after 14 weeks, the researchers found new cells integrating into the heart tissue in animals treated with the nanogel. In mice treated with naked cardiomyocytes, all the therapeutic cells were gone.

Link: http://cen.acs.org/articles/92/web/2014/09/Nanogel-Delivers-Cellular-Patches-Damaged.html

For some years now the Glenn Foundation for Medical Research has been establishing a network of labs to work on aging and longevity, seeding them with grants of a few million dollars apiece. The research they carry out is fairly mainstream, such as investigation of calorie restriction mimetics as a way to slightly slow aging, and thus I don't expect to see meaningful results in terms of added years of life in the current form of these laboratory groups. Their primary output will be knowledge and data relating to the fine details of the intersection of metabolism and aging, leading to a better understanding of the causes of natural variations in longevity.

However this is a good example of the growing focus on aging as a treatable condition in the research community, and the Glenn Consortium is exactly the sort of research network we'd like to see pick up work on the rejuvenation biotechnology of SENS in the future. With more results, support, and tools generated by existing SENS research, it will become ever more attractive for scientists working on the go-nowhere path of slowing aging through metabolic manipulation to switch to reversing aging through repair of cellular and molecular damage. That is the only way forward likely to produce meaningful extension of healthy life within our lifetimes. For that switch to happen, it isn't just necessary for SENS to make progress, but there also must be more of a mainstream community whose members are interested in intervention in the aging process in the first place.

A $3 million grant from The Glenn Foundation for Medical Research will allow the University of Michigan to establish a national center of excellence in biogerontology research. The Glenn Center for Aging Research at U-M will focus on exploiting and expanding the growing evidence that drugs can slow the effects of aging and postpone diseases in animal models. Researchers aim to unlock mechanisms of aging that can help develop medications that may help people live longer, healthier lives. The award recognizes U-M as among a select group of elite members of The Glenn Consortium for Research in Aging in the country.

The Glenn Foundation for Medical Research sponsors outstanding laboratories and scientists conducting research to understand the biology that governs normal human aging and its related physiological decline, with the objective of developing interventions that will extend the human health span. The grant recognizes the quality and productivity of the U-M Geriatrics Center's biogerontology program by the Foundation, which does not solicit proposals but funds highly-promising research in gerontology.

The Glenn Center at U-M will have two components: The Model Systems Unit will analyze pharmaceutical agents using worms, flies and cultured cell lines, [while] the Slow-Aging Mouse facility [will] use these animals to discover the pathways by which the drugs slow the effects of aging and postpone disease.

Link: http://www.uofmhealth.org/news/archive/201409/3-m-grant-funds-paul-f-glenn-center-aging-research

Decellularization of donor organs and tissue sections has been demonstrated in laboratory animals and trialed in humans for some years now. It is clearly an improvement over straight organ donation in that it greatly reduces transplant rejection, and may even put a dent in the issue of organ availability by allowing the xenotransplantation of pig organs repopulated with human cells.

Absent some bold, unexpected, and rapid advances in tissue engineering, I would expect that decellularization will become the mainstay technology for organ and tissue transplantation for the next two decades or so. The process of removing cells from tissue while leaving behind the extracellular matrix and its chemical guides is comparatively simple and it dovetails well with present progress in control over stem cells and cell growth, enabling emptied organs to be reliably repopulated with a patient's own cells and made to work once again. Further, it circumvents a very hard problem, which is to say the challenge of creating an artificial scaffold that works as well as a biological extracellular matrix for these purposes. That has only been effectively achieved for small amounts of comparatively simple tissues such as muscle, and even there the real thing is generally better. There is a way to go yet in tissue engineering before decellularization will cease to be an extremely useful technology.

These publicity materials note recent work on engineering replacement heart valves for children using decellularized tissues, something that was being done in Europe far back as six years ago. Research proceeds on an uneven front, and some groups are always years out in front of others. This is but one among many applications of decellularization that will follow in the years ahead, and the expertise and inclination to follow this path is spreading, albeit more slowly than we'd all like.

Skin Cells Can Be Engineered Into Pulmonary Valves for Pediatric Patients

Researchers have found a way to take a pediatric patient's skin cells, reprogram the skin cells to function as heart valvular cells, and then use the cells as part of a tissue-engineered pulmonary valve. "Current valve replacements cannot grow with patients as they age, but the use of a patient-specific pulmonary valve would introduce a 'living' valvular construct that should grow with the patient. Our study is particularly important for pediatric patients who often require repeated operations for pulmonary valve replacements." While the study was conducted in vitro (outside of the body), the next step will be implanting the new valves into patients to test their durability and longevity.

Engineering Patient-Specific Valves Using Stem Cells Generated From Skin Biopsy Specimens

We generated induced pluripotent stem cells (iPSCs) by reprogramming skin fibroblast cells. We then differentiated iPSCs to mesenchymal stem cells (iPCSs-MSCs) using culture conditions that favored an epithelial-to-mesenchymal transition. Next, decellularized human pulmonary heart valves were seeded with iPCS-MSCs using a combination of static and dynamic culture conditions and cultured up to 30 days. Our results demonstrate the feasibility of constructing a biologically active human pulmonary valve using a sustainable and proliferative cell source. The bioactive pulmonary valve is expected to have advantages over existing valvular replacements, which will require further validation.

Ultimately even very sophisticated transplants are a stepping stone technology: no-one really wants to be opened up for surgery if there are better alternatives. The better alternative will probably emerge naturally as control over cells continues to evolve. Don't build the ship outside the bottle if you can build it inside the bottle. Find ways to control the necessary regrowth and regeneration of damaged organs in situ by making the cells already present in the body perform the needed actions in concert. That lies a way beyond decellularization as a practical and going concern, widespread in hospitals and clinics, but not a very long way beyond.

An unusual characteristic of some songbirds is that parts of their brain vary greatly in size between seasons. Researchers believe that finding the exact mechanisms that trigger this atrophy and regrowth of neurons will lead to ways to spur the latter part of this process in humans, forming the basis for treatments that can increase the slow pace of natural regeneration in the mammalian brain:

Neuroscientists have long known that new neurons are generated in the adult brains of many animals, but the birth of new neurons - or neurogenesis - appears to be limited in mammals and humans, especially where new neurons are generated after there's been a blow to the head, stroke or some other physical loss of brain cells. That process, referred to as "regenerative" neurogenesis, has been studied in mammals since the 1990s.

The researchers worked with Gambel's white-crowned sparrows, a medium-sized species 7 inches (18 centimeters) long that breeds in Alaska, then winters in California and Mexico. Like most songbirds, Gambel's white-crowned sparrows experience growth in the area of the brain that controls song output during the breeding season when a superior song helps them attract mates and define their territories. At the end of the season, probably because having extra cells exacts a toll in terms of energy and steroids they require, the cells begin dying naturally and the bird's song degrades.

As the [steroid] hormone levels decrease, the cells in the part of the brain controlling song no longer have the signal to 'stay alive.' Those cells undergo programmed cell death - or cell suicide as some call it. As those cells die it is likely they are releasing some kind of signal that somehow gets transmitted to the stem cells that reside in the brain. Whatever that signal is then triggers those cells to divide and replace the loss of the cell that sent the signal to begin with.

"This paper doesn't describe the exact nature of the signals that stimulate proliferation. We're just describing the phenomenon that there is this connection between cells dying and this stem cell proliferation. Finding the signal is the next step. [The researchers] nailed this down by going in and blocking cell death at the end of the breeding season. There are chemicals you can use to turn off the cell suicide pathway. When this was done, far fewer stem cells divided. You don't get that big uptick in new neurons being born. That's important because it shows there's something about the cells dying that turns on the replacement process. There's no reason to think what goes on in a bird brain doesn't also go on in mammal brains, in human brains. As far as we know, the molecules are the same, the pathways are the same, the hormones are the same. That's the ultimate purpose of all this, to identify these molecular mechanisms that will be of use in repairing human brains."

Link: http://www.washington.edu/news/2014/09/23/dying-brain-cells-cue-new-brain-cells-to-grow-in-songbird/

There are all sorts of longevity-associated genetic manipulations either demonstrated or postulated to produce benefits in mice. Why not try them all at once to see what happens? If you think that slowing aging through alteration of metabolism to reduce the impact of the cellular and molecular damage that causes aging is a useful strategy, or you believe that aging is programmed and not actually caused by damage, then this is an ambitious (though possibly overoptimistic) plan of exploration that wouldn't require more than a few million dollars to carry out.

To my eyes, however, this is merely a way to spend more money avoiding the better approach of repairing that damage. Slowing aging - slowing down damage - won't benefit the old who are already heavily damaged, and it won't produce as large an effect as repairing that damage. Yet it will be much more expensive and complicated: researchers have made only small inroads into sufficient understanding of metabolism and aging in detail to know how to make safe alterations, and can't even yet fully explain how natural age-slowing processes such as calorie restriction work, but we already have a comprehensive research program for repair planned out and know more than enough to steer it to near completion. Time is ticking and we don't have the luxury of being able to spend more to produce less when it comes to treatments for degenerative aging.

This research proposal comes from scientists associated with the Russian language advocacy community and the Science for Life Extension Foundation. They have had some success in the last few years raising funds from the community for smaller projects with mice, and may manage to get this funded the same way:

We propose developing a gene therapy that will radically extend lifespan. Genes that promote longevity of model animals will be used as therapeutic agents. We will manipulate not a single gene, but several aging mechanisms simultaneously. A combination of different approaches may lead to an additive or even a synergistic effect, resulting in a very long life expectancy.

11 genes that are most promising in terms of life extension will be used as targets for gene therapy. We will affect both the biological aging mechanisms, common to all the cells of the organism, as well as the primary neuroendocrine center, that regulates the whole organism's longevity - the hypothalamus. The expression increase or decrease of these genes in animal models was shown to result in boosted longevity. If the increase in expression of a particular gene is necessary for longevity, we will deliver this gene into the body. If, on the other hand, longevity depends on the inhibition of a certain gene's expression, we will introduce a genetic construct that encodes small RNAs that inhibit the expression of the target gene.

In addition, we will deliver 8 genes that prevent the individual tissue function disruption in old age. Each of these genes separately has previously been successfully used for gene therapy of one of the age-related diseases in rodent models.

All groups of mice will be regularly tested for aging markers, and also the blood and adipose tissue transcriptome, proteome and metabolome will be analyzed. All age-related histological and physiological changes will be studied. Behavioral test will be performed to analyze cognitive ability and locomotor activity in mice. The average and maximum lifespan of mice will be determined. In addition, a detailed study of side effects will be performed. Mice will be compared with old mice of the control group as well as with young mice.

Link: http://mariakonovalenko.wordpress.com/2014/09/23/longevity-gene-therapy-is-the-best-way-to-defeat-aging/

Growth hormone receptor knockout (GHRKO) mice are one of the longest-lived genetically engineered mouse lineages produced to date, and this is one of the few interventions that can slow aging and extend life to a greater degree in mice than is possible via the practice of calorie restriction. It produces dwarf mice with low body temperatures and improved insulin metabolism, alongside a range of other improvements such as greater stress resistance, reduced inflammation, increased reservoirs of pluripotent stem cells, and improved genome maintenance. It is worth recalling, however, that it seems much easier to extend life in short-lived species such as mice. There is a human population with a growth hormone receptor mutation that has a similar impact, people who have inherited Laron-type dwarfism. These individuals do not appear to live any longer than the rest of us, however, though they may be more resistant to some age-related disease.

Pursuing ways to slow down aging through alteration of metabolism is a poor strategy for the future of our health and longevity, and one of the reasons why this is the case is that it is an immensely complex undertaking, and we stand more or less at the beginning of it. The intersection of metabolism and aging is still only just beginning to be cataloged, and even for noted and comparatively well-studied ways to slow aging in mammals in the laboratory - such as GHRKO - it is still an open question as to how it actually works. Just for this one method, one single alteration to a single gene, years of hard work and funding have passed just to get to the point at which I can say "this has barely started." There is enough here in the effects of this single gene to keep teams of researchers occupied for years to come, and at a great cost. We've seen this elsewhere too, in the billion dollars consumed by work on a few sirtuin genes and their possible role in calorie restriction. Yet at the end of the day, we shouldn't expect to see practical results emerge. Knowledge, yes, but not great lengthening of life or reversal of aging. We already know what happens in humans when you disable the function of the growth-hormone receptor, and it isn't anything to write home about.

The knowledge is interesting, however. Just bear in mind that this isn't rejuvenation research: it is exploring how and why the natural pace of aging is somewhat plastic, and detailing the important mechanisms involved. To use an analogy, it tells us how we can marginally affect engine failure rates in cars with choice of oil and driving routes. It says nothing about how to periodically repair wear and damage so as to extend prime operational life far beyond the natural outcome of leaving an engine alone to fail in its own time. If you want repair and reversal of aging, you need to look to the sorts of research approaches detailed in the SENS outline rather than investigations of the details of the progression of aging, most of which deal with operation while being somewhat irrelevant to repair.

Specific suppression of insulin sensitivity in growth hormone receptor gene-disrupted (GHR-KO) mice attenuates phenotypic features of slow aging

Insulin sensitivity, defined as the efficacy and kinetics of glucose clearance from the blood, is highly positively correlated to modifications of longevity, whether induced by genetic or dietary interventions, and many studies of long-lived mutants have investigated their insulin sensitivity and related it to their enhanced survivorship. Although there is a wealth of data showing a clear association between the two, the proffered mechanisms for how insulin sensitivity might engender longevity are few, and those that have been proposed remain untested. Endeavoring to address multiple aging-associated maladies by study of the basic biology of longevity, as outlined in the concept of the Longevity Dividend, we investigated the positive association between insulin sensitivity and retained healthspan.

Increased insulin sensitivity and efficient homeostatic control of blood glucose have been associated with extended survival and retention of good health and functionality in exceptionally long-lived mice and humans (centenarians and long-lived families). Over the past fifteen years, the concept of an endocrinological component to the regulation of longevity has been substantiated by a considerable number of studies integrating endocrinology and gerontology. We have conducted many associative studies of this type with long-lived, somatotrophic signaling-defective mutant mice; we now progress to the first steps in testing the necessity for enhanced insulin sensitivity for the delayed senescence of these mice or the sufficiency of improved blood glucose homeostatic control for delayed aging in their normal counterparts.

The GHR-KO mouse has multiple, gerontologically intriguing characteristics, including increased circulating GH concentration, conversely decreased GH hormonal signaling, decreased circulating IGF-1 concentration, decreased body size, obesity, and altered endocrine function. In order to exclusively test whether the insulin sensitivity due to decreased insulin production/secretion in the GHR-KO mouse is necessary for the delayed and decreased pace of senescence of this mouse, we have used a GHR-KO mouse that carries a transgene driving expression of rat Igf-1 under the potent, β-cell-expression-enriching rat insulin promoter 1 (RIP) (the GHR-KO;RIP::IGF-1 double mutant). This transgene partially corrects the reduction in pancreatic islet cell mass and size present in the GHR-KO mouse, potentially increasing blood insulin levels and thus decreasing insulin sensitivity. If decreased β-cell production and/or secretion of insulin is necessary for the full longevity of the GHR-KO mouse, then a GHR-KO mouse with partially normalized β-cell production of insulin should age sooner/faster than a standard GHR-KO mouse.

The insulin sensitivity-suppressed GHR-KO;RIP::IGF-1 double mutant differs from the GHR-KO mouse in slow-aging-related parameters but in few, if any other, characteristics. This supports the hypothesis that enhanced insulin sensitivity is necessary for the retardation of senescence in the GHR-KO mouse. Lifespan was not assessed as part of our study. Future analyses of whether GHR-KO;RIP::IGF-1 mice live shorter than their standard GHR-KO counterparts, as the data that we have presented would suggest, are clearly required.

The objective of this study was to test the hypothesis that the insulin sensitivity of the GHR-KO mouse is causal in the decreased rate of aging of this long-lived animal. Employing a twenty-fold range of insulin concentrations, we showed that the RIP::IGF-1 transgene normalizes the widely studied insulin sensitivity of slow-aging GHR-KO mice. Although there were other blood glucose regulation-related phenotypes engendered by the transgene, it is this normalization effect on insulin responsiveness that provided the basis for testing the potential effect of the transgene on other slow-aging-associated characteristics.

You'll find a lot of details in this open access paper, but I think the telling one is that the GHRKO mice with additional insulin ate more. The effects of calorie intake on life span in mice are large in comparison to most others, and probably make this work of little value beyond pointing the way to trying again but with calorie controlled diets this time. The hypothesis that insulin metabolism drives alterations in natural longevity is an interesting one, and has a lot of supporting evidence, but if more conclusively proven it just moves the point of investigation one step deeper into the operation of metabolism. One has to again ask "why?" and spend much money and time to make the next step.

Bearing in mind that investigations of insulin, IGF-1, and aging have been ongoing for a couple of decades in earnest, it becomes very clear that this is no way to work effectively on extending human life and addressing the causes of aging in the near term. A better path and more efficient forward is very much needed. Fortunately it exists in the form of SENS, only needing the research community and its extremely conservative funding institutions to buy in to a greater degree.

Artificial organs capable of performing some of the functions of the real thing don't have to look or be structured in the same way as our evolved organs. They just have to work. Efforts to develop artificial organs have benefited from progress in the ability to control and manage cell populations, giving rise to a first generation of hybrid devices that use both cells and machinery. A number of bulky prototypes to augment various kidney, pancreatic, lung, and liver functions with engineered tissue have been developed in recent years. In these cases the necessary cells can be grown and maintained outside the body and a patient's blood circulated through them on a regular basis. Miniaturization isn't necessary in order to obtain these benefits, which makes the research and development process much easier. In the future one might imagine that smaller and more efficient versions could be implanted, putting this technology in competition with regenerative medicine and tissue engineering of replacement organs.

Physicians and scientists are testing a novel, human cell based, bioartificial liver support system for patients with acute liver failure, often a fatal diagnosis. "Liver failure patients and their doctors have long been frustrated by the critical need to provide the kind of life-saving care kidney patients are afforded by dialysis. The quest for a device that can fill in for the function of the liver, at least temporarily, has been underway for decades. A bioartificial liver, also known as a BAL, could potentially sustain patients with acute liver failure until their own livers self-repair."

In the bioartificial liver under investigation, blood is drawn from the patient via a central venous line, and then is filtered through a component system featuring four tubes, each about 1 foot long, which are embedded with liver cells. The external organ support system is designed to perform critical functions of a normal liver, including protein synthesis and the processing and cleaning of a patient's blood. The filtered and treated blood is then returned to the patient through the central line. "If successful, a bioartificial liver could not only allow time for a patient's own damaged organ to regenerate, but also promote that regeneration. In the case of chronic liver failure, it also potentially could support some patients through the long wait for a liver transplant."

Link: http://cedars-sinai.edu/About-Us/News/News-Releases-2014/Researchers-Testing-Artificial-Liver-as-Potential-Therapy-for-Patients-with-Alcohol-Related-Organ-Failure.aspx

Most cancers kill through metastasis, the spread of cancerous cells throughout the body to seed numerous secondary tumors. Without this process cancer would be much less threatening and more amenable to treatment. Thus numerous research groups are investigating ways to shut down or otherwise interfere with metastasis, and here is a recent example:

[Researchers have] developed a protein therapy that disrupts the process that causes cancer cells to break away from original tumor sites, travel through the blood stream and start aggressive new growths elsewhere in the body. Today doctors try to slow or stop metastasis with chemotherapy, but these treatments are unfortunately not very effective and have severe side effects. [This] team seeks to stop metastasis, without side effects, by preventing two proteins - Axl and Gas6 - from interacting to initiate the spread of cancer.

Axl proteins stand like bristles on the surface of cancer cells, poised to receive biochemical signals from Gas6 proteins. When two Gas6 proteins link with two Axls, the signals that are generated enable cancer cells to leave the original tumor site, migrate to other parts of the body and form new cancer nodules. To stop this process [researchers] used protein engineering to create a harmless version of Axl that acts like a decoy. This decoy Axl latches on to Gas6 proteins in the blood stream and prevents them from linking with and activating the Axls present on cancer cells.

The researchers gave intravenous treatments of this bioengineered decoy protein to mice with aggressive breast and ovarian cancers. Mice in the breast cancer treatment group had 78 percent fewer metastatic nodules than untreated mice. Mice with ovarian cancer had a 90 percent reduction in metastatic nodules when treated with the engineered decoy protein. "This is a very promising therapy that appears to be effective and non-toxic in pre-clinical experiments. It could open up a new approach to cancer treatment."

Link: http://www.sciencedaily.com/releases/2014/09/140921145112.htm

There will always be naysayers when it comes to the prospects for enhanced health and longevity: people who claim that they want to die younger than they might, that they don't want to do anything about the aging process, and that they'll be content with a lifespan that is the same as their parents and their peers. They tend to say all this while materially benefiting from medical technologies that didn't exist for their parents and grandparents, and the fact that a great many people presently say that they don't want to extend their lives through advances in medicine has a lot to do with the fact that the necessary technologies don't yet exist. They are just around the corner, a few decades away, something that needs work and advocacy and funding support to come in to existence.

If rejuvenation treatments after the SENS model existed in the clinic, providing accessible ways to turn back aging and live in good health for decades longer, then I think that the number of naysayers would be much smaller. Consider the modest population of people who today refuse a range of effective, proven forms of medical care for religious or other reasons and suffer as a consequence. They are very much in the minority. That is the future for people who decide not to undertake treatment of their aging process: there won't be many of them once rejuvenation treatments are a reality for all the same bland cultural reasons that exist today. It is done because most people do it, and that is the way of things whether it involves helping yourself with medicine or hurting yourself with cigarettes and too many calories.

All of this presents quite the obstacle when we are right on the verge of promising new medicine to address aging, standing at the point at which support is needed for rapid progress towards the creation of effective treatments capable of reversing the specific root causes of age-related disease. All too few people are willing to stand up in public to say "go for it!", and for every one of those someone else dolefully touts the path of resignation, relinquishment, and aging to death on a predetermined schedule. It is probably extremely charitable to believe that any of these people would hold the same views were they born fifty years later: they'd be using health assurance treatments that repair metabolic damage to hold back aging and maintain youthful health and vigor just like near everyone else.

Still, there will always be naysayers. Just not so many of them as there are today. The fellow quoted below seems to me to be touting a position that is the result of a profound failure of the imagination and ambition. He fails to see that the current state of medicine for the elderly is the outcome of failing to treat the causes of aging, but rather just trying to shore up the consequences. That never works well: you can't make a failing machine work well unless to address the cause of failure. He fails to mention that the field is changing to move in that direction: the future of treatments for age-related disease and trends in healthy life span will have little to do with the past. A discontinuity is coming as the result of a change in fundamental strategy coupled with a sudden leap in the capabilities of biotechnology over a few short decades. Further, I really have to complain about anyone who claims that refusing medical care in late life equates to "going quietly." That the unassisted end of life is a simple fade to black is a malicious lie propagated by those who, for often petty reasons, like to keep the suffering in this world behind curtains and out of sight. The end of old age is painful, bloody, drawn out, and horrible. Many of the options include some of the worst things that can happen to anyone, and that process as a whole happens to everyone.

Why I Hope to Die at 75

That's how long I want to live: 75 years. I am sure of my position. Doubtless, death is a loss. It deprives us of experiences and milestones, of time spent with our spouse and children. In short, it deprives us of all the things we value. But here is a simple truth that many of us seem to resist: living too long is also a loss. It renders many of us, if not disabled, then faltering and declining, a state that may not be worse than death but is nonetheless deprived. It robs us of our creativity and ability to contribute to work, society, the world.

I am talking about how long I want to live and the kind and amount of health care I will consent to after 75. Americans seem to be obsessed with exercising, doing mental puzzles, consuming various juice and protein concoctions, sticking to strict diets, and popping vitamins and supplements, all in a valiant effort to cheat death and prolong life as long as possible. This has become so pervasive that it now defines a cultural type: what I call the American immortal. I reject this aspiration. I think this manic desperation to endlessly extend life is misguided and potentially destructive. For many reasons, 75 is a pretty good age to aim to stop.

Once I have lived to 75, my approach to my health care will completely change. I won't actively end my life. But I won't try to prolong it, either. Today, when the doctor recommends a test or treatment, especially one that will extend our lives, it becomes incumbent upon us to give a good reason why we don't want it. The momentum of medicine and family means we will almost invariably get it.

Doctors wanted to extend life. Instead they extended death

There's this idea that as we grow older we'll be healthier. I call it the rectangularization of life. You go on as healthy as you've always been and then at the end you just fall off a cliff and die of a heart attack or stroke or something. But over the last 30 years the data has said the opposite. As we add years of life we're adding more years of life with disabilities. We are saving more people who have strokes. That's a triumph. But the consequence is people are living after strokes and they typically have disabilities - they have speech problems or cognitive problems. There's a tradeoff. We have extended the dying process.

This is a view of a future of stasis. If you think that it is going to be more of the same, forever and always, then one might ask what the point of it all is. Nihilism starts with "why live longer," and moves on to "why live at all," but people making arguments like those quoted above are to my eyes living in an incoherent half-way house somewhere distant from any point of actual conviction. Live if you want to live. Die if you want to die. But above all do something about it, don't just lie back in your chair and exist or fail to exist at the whim of fate and the machinations of your own cells. Show some agency.

Telomerase is the enzyme responsible for lengthening telomeres, caps of repeating DNA sequences at the end of chromosomes. Telomere length acts as a clock of sorts, as telomeres shorten with each cell division. This is one part of a complicated mechanism that limits the replicative life span of ordinary somatic cells that make up the bulk of tissues, producing the well-known Hayflick limit. Telomerase is active in differerent cell populations to different degrees: in stem cells, for example, it operates to consistently maintain lengthy telomeres, such that the stem cells can renew their own population throughout life, while still periodically creating fresh new batches of somatic cells to replace lost cells in the tissue they support.

Average telomere length is fairly dynamic, depending on the details of tissue maintenance and delivery of fresh cells, and tends to shorten with age and illness. It is most commonly measured in white blood cells, which may have more of a correlation with illness than if measured in other tissues. Telomere length is largely thought of as a marker of age-related damage, not a primary cause of aging, but nonetheless delivery of additional telomerase to mice via genetic engineering has been shown to extend life. It is still an open question as to how exactly this works: slowing the onset of tissue frailty through cell loss is one possibility, but it has been suggested that telomerase may interact with mitochondria in ways that reduce their impact on aging. Mice have quite different telomere dynamics from humans, and delivery of telomerase comes with an associated concern of raised cancer risk: all cancers incorporate mechanisms to keep telomeres long in their cells despite frequent cell divisions.

Here researchers present an interesting new finding about the mechanisms of telomerase, which will no doubt be incorporated into existing initiatives aiming to use telomerase as a way to intervene in the aging process:

In our bodies, newly divided cells constantly replenish lungs, skin, liver and other organs. However, most human cells cannot divide indefinitely - with each division, a cellular timekeeper at the ends of chromosomes shortens. When this timekeeper, called a telomere, becomes too short, cells can no longer divide, causing organs and tissues to degenerate, as often happens in old age. But there is a way around this countdown: some cells produce an enzyme called telomerase, which rebuilds telomeres and allows cells to divide indefinitely.

In a new study [scientists] have discovered that telomerase, even when present, can be turned off. "Previous studies had suggested that once assembled, telomerase is available whenever it is needed. We were surprised to discover instead that telomerase has what is in essence an 'off' switch, whereby it disassembles." Understanding how this "off" switch can be manipulated - thereby slowing down the telomere shortening process - could lead to treatments for diseases of aging (for example, regenerating vital organs later in life).

Every time a cell divides, its entire genome must be duplicated. While this duplication is going on, [researchers] discovered that telomerase sits poised as a "preassembly" complex, missing a critical molecular subunit. But when the genome has been fully duplicated, the missing subunit joins its companions to form a complete, fully active telomerase complex, at which point telomerase can replenish the ends of eroding chromosomes and ensure robust cell division.

Surprisingly, however, [researchers] showed that immediately after the full telomerase complex has been assembled, it rapidly disassembles to form an inactive "disassembly" complex - essentially flipping the switch into the "off" position. They speculate that this disassembly pathway may provide a means of keeping telomerase at exceptionally low levels inside the cell. Although eroding telomeres in normal cells can contribute to the aging process, cancer cells, in contrast, rely on elevated telomerase levels to ensure unregulated cell growth. The "off" switch [may] help keep telomerase activity below this threshold.

Link: http://www.salk.edu/news/pressrelease_details.php?press_id=2052

Philanthropist Peter Thiel is one of the patrons of the SENS Research Foundation, perhaps the only organization in the world at this point that is coordinating and funding serious efforts to build rejuvenation treatments. Thiel recently published a book, and by the alchemy involved in these matters we are thus seeing more press of late on his views and the causes he supports:

An hour into my conversation with Peter Thiel the conversation turns, as it seems conversations with Thiel often do, to the question of death. 'Basically,' Thiel says earnestly, 'I'm against it.' What he calls 'the problem of death' is a topic that he returns to often. 'I think there are probably three main modes of approaching it,' he says. 'You can accept it, you can deny it or you can fight it. I think our society is dominated by people who are into denial or acceptance, and I prefer to fight it.'

Thiel is an amiable, softly spoken man who gives the impression of thinking out loud. Questions are frequently greeted with a series of 'ums... aahs... I think... let me put it this way...', beginning a thought, stopping, trying another, and then another, as if he is testing the best way to be as precise as he can possibly be. 'Hobbes said that in the state of nature life is nasty, brutish and short,' he says. 'And, um, I do think we want to overcome the state of nature. It is true that you can say that death is natural, but it is also natural to fight death. But if you stand up and say this is a big problem, we should do something about this, that makes people very uncomfortable, because they've made their peace with death. In some ways it's a microcosm of the whole complacency of the Western world. I do think there is this danger that our society has made its peace with decline. I'd like to jolt them out of their complacency a little bit.'

He has poured millions of dollars into what he calls 'the immortality project'. 'I would like to live longer, and I would like other people to live longer.' His belief is such that he has signed up with Alcor, the leading company in the field of cryonics, to be deep-frozen at the time of his death - as much as an 'ideological statement', he says, as in any expectation of being thawed out any time in the near future. 'In telling you that I've signed up for it cryonics, there's always this reaction that it's really crazy, it's disturbing. But my take on it is it's only disturbing because it challenges our complacency.'

He is, as you might expect, a definite optimist. Thiel believes there will be a cure for cancer in the next 20 years, and that a cure for Alzheimer's is within reach. Immortality, he allows, may take a little longer. He has given more than $6 million to support the work of Aubrey de Grey, the English gerontologist who co-founded the Methuselah Foundation, and is now the chief research scientist of SENS Research Foundation (Strategies for Engineered Negligible Senescence). De Grey has famously pronounced that he believes the first person to live to 1,000 is already alive today.

The 'life extension project', Thiel says, is as old as science itself. 'It was probably even more important than alchemy. Finding élan vital, the water of life, was of greater interest than finding something that could transmute everything into gold. And I do think people would prefer immortality to lots of gold. On a fundamental level, the question is whether ageing can be reversed or not. Many biological processes appear to be irreversible, but computational processes are reversible. If it is possible to understand biological systems in informational terms, could we then reverse these biological processes, including the process of ageing? I do think that the genomics revolution promises a much greater understanding of biological systems and opens the possibility of modifying these seemingly inevitable trajectories in far more ways than we can currently imagine.' So immortality may be possible? 'Well, "immortal" is a long time.

'There are many arguments against life extension, and they all strike me as extraordinarily bad: it's not natural; there will be too many people; you will be bored. But I don't think it would be boring at all.' He pauses. 'People always say you should live your life as if it were your last day. I think you should live your life as though it will go on for ever; that every day is so good that you don't want it to end.'

Link: http://www.telegraph.co.uk/technology/11098971/Peter-Thiel-the-billionaire-tech-entrepreneur-on-a-mission-to-cheat-death.html

A gulf presently lies between the nanoscale engineering of materials science on the one hand and the manipulation and understanding of evolved biological machinery on the other. In time that gulf will close: future industries will be capable of producing and controlling entirely artificial machines that integrate with, enhance, or replace our natural biological machines. Meanwhile biologists will be manufacturing ever more artificial and enhanced versions of cellular components, finding ways to make them better: evolution has rarely produced the best design possible for any given circumstance. Both sides will work towards one another and eventually meet in the middle.

Insofar as aging goes, a process of accumulating damage and malfunction in our biology, it is likely that this will first be successfully addressed and brought under medical control by producing various clearly envisaged ways to repair and maintain our cells just as they are: remove the damage, restore youthful function, and repeat as necessary. We stand much closer to that goal than the far more ambitious undertaking of building a better, more resilient, more easily repaired cell - a biology 2.0 if you like. That will happen, however. Our near descendants will be as much artificial as natural, and more capable and healthier for it.

The introduction of machinery to form a new human biology won't happen all at once, however, and it isn't entirely a far future prospect. There will be early gains and prototypes, the insertion of simpler types of machine into our cells for specific narrow purposes: sequestering specific proteins or wastes, or as drug factories to produce a compound in response to circumstances, or any one of a number of other similar tasks. If you want to consider nanoparticles or engineered assemblies of proteins capable of simple decision tree operations as machines then this has already happened in the lab:

Researchers Make Important Step Towards Creating Medical Nanorobots

Researchers [have] have made an important step towards creating medical nanorobots. They discovered a way of enabling nano- and microparticles to produce logical calculations using a variety of biochemical reactions. Many scientists believe logical operations inside cells or in artificial biomolecular systems to be a way of controlling biological processes and creating full-fledged micro-and nano-robots, which can, for example, deliver drugs on schedule to those tissues where they are needed.

Further, there is a whole branch of cell research that involves finding ways to safely introduce ever larger objects into living cells, such as micrometer-scale constructs. In an age in which the state of the art for engineering computational devices is the creation of 14 nanometer features, there is a lot that might be accomplished in the years ahead with the space contained within a 1000 nanometer diameter sphere.

Introducing Micrometer-Sized Artificial Objects into Live Cells: A Method for Cell-Giant Unilamellar Vesicle Electrofusion

Direct introduction of functional objects into living cells is a major topic in biology, medicine, and engineering studies, since such techniques facilitate manipulation of cells and allows one to change their functional properties arbitrarily. In order to introduce various objects into cells, several methods have been developed, for example, endocytosis and macropinocytosis. Nonetheless, the sizes of introducible objects are largely limited: up to several hundred nanometers and a few micrometers in diameter. In addition, the uptake of objects is dependent on cell type, and neither endocytosis nor macropinocytosis occur, for example, in lymphocytes. Even after successful endocytosis, incorporated objects are transported to the endosomes; they are then eventually transferred to the lysosome, in which acidic hydrolases degrade the materials. Hence, these two systems are not particularly suitable for introduction of functionally active molecules and objects.

To overcome these obstacles, novel delivery systems have been contrived, such as cationic liposomes and nanomicelles, that are used for gene transfer; yet, only nucleic acids that are limited to a few hundred nanometers in size can be introduced. By employing peptide vectors, comparatively larger materials can be introduced into cells, although the size limit of peptides and beads is approximately 50nm, which is again insufficient for delivery of objects, such as DNA origami and larger functional beads.

Here, we report a method for introducing large objects of up to a micrometer in diameter into cultured mammalian cells by electrofusion of giant unilamellar vesicles (GUVs). We prepared GUVs containing various artificial objects using a water-in-oil emulsion centrifugation method. GUVs and dispersed HeLa cells were exposed to an alternating current (AC) field to induce a linear cell-GUV alignment, and then a direct current (DC) pulse was applied to facilitate transient electrofusion.

With uniformly sized fluorescent beads as size indexes, we successfully and efficiently introduced beads of 1 µm in diameter into living cells along with a plasmid mammalian expression vector. Our electrofusion did not affect cell viability. After the electrofusion, cells proliferated normally until confluence was reached, and the introduced fluorescent beads were inherited during cell division. Analysis by both confocal microscopy and flow cytometry supported these findings. As an alternative approach, we also introduced a designed nanostructure (DNA origami) into live cells. The results we report here represent a milestone for designing artificial symbiosis of functionally active objects (such as micro-machines) in living cells. Moreover, our technique can be used for drug delivery, tissue engineering, and cell manipulation.

Cell machinery will be a burgeoning medical industry of the 2030s, I imagine. To my eyes the greatest challenge in all of this is less the mass production of useful machines per se, and more the coordination and control of a body full of tens of trillions of such machines, perhaps from varied manufacturers, introduced for different goals, and over timescales long in comparison to business cycles and technological progress. That isn't insurmountable, but it sounds like a much harder problem than those inherent in designing these machines and demonstrating them to be useful in cell cultures. It is a challenge on a scale of complexity that exceeds that of managing our present global communications network by many orders of magnitude. If you've been wondering what exactly it is we'll be doing with the vast computational power available to us in the decades ahead, given that this metric continues to double every 18 months or so, here is one candidate.

Subcultures and initiatives that support the extension of healthy life through medical research have grown considerably in the past twenty years, finding one another and merging with the spread of the internet, then raising funds and attracting attention in increasingly large cycles. Prior to this, however, these subcultures were thin threads indeed, tiny groups and single individuals out on the fringes of culture. Yet these roots of the present day life extension movements extend back a long way, and as is argued in the book "A History of Life Extensionism in the Twentieth Century" they were influential upon medicine even then. Here is an interesting review that touches upon the greater public support for extending healthy life that exists in Eastern Europe and Russia versus the West, something that has been noted in recent years with greater contact and collaboration between the English language and Russian language longevity science communities:

A History of Life-Extensionism in the Twentieth Century by Ilia Stambler is the most thorough treatment to date of the ideas of famous thinkers and scientists who attempted to prolong human lifespans. In this detailed and impressively documented work - spanning 540 pages - Dr. Stambler explores the works of life-extensionist thinkers and practitioners from a vast variety of ideological, national, and methodological backgrounds.

In substance, I agree with Dr. Stambler's central observation that life-extensionist thinkers tended to adapt to the political and ideological climates of the societies in which they lived. I do suspect that, in some regimes (e.g., communist and fascist ones), the adaptation was partly a form of protection from official persecution. Even then, Soviet life-extensionists were unable to avoid purges and denunciations if they fell out of favor with the dominant scientific establishment. My own thinking is that life-extensionism is a powerful enough human motive that it will attempt to thrive in any society and under any regime. However, some regimes are more dangerous for life-extensionism than others - especially if they explicitly persecute those who work on life extension.

Even so, I have been tremendously interested to delve into Dr. Stambler's discussion of the deep roots of life-extensionist thought in Russian society, where ideas favoring life prolongation have taken hold despite a long history of authoritarianism and more general human suffering. I even remember my own very early years in Minsk, where I found it easy to adopt an anti-death attitude the moment I learned about death - and where, even in childhood, I found my support for human life extension to be largely uncontroversial from an ethical standpoint. When I moved to the United States, I encountered far more resistance to this idea than I ever did in Belarus.

While most Americans are not opposed to advanced medicine and concerted efforts to fight specific diseases of old age, there does still seem to be a culturally ingrained perception of some "maximum lifespan" beyond which life extension is feared, even though it is considered acceptable up to that limit. I think, however, that the dynamics of a competitive economy with some degree of freedom of research will ultimately enable most Americans to accept longer lifespans in practice, even if there is no intellectual revolution in their minds.

Link: http://ieet.org/index.php/IEET/more/stolyarov20140918

Researchers have identified a novel mechanism by which neural stem cells can help to repair and assist other brain cells:

Stem cells hold great promise as a means of repairing cells in conditions such as multiple sclerosis, stroke or injuries of the spinal cord because they have the ability to develop into almost any cell type. Now, new research shows that stem cell therapy can also work through a mechanism other than cell replacement. A team of researchers [has] shown that stem cells "communicate" with cells by transferring molecules via fluid filled bags called vesicles, helping other cells to modify the damaging immune response around them. "These tiny vesicles in stem cells contain molecules like proteins and nucleic acids that stimulate the target cells and help them to survive - they act like mini "first aid kits". Essentially, they mirror how the stem cells respond to an inflammatory environment like that seen during complex neural injuries and diseases, and they pass this ability on to the target cells. We think this helps injured brain cells to repair themselves."

Mice with damage to brain cells - such as the damage seen in multiple sclerosis - show a remarkable level of recovery when neural stem/precursor cells (NPCs) are injected into their circulatory system. PCs make vesicles when they are in the vicinity of an immune response, and especially in response to a small protein, or cytokine, called Interferon-g which is released by immune cells. A highly specific pathway of gene activation is triggered in NPCs by IFN-g, and that this protein also binds to a receptor on the surface of vesicles. When the vesicles are released by the NPCs, they adhere and are taken up by target cells. Not only does the target cell receive proteins and nucleic acids that can help them self-repair, but it also receives the IFN-g on the surface of the vesicles, which activates genes within the target cells.

Link: http://www.cam.ac.uk/research/news/stem-cells-use-first-aid-kits-to-repair-damage

Some of the most important work taking place in the stem cell research community is not in fact directly focused on producing treatments. Instead it consists of infrastructure improvements: creating ways to obtain more cells of a specific type, more reliably, more rapidly, and at a lower cost. This is important because falling costs accelerate further research and development, such as by broadening the number of laboratories that can budget projects in the field, and by expanding what can be accomplished within the budget of any given research group. Ultimately this will also make the resulting treatments cheaper and better, but at this point that is somewhat less important given where the field stands today. Cell therapies deployed to date have proved beneficial, but are just a first pass at the problem space, a fragment of what is possible. That initial success over the past decade has served to draw in enough money and interest for the next cycle to expand considerably. It will produce a panoply of far better, far more diverse approaches to the control of cells in medicine. It will be an explosion of variety and utility for patients, and the cheaper the tools the greater the result and the sooner it will arrive.

This is why it doesn't hurt to keep a weather eye on progress in enabling technologies and infrastructure in stem cell research. For those of us likely to need or benefit from regenerative treatments a decade or two from now, the pace of progress in tools today provides some insight as to the likely future landscape of therapies. Take these few items as illustrated of current work on the creation of reliable and low-cost sources of stem cells, for example:

Scientists Report Reliable and Highly Efficient Method for Making Stem Cells

Using the new technique in mice, the researchers increased the number of stem cells obtained from adult skin cells by more than 20-fold compared with the standard method. They say their technique is efficient and reliable, and thus should generally accelerate research aimed at using stem cells to generate virtually any tissue.

The standard method for reprogramming skin, blood, or other tissue-specific cell types into "induced pluripotent stem cells" (iPSCs) involves the artificial expression of four key genes dubbed OKSM (for Oct4, Klf4, Sox2 and myc) whose collective activity slowly prods cells into an immature state much like that of an early embryonic cell. Converting most cell types into stable iPSCs occurs at rates of 1 percent or less, and the process can take weeks. Researchers throughout the world have been searching for ways to boost this efficiency, and in some cases have reported significant gains. These procedures, however, often alter vital cellular genes, which may cause problems for potential therapies.

Adding to fibroblasts engineered to express OKSM either vitamin C, a compound to activate Wnt signaling, or a compound to inhibit TGF-β signaling increased iPSC-induction efficiency weakly to about 1% after a week of cell culture. Combining any two worked a bit better. But combining all three brought the efficiency to about 80 percent in the same period of time.

New molecule allows for up to 10-fold increase in stem cell transplants

Investigators have just published the announcement of the discovery of a new molecule, the first of its kind, which allows for the multiplication of stem cells in a unit of cord blood. Umbilical cord stem cells are used for transplants aimed at curing a number of blood-related diseases, including leukemia, myeloma and lymphoma. For many patients this therapy comprises a treatment of last resort. The research has the potential to multiply by 10 the number of cord blood units available for a transplant in humans. In addition, it will considerably reduce the complications associated with stem cell transplantation.

Pyrimidoindole derivatives are agonists of human hematopoietic stem cell self-renewal

The small number of hematopoietic stem and progenitor cells in cord blood units limits their widespread use in human transplant protocols. We identified a family of chemically related small molecules that stimulates the expansion ex vivo of human cord blood cells capable of reconstituting human hematopoiesis for at least 6 months in immunocompromised mice. The potent activity of these newly identified compounds, UM171 being the prototype, is independent of suppression of the aryl hydrocarbon receptor, which targets cells with more-limited regenerative potential. The properties of UM171 make it a potential candidate for hematopoietic stem cell transplantation and gene therapy.

This article is an example of the rising awareness of ongoing research into altering the pace of aging so as to extend healthy life. This is a good thing if you are thinking about raising funds for research on therapies for aging, as the more public attention the better, even if it is focused at first on a poor choice of scientific strategy. Working to slow aging is a course that will produce only marginal benefits and a slight change in the course of life and structure of society: people will live a little longer, and the present trend of adding a year to adult life expectancy each decade will continue or speed up a little. Everything will be essentially the same at the end of the day, however, and we will all still suffer horribly from age-related diseases and die because of aging.

Aging is an accumulation of damage at the level of cells and protein structures, and altering our metabolism to slightly slow down that process is both hard and not all that beneficial, since none of the prospective or envisaged treatments can slow it down all that much. The best of paths to actual therapies at this point in time are not as beneficial as the practice of regular exercise or calorie restriction, and that isn't something that is expected to change any time soon.

My hope is that the current enthusiasm for slowing aging will give way to work on reversing aging, producing actual rejuvenation by repairing the damage of aging rather than just slowing it down. For that to happen, the currently minority field of rejuvenation research needs enough funding to demonstrate that it can produce far better results and for far less investment - which should be the case just as soon as the first prototype treatments are deployed in mice. Repair of a failing system is obviously better than building a new system that fails more slowly: existing old machinery can be restored, and that repair process can be performed over and again to extend its healthy life indefinitely. Further, the causes of aging are very much simpler and more completely understood than the details of our metabolic machinery; building ways to repair these causes is a much easier prospect than reengineering metabolism.

Viewed globally, the lengthening of life spans seems independent of any single, specific event. It didn't accelerate much as antibiotics and vaccines became common. Nor did it retreat much during wars or disease outbreaks. A graph of global life expectancy over time looks like an escalator rising smoothly. The trend holds, in most years, in individual nations rich and poor; the whole world is riding the escalator. Projections of ever-longer life spans assume no incredible medical discoveries - rather, that the escalator ride simply continues. If anti-aging drugs or genetic therapies are found, the climb could accelerate. Centenarians may become the norm, rather than rarities who generate a headline in the local newspaper.

Pie in the sky? On a verdant hillside in Marin County, California - home to hipsters and towering redwoods, the place to which the Golden Gate Bridge leads - sits the Buck Institute, the first private, independent research facility dedicated to extending the human life span. Since 1999, scientists and postdocs there have studied ways to make organisms live much longer, and with better health, than they naturally would. Already, the institute's researchers have quintupled the life span of laboratory worms. Most Americans have never heard of the Buck Institute, but someday this place may be very well known.

Buck is not alone in its pursuit. The University of Michigan, the University of Texas, and the University of California at San Francisco are studying ways to slow aging, as is the Mayo Clinic. Should research find a life-span breakthrough, the proportion of the U.S. population that is elderly - fated to rise anyway, considering declining fertility rates, the retirement of the Baby Boomers, and the continuing uplift of the escalator - may climb even more. But the story might have a happy ending. If medical interventions to slow aging result in added years of reasonable fitness, life might extend in a sanguine manner, with most men and women living longer in good vigor, and also working longer, keeping pension and health-care subsidies under control. Indeed, the most-exciting work being done in longevity science concerns making the later years vibrant, as opposed to simply adding time at the end.

Link: http://www.theatlantic.com/features/archive/2014/09/what-happens-when-we-all-live-to-100/379338/

An interview with the director of the Translational Tissue Engineering Center at Johns Hopkins University School of Medicine can be found at the Methuselah Foundation blog:

We named it the Translational Tissue Engineering Center because we're focused not just on the development of new technologies in regenerative medicine, but on addressing clinical challenges and developing new therapeutic outcomes for patients. In my lab, we're looking at a number of different applications in orthopedic surgery, rheumatology, and musculoskeletal repair. We're working on the regeneration of cartilage tissue, which lines the surfaces of joints. We're also looking at bone repair, which is important for joints and in craniofacial reconstruction, and exploring what can be done with muscle disease to repair tissues and treat the underlying disease. Then there are the plastic surgery applications - reconstruction of tissues and wound healing in the craniofacial region and soft tissue throughout the body. We're also in an ophthalmology building, so we're surrounded by a lot of clinicians focused on the eye, and we've begun projects looking at both corneal repair and retinal repair.

What's interesting right now is that there seems to be a renewed excitement for cell therapies and gene therapies, both among students and in the commercial sector. These types of industrial investment and commercial excitement tend to go through ups and downs, and I think there's a lot of excitement right now that we definitely want to get more and more connected with. One of the biggest gaps in my mind is what happens at the university versus what's feasible in commercial settings, and there are a number of these so-called valleys of death between the two. There's a valley of death in the laboratory of moving to proof of concept and actual efficacy in the most relevant pre-clinical models that the FDA will approve. Then there's another valley of death when you come out of the laboratory regarding how to manufacture and deliver whatever technology you're working with, and how to make it commercially viable.

Right now, I'm most encouraged by the interface between regenerative medicine and transplantation. There have been some exciting advances in transplantation and microsurgery, for example, with very complex grafts on the face, hands, and arms. And in order to take it beyond that, and make it less of a rare, boutique occurrence into something more widespread and accessible to a larger number of people, I think it could be very interesting to combine the latest work in cell therapy with the latest in both materials and immunomodulation. Also, I think some of the recent advancements in cancer immunology, which is really a type of regenerative medicine engineering - in other words, engineering the immune system to treat a disease - involve principles that are very promising and can be applied to many other things.

Link: http://mfoundation.org/blog/?p=196

The types of stem cell that can be extracted from accessible fetal tissues such as the umbilical cord and amniotic fluid are somewhat different to both adult stem cells and embryonic stem cells. Ultimately all of these various sources will go away in favor of cell reprogramming on the grounds that pretty much anything other than sourcing cells from a skin or blood sample from the patient in front of you is going to result in excessively costly treatments. It is simply too troublesome to manage the collection and preservation of fetal cells on an industrial scale unless it is the only useful alternative, which is not to mention that they cannot be patient-matched cells in any but the most rare of circumstances.

From a research perspective finding out what these various types of stem cell can achieve in terms of regenerative therapies is a necessary part of the process of guiding advances in cell programming. Embryonic and fetal stem cells provide aiming points and comparisons for cell reprogramming efforts, but that is only helpful if scientists know how to use these cells to produce therapies. Thus even as the production of induced pluripotent stem cells from ordinary skin cells is moving ahead, the first clinical trials are beginning, and researchers are becoming ever better at producing stem cells that are increasingly like those seen in various stages of embryonic development, it is still the case that various research groups are exploring what can be done with fetal and embryonic stem cells.

Here is an interesting review that notes fetal stem cells work in muscle regeneration in much the same way as other stem cell treatments have been shown to produce effects: they are not acting directly to restore tissue, but rather changing the signaling environment to alter the behavior of native cells. At some point the cell part of many cell therapies will fall away in favor of directly manipulating cell signaling, but there is still much to be discovered about which signals are needed and how to deliver them in a way that mimics the presence of stem cells.

Fetal stem cells and skeletal muscle regeneration: a therapeutic approach

More than 40% of the body mass is represented by muscle tissue, which possesses the innate ability to regenerate after damage through the activation of muscle-specific stem cells, namely satellite cells. Muscle diseases, in particular chronic degenerative states of skeletal muscle such as dystrophies, lead to a perturbation of the regenerative process, which causes the premature exhaustion of satellite cell reservoir due to continuous cycles of degeneration/regeneration. Nowadays, the research is focused on different therapeutic approaches, ranging from gene and cell to pharmacological therapy, but still there is no definitive cure in particular for genetic muscle disease. Keeping this in mind, in this article, we will give special consideration to muscle diseases and the use of fetal derived stem cells as a new approach for therapy. Cells of fetal origin, from cord blood to placenta and amniotic fluid, can be easily obtained without ethical concern, expanded and differentiated in culture, and possess immune-modulatory properties. The in vivo approach in animal models can be helpful to study the mechanism underneath the operating principle of the stem cell reservoir, namely the niche, which holds great potential to understand the onset of muscle pathologies.

Muscle pathologies are devastating diseases and nowadays researchers still make efforts to find a cure and not a therapy alone. It has been demonstrated that, after injection in injured or diseased muscle, fetal stem cells act through a mechanism that is mostly due to a bystander effect rather than a direct differentiation. The indirect action is mainly supposed to enhance the production of cytokines, such as VEGF, that stimulate the temporary restoring of the tissue function. To obtain a long lasting action due to efficient cell integration and tissue repopulation, fetal stem cells need to be genetically modified, forcing their differentiation in tissue-specific cells. Nevertheless, the development of safe genetic manipulation methods could make cells of fetal origin appealing for therapeutic application.

Conversely, the long-term positive effect observed using freshly isolated murine amniotic fluid stem (AFS) cells, highlights that they could have a decisive role in replenishing the muscle stem cell niche, which represent the reservoir of cells able to rescue the defect. Indeed, AFS cells are a safe and immune-privileged cell source prone to integrate in muscle tissue. This knowledge opens the challenge to improve the culture protocol for the AFS cells of human origin, which, so far, is still a limit to overcome for future clinical application to treat genetic and non-genetic muscle dysfunctions (dystrophies, skeletal muscle malformations, traumatic injuries).

The heat shock response is an important process in cell maintenance, a coordinated set of mechanisms that recycle damaged proteins, activated by conditions likely to cause that damage. It is not only triggered by heat, but also by a variety of other potentially damaging circumstances such as raised levels of reactive oxygen species released by mitochondria during exercise, the presence of many types of toxic molecules, and so on. Increased heat shock response is involved in some of the methods demonstrated to slow aging in laboratory animals, and a few research teams are working towards ways to trigger it safely as a therapy - though as for the prospect of artificially inducing autophagy, another of the principal cell maintenance processes, there seems to be a lot of early stage research and little concrete progress towards this goal as yet.

Heat shock proteins protect the molecules in all human and animal cells with factors that regulate their production and work as thermostats. In new research [scientists] report for the first time that a protein called translation elongation factor eEF1A1 orchestrates the entire process of the heat shock response. By doing so, eEF1A1 supports overall protein homeostasis inside the cell, ensuring that it functions properly under various internal and external stress conditions. The researchers suggest that this finding could reveal a promising, new drug target for neurodegenerative diseases and cancer.

Heat shock proteins (HSPs) chaperone other proteins, helping them to fold properly and supporting their function. With neurodegenerative diseases, neurons lack enough protective HSPs that insulate them from protein-damaging stress. A hallmark of most neurodegenerative diseases is protein misfolding. If the heat shock response could be restored to its full capacity in aging neurons, then misfolded proteins might fold properly, potentially avoiding or halting progression of diseases such as Alzheimer's, Parkinson's, or amyotrophic lateral sclerosis (ALS). In contrast, many types of cancer cells rely on HSPs to survive. Because high levels of HSPs enable cancer cells to grow and proliferate, depleting these cells of HSPs could sensitize tumors to chemotherapy and radiation therapies. "It's a bit early, but we think that eventually we could design small-molecule activators and inhibitors that tweak the heat shock response. eEF1A1 controls every single step of the heat shock response simultaneously."

The eEF1A protein is expressed in two similar forms, 1 and 2, in different tissues. Motor neurons express form 2 (eEF1A2), which does not support the heat shock response. [Researchers] believe that this is the reason why these specialized cells cannot mount the heat shock response and therefore are particularly vulnerable to stress and diseases such as ALS. The challenge in drug development will be restoring the heat shock response in motor neurons by modulating the activity of eEF1A.

Link: http://www.eurekalert.org/pub_releases/2014-09/nlmc-sit091514.php

Our bones become dangerously weak with advancing age. A lot of this stems from a growing failure of maintenance processes and an imbalance in the bone remodeling that constantly takes place - too much bone removal, and not enough creation. In addition, however, rising levels of the sugary metabolic wastes known as advanced glycation endproducts (AGEs) are also thought to play a role in weakening tissue structures like bone. There are many different types of AGE and not all are relevant to this type of dysfunction: some are short-lived and usually cleared out by the body, and thus their presence indicates a failure in clearance mechanisms or some form of metabolic dysfunction such as diabetes, while others are long-lived and hard for the body to break down, and these build up steadily over time. There is a wide range of current capabilities for measuring and manipulating AGEs: the basic toolkit for working with the most important long-lived human AGE glucosepane is only now being developed, for example.

Here researchers demonstrate an association between one common species of AGE and increasing bone frailty independent of the loss of bone density. Because of the points noted above this is a case of measuring what you can measure with the data to hand - it would be interesting to see this same data with glucosepane levels, as the measured form of AGE may be just a marker rather than a measure of the agent of harm:

Advanced glycation end products (AGE) in bone tissue are associated with impaired biomechanical properties and increased fracture risk. Here we examine whether serum levels of the AGE carboxy-methyl-lysine (CML) are associated with risk of hip fracture. We followed 3373 participants from the Cardiovascular Health Study (age 78 years; range, 68-102 years; 39.8% male) for a median of 9.22 years. Rates of incident hip fracture were calculated by quartiles of baseline CML levels, and hazard ratios were adjusted for covariates associated with hip fracture risk. A subcohort of 1315 participants had bone mineral density (BMD) measurement.

There were 348 hip fractures during follow-up, with incidence rates of hip fracture by CML quartiles of 0.94, 1.34, 1.18, and 1.69 per 100 participant-years. The unadjusted hazard ratio of hip fracture increased with each 1 standard deviation increase (189 ng/mL) of CML level (hazard ratio 1.27). Sequential adjustment for age, gender, race/ethnicity, body mass index (BMI), smoking, alcohol consumption, prevalent coronary heart disease (CHD), energy expenditure, and estimated glomerular filtration rate (based on cystatin C), moderately attenuated the hazard ratio for fracture to 1.17. In the cohort with BMD testing, total hip BMD was not significantly associated with CML levels. We conclude that increasing levels of CML are associated with hip fracture risk in older adults, independent of hip BMD. These results implicate AGE in the pathogenesis of hip fractures.

Link: http://dx.doi.org/10.1002/jbmr.2123

The New Organ initiative aims to greatly speed progress towards the tissue engineering of patient-matched organs as needed: a vision of no more waiting, no more transplant rejection, and a much lower cost of organ renewal, all leading to a far greater number of people who may benefit from these medical advances. The initiative is managed by the Methuselah Foundation, alongside the Mprize for longevity science, early stage investments in tissue engineering companies such as Organovo, and a range of other distinct projects such as sequencing the bowhead whale genome in search of greater insight as to why the range of mammalian longevity is so wide. The Methuselah Foundation was also at one point the home of SENS rejuvenation research programs before they spun off into their own organization, the SENS Research Foundation.

Late last year, the New Organ Liver Prize launched at the World Stem Cell Summit, a $1 million research prize to accelerate the creation of a functional bioengineered replacement liver. Today the Methuselah Foundation announced the first six contending teams. These researchers take a broad range of different approaches to organ tissue engineering, and one thing to bear in mind is that an engineered organ doesn't necessarily have to look like or be structured in the same way as the evolved organ it replaces or augments - it just has to do the same job. Can a patient benefit from scores of tiny liver-like tissue masses sheltered in lymph nodes that perform some of the functions of a damaged liver? Quite possibly.

Initial Six Teams to Compete for New Organ Liver Prize

Great news! Today, we're announcing a major milestone: the first six teams to officially compete for the New Organ Liver Prize. These teams represent scientists from Harvard Medical School, Massachusetts General Hospital, Northwick Park Institute for Medical Research, University College of London, University of Florida, University of Oxford, University of Pittsburgh, and Yokohama City University, and are being led by:

• Dr. Tahera Ansari (Team Hepavive): Pursuing the 'decell-recell' approach to bioengineering a liver.
• Dr. Stephen Badylak (Team Badylak): A pioneer in biologic scaffolds using extracellular matrix.
• Dr. Eric Lagasse (Team Ectogenesis): Grew mini-livers inside the lymph nodes of mice with liver disease.
• Dr. Bryon Petersen (Team Petersen): An authority on the role of hepatic stem cells in liver pathology.
• Dr. Takanori Takebe (Team Organ Creative): Created tiny 'liver buds' that grew and functioned in mice.
• Dr. Basak Uygun (Team HepaTx): First proof-of-principle transplantation of engineered liver grafts.

For full bios, please visit the team page and let us know what you think. Additional teams are also under review and will be announced in a future update. Good luck to all!

New Organ Founder and Methuselah CEO David Gobel: "We are gratified to see the initial interest in the Liver Prize. We are doing this because of the millions who need new organs. Organ disease, and the associated organ shortage, represents one of the greatest medical challenges that can be solved. A scientific foundation has been built over the last 15 years to pursue the vision of organs on demand. It's time for a significant societal commitment to that vision."

Representing distinguished leaders within regenerative medicine, the Founding Fellows of the Tissue Engineering and Regenerative Medicine International Society (TERMIS) remarked: "We strongly and enthusiastically endorse New Organ. Regenerative medicine has made significant advances in the past 15 years and the New Organ Liver Prize represents a golden opportunity for the next leap forward. The public and the medical community will realize a remarkable clinical benefit with the availability of 'off the shelf' whole livers obviating the need for donor organs, and the medical health care system will simultaneously benefit. We hope this forward-looking effort sets the standard that inspires other initiatives to focus all the resources of regenerative medicine on solving major health care challenges."

In a recent newsletter from the Methuselah Foundation there is further news on where things are going with the New Organ Alliance program: there is more of a focus on arms of the US government as a potential source of funds it seems, in addition to building relationships with other groups whose members are working to advance the state of the art in the organ transplant space.

On July 29th, New Organ facilitated a meeting hosted by the Department of Health and Human Services that brought together 10 federal agencies and other stakeholders to explore current efforts in tissue engineering and regenerative medicine (TERM) and the role that incentivized innovation can play in advancing specific challenge targets.

We've also submitted a proposal for a workshop entitled "Building a TERM Roadmap for Organ Disease" to several potential convening partners. The outline proposes a gathering of 75 scientific, government, industry, and philanthropic leaders committed to advancing biomedical engineering and regenerative medicine breakthrough technologies to address organ disease. Participants will define key challenges at the science and system level; identify enabling technologies and quantitative milestones that can be used to inform future research efforts and challenge prize targets; and examine tools and innovation models that can be applied to advance specific goals. Please contact us if you're interested in supporting this effort.

New Organ's close collaboration with the Organ Preservation Alliance (OPA) continues. OPA has proposed key ideas and facilitated input for several Small Business Innovation Research and Small Business Technology Transfer proposals on tissue and organ cryopreservation, currently under review. OPA also secured basic underwriting for the first global "Grand Challenges in Organ Banking" Summit, to be held in Palo Alto, CA in February of 2015. They've also updated draft rules for the proposed Organ Banking Prize: a challenge competition to demonstrate long-term storage of a solid organ and subsequent transplantation into a human or large animal.

Finally, New Organ is considering the possibility of a new Vasculature Prize to stimulate the vascularization of thick, functional tissue. Details on this effort, which is currently being explored in coordination with a federal agency, will be forthcoming as discussions progress.

Heat shock proteins are one portion of an array of cellular housekeeping and repair mechanisms that swing into action in response to circumstances that cause elevated levels of damage to protein machinery: heat, exercise, toxins, and so forth. Some research groups are interested in building therapies based on inducing greater repair activity by raising the levels of heat shock proteins present in cells, but most researchers in the field are gathering data only:

Many members of the heat shock protein family act in unison to refold or degrade misfolded proteins. Some heat shock proteins also directly interfere with apoptosis. These homeostatic functions are especially important in proteinopathic neurodegenerative diseases, in which specific proteins misfold, aggregate, and kill cells through proteotoxic stress. Heat shock protein levels may be increased or decreased in these disorders, with the direction of the response depending on the individual heat shock protein, the disease, cell type, and brain region. Aging is also associated with an accrual of proteotoxic stress and modulates expression of several heat shock proteins.

We speculate that the increase in some heat shock proteins in neurodegenerative conditions may be partly responsible for the slow progression of these disorders, whereas the increase in some heat shock proteins with aging may help delay senescence. The protective nature of many heat shock proteins in experimental models of neurodegeneration supports these hypotheses. Furthermore, some heat shock proteins appear to be expressed at higher levels in longer-lived species. However, increases in heat shock proteins may be insufficient to override overwhelming proteotoxic stress or reverse the course of these conditions, because the expression of several other heat shock proteins and endogenous defense systems is lowered. In this review we describe a number of stress-induced changes in heat shock proteins as a function of age and neurodegenerative pathology, with an emphasis on the heat shock protein 70 (Hsp70) family and the two most common proteinopathic disorders of the brain, Alzheimer's and Parkinson's disease.

Link: http://dx.doi.org/10.1007/s12079-014-0243-9

Here is a little more on some of the initiatives arising in the Bay Area venture and technology communities: the SENS Research Foundation, Calico Labs, and the Palo Alto Longevity Prize. As I pointed out a few days back, it's not just a matter of attracting money, however. The goal of bringing aging under medical control requires spending that money on the right research initiatives:

Some scientists in Palo Alto are offering a $1 million prize to anyone who can end aging. "Based on the rapid rate of biomedical breakthroughs, we believe the question is not if we can crack the aging code, but when will it happen." The Palo Alto Prize is also working with a number of angel investors, venture capital firms, corporate venture arms, institutions and private foundations within Silicon Valley to create health-related incentive prize competitions in the future.

It's a fantastical idea: curing the one thing we will all surely die of if nothing else gets us before that. I sat down with Aubrey de Grey, the chief science officer of the SENS Research Foundation and co-author of "Ending Aging," to discuss this very topic a few days back. According to him, ending aging comes with the promise to not just stop the hands of time, but to actually reverse the clock. We could, according to him, actually choose the age we'd like to exist at for the rest of our (unnatural?) lives. But we are far off from possibly seeing this happen in our lifetime, says de Grey. "With sufficient funding we have a 50/50 chance to getting this all working within the next 25 years, but it could also happen in the next 100," he says.

If you ask Ray Kurzweil, life extension expert, futurist and part-time adviser to Google's somewhat stealth Calico project, we're actually tip-toeing upon the cusp of living forever. "We'll get to a point about 15 years from now where we're adding more than a year every year to your life expectancy," he told the New York Times in early 2013. He also wrote in the book he co-authored with Terry Grossman, M.D., that "Immortality is within our grasp." That's a bit optimistic to de Grey (the two are good friends), but he's not surprised this prize is coming out of Silicon Valley. "Things are changing here first. We have a high density of visionaries who like to think high."

And he believes much of what Kurzweil says is true with the right funding. "Give me large amounts of money to get the research to happen faster," says de Grey. He then points out that Google's Calico funds are virtually unlimited. "Kurzweil asked Larry [Page] and Sergey [Brin] how much he had to work with and they said to let him know when he runs out of money and they'll send more," de Grey tells me.

Link: http://techcrunch.com/2014/09/15/the-1-million-race-for-the-cure-to-end-aging/

The immune system is a very efficient mechanism for certain types of task, if it can just be harnessed and put to work. Left to its own devices throughout most of a life span it can effectively destroy misbehaving cells, remove some types of harmful protein aggregates, and of course defend against self-replicating invaders of many different types. There is more besides, but if you want some biological line item in the body destroyed, then you could do worse than trying to use the immune system as your tool. Given this, it shouldn't be surprising to see that this dawning age of cell biology involves numerous efforts to produce immune therapies: ways to enhance and direct the immune system's actions to treat medical conditions. In the case of Alzheimer's disease immunotherapies gaining the most press in recent years have been those that aim to directly remove the amyloid beta deposits characteristic of the disease. There are a variety of ways in which that can goal might be achieved, such as through the use of a designed compound that is targeted by immune cells and happens to bind to amyloid beta, or by altering immune cells so that they target amyloid directly. The immune system is built around acquisition and management of recognition of protein fragments, so this sort of approach plays to its strengths.

There are other approaches, however. Microglia are specialized immune cells of the central nervous system and are already capable of attacking and removing amyloid beta. Like the rest of the immune system, their activity diminishes with age, however. There are groups working on the foundations of treatments based on the transplant of young microglia into old brains, a potential methodology that is becoming increasingly attractive given recent discoveries about aging and stem cells. Delivering young stem cells into old tissue can have the effect of reversing some of the responses to aging in native stem cells, restoring them to more youthful levels of activity as the environment of signals and proteins levels is temporarily shifted. Will this raise cancer risk due to more cellular activity in a damaged environment, and can that risk be well managed, as it has been in the cell therapy field to date? Time will tell, but I expect so.

Along these lines, the researchers quoted below are working on a way to skip the cell transplants and jump straight to the renewed cellular activity part of the treatment. Ultimately I expect much of the cell therapy field to evolve to use this sort of technique, in which the bulk of the work is direct manipulation or reprogramming of native cells, often by altering the levels of specific proteins present in the tissue environment. Currently such efforts are comparatively crude, but they will improve rapidly in years to come as cell biology becomes less of a jungle and more of a well-mapped city:

Targeted immune booster removes toxic proteins in mouse model of Alzheimer's disease

Using dementia-prone mice, the team gave monthly injections of an immune system booster known as a type B, CpG, oligodeoxynucleotide that specifically binds to Toll-like receptor 9, or TLR9 for short. Activation of TLR9 triggers an immune response. Tests in mice that received the immune system booster injections showed that amyloid plaque formation was 50 percent to 70 percent less than in mice that received no therapy. Reductions in amyloid beta were almost the same for mice treated early on, at age 7 months, and before disease onset, compared to mice treated at age 11 months, which already had mild dementia. Immunostaining tests on brain tissue in treated mice showed one to two times fewer damaged neurons containing disease-related tau aggregates than in untreated mice.

According to researchers, treated mice behaved "almost like normal" mice that never develop Alzheimer's-like symptoms. Unlike vaccines, which try to trigger an antibody-mediated stimulation of the body's immune system, [the] team's new approach attempts to "jump start and rejuvenate" the brain's natural microglial cell repair function. The breakdown of microglial repair - possibly from aging - has been linked for decades to the formation and removal of amyloid plaques and tau tangles in Alzheimer's disease.

Researchers say they selected TLR9 as the immune booster because it was a known stimulant for removing germs. A bacterial cytosine-guanosine sequence, or CpG, such as type B, CpG, oligodeoxynucleotide, was chosen to help activate TLR9 on brain cells because previous testing had shown it to be effective at triggering an immune response in both mice and humans, with very few side effects. "Now that we have shown that we can influence microglial function in Alzheimer's disease, to both prevent and repair tau-damaged brain tissue, then it is highly plausible that our treatment approach could also be applied to other neurodegenerative diseases tied to aging."

Amyloid beta and Tau Alzheimer's Disease Related Pathology is reduced by Toll-like Receptor 9 Stimulation

We have hypothesized that stimulation of the innate immune system via Toll-like receptor 9 (TLR9) agonists, such as type B CpG oligodeoxynucleotides (ODNs), might be an effective way to ameliorate AD related pathology. In the present study, we used the 3xTg-AD mice with both Aβ and tau related pathology. The mice were divided into 2 groups treated from 7 to 20 months of age, prior to onset of pathology and from 11 to 18 months of age, when pathology is already present. We demonstrated that immunomodulatory treatment with CpG ODN reduces both Aβ and tau pathologies, as well as levels of toxic oligomers, in the absence of any apparent inflammatory toxicity, in both animal groups. This pathology reduction is associated with a cognitive rescue in the 3xTg-AD mice.

There is a distinction to be drawn between primary and secondary aging, which at this time we might consider as the division between the things you can't yet do anything about on the one hand versus the things can you do something about on the other. Unfortunately the former are much more of a determinant of aging and age-related disease than the latter. Primary aging consists of damage-generating metabolic processes that we don't yet have the biotechnology to address, as described in the SENS view of aging. Secondary aging consists of the biochemical consequences of becoming fat and sedentary, or at least that is the bulk of it. We live in an age of comparative comfort in which becoming fat and sedentary is increasingly the norm, but that comes with a significant cost to long-term health.

Leptin is produced mainly in the white adipose tissue and emerged as one of the key catabolic regulators of food intake and energy expenditure. During the course of aging characteristic alterations in body weight and body composition in humans and mammals, i.e. middle-aged obesity and aging anorexia and cachexia, suggest age-related regulatory changes in energy balance in the background. Aging has been associated with increased fat mass, central and peripheral leptin resistance as indicated by its failure to reduce food intake, to increase metabolic rate and thereby to induce weight loss.

Leptin resistance is a common feature of aging and obesity (even in the young). The question arises whether aging or fat accumulation plays the primary role in the development of this resistance. The review focuses mainly on mechanisms and development of central leptin resistance. Age-related decline primarily affects the hypermetabolic component of central catabolic leptin actions, while the anorexigenic component is even growing stronger in the late phase of aging. Obesity enhances resistance to leptin at any age, particularly in old rats, calorie-restriction, on the other hand, increases responsiveness to leptin, especially in the oldest age-group. Thus, without obesity, leptin sensitivity appears not to decrease but to increase by old age. Interactions with other substances (e.g. insulin, cholecystokinin, endogenous cannabinoids) and life-style factors (e.g. exercise) in these age-related changes need to be investigated.

Link: http://www.ncbi.nlm.nih.gov/pubmed/25218974

Chronic inflammation increases with aging due to a progressive dysfunction of the immune system: it is overactive but yet ineffective, like a failing engine running hot. Inflammation is a necessary part of the immune response, but if it is turned on all the time it causes all sorts of secondary forms of damage, and is associated with an increased risk of developing many of the common forms of age-related disease. Thus many research groups are interested in finding effective ways to reduce inflammation in aging, either by addressing the root causes of immune dysfunction, or more commonly, and as is the case here, by trying to alter biochemical signals and responses to those root causes:

Aging is associated with an overt inflammatory phenotype and physiological decline. Specialized proresolving lipid mediators (SPMs) are endogenous autacoids that actively promote resolution of inflammation. In this study, we investigated resolution of acute inflammation in aging and the roles of SPMs. Using a self-resolving peritonitis and resolution indices coupled with lipid mediator metabololipidomics, we found that aged mice had both delayed resolution and reduced SPMs.

The SPM precursor docosahexaenoic acid accelerated resolution via increased SPMs and promoted human monocyte reprogramming. In aged mice, novel nanoproresolving medicines carrying aspirin-triggered resolvins D1 and D3 reduced inflammation by promoting efferocytosis. These findings provide evidence for age-dependent resolution pathways in acute inflammation and novel means to activate resolution.

Link: http://dx.doi.org/10.4049/jimmunol.1401313

The cure for aging is often naively envisaged as a single treatment, but this won't be the case in reality. Aging is caused by a variety of distinct parallel processes all running at the same time, producing forms of damage that accumulate in and between cells. These consequences interact with and exacerbate one another in a stochastic fashion to produce quite different individual outcomes within a process that is basically the same for everyone. It is the grand lottery: which vital system will give way first. So aging will be brought under medical control one piece at a time, because dealing with each root cause is a very different type of project, suited to different career specialists and research teams. Research doesn't run to any more of a fixed schedule than the processes of aging, and it's hard to say when and for which of the causes of aging the first effective treatments will emerge. There won't be a single cure for aging, and neither will the treatments making up the first generation rejuvenation toolkit for humans emerge all at once. There will be a period of transition, probably just two decades or so judging from the present pace of development in the life sciences, in which all of the unpleasant physical aspects of being old and causes of mortality will be eliminated slice by slice.

It is obviously the case that medical expenditures per year will drop dramatically when old people are no longer physically old. At present the vast majority of medical expenditures are needed by the old: it is hard and expensive to keep a failing system working when you are not addressing the underlying reasons for its failing state. Physically young people have little need for treatment, and the rejuvenation therapies of tomorrow will be cheap in the long run. Everyone ages for the same root causes, and the damage of aging is the same, and further you could run a good few decades between treatments with few consequences. Thus treatments will largely be mass-produced infusions, administered by bored clinicians who have to do little more than push a button. That is not a recipe for great expense: all the really expensive processes in medicine are expensive because they require a lot of time and attention from highly trained individuals, but that will not be the case for rejuvenation therapies that work by repairing the underlying cellular and molecular damage that causes aging.

Equally it is obviously the case that if you live for thousands of years as a physically young individual your lifetime medical expenditures for insurance alone, while small year by year, will eventually outweigh the expense of a short aging life span of a century. But so what? You don't hear people complaining about lifetime costs of food going up if they were to live longer. Life is opportunity, a process. You earn, you spend. It only stops being that way when you become too sick to earn - which is for most people only the case due to aging.

In the transitional period between today and a future in which the last piece of the rejuvenation toolkit is in place, piecemeal progress will produce interesting and sometimes counterintuitive effects on medical costs. To my eyes living an extra year without suffering an pain is an opportunity, and if it means you spend more to do it, so be it. You could always choose the alternative. Never forget that we live lives of privilege in comparison to the billions who have gone before, people who didn't have the luxury of the medicine we have now, never mind the medicine we might have tomorrow.

Sadly much of the public discussion of medical costs is distorted by the present baroque system of entitlements and regulation. Few people in wealthier regions of the world pay for medical care directly, money often comes from government funds, and thus the incentives are aligned against progress and efficiency. Prices have no connection to reality, competition is muted, and providers have little direct incentive to deliver good services, or improve upon their offerings. Everyone involved recognizes that the system is terrible, but their short-term incentives are to go along with it, even as it becomes progressively worse and more harmful to progress and quality over time. This is largely why there is a lot of attention paid to measures of life time medical costs, as there are people who want that number to be lower because it is paid for by entitlements, or because it is inflated by a broken system of regulation that stifles price competition, and so forth.

Here is a fairly coherent paper on the subject of cost and piecemeal medical progress. It is useful from the point of view of forming a mental model of what is likely to happen in the years ahead as aging is brought under control one slice at a time. Many of us will live through the transition decades from a point of no treatments for the causes of aging to a point of comprehensive rejuvenation therapies, so it is perhaps worth thinking ahead just a little:

Disease Prevention: Saving Lives or Reducing Health Care Costs?

Disease prevention has been claimed to reduce health care costs. However, preventing lethal diseases increases life expectancy and, thereby, indirectly increases the demand for health care. Previous studies have argued that on balance preventing diseases that reduce longevity increases health care costs while preventing non-fatal diseases could lead to health care savings. The objective of this research is to investigate if disease prevention could result in both increased longevity and lower lifetime health care costs.

Mortality rates for Netherlands in 2009 were used to construct cause-deleted life tables. Data originating from the Dutch Costs of Illness study was incorporated in order to estimate lifetime health care costs in the absence of selected disease categories. We took into account that for most diseases health care expenditures are concentrated in the last year of life.

Elimination of diseases that reduce life expectancy considerably increase lifetime health care costs. Exemplary are neoplasms that, when eliminated would increase both life expectancy and lifetime health care spending with roughly 5% for men and women. Costs savings are incurred when prevention has only a small effect on longevity such as in the case of mental and behavioural disorders. Diseases of the circulatory system stand out as their elimination would increase life expectancy while reducing health care spending.

The stronger the negative impact of a disease on longevity, the higher health care costs would be after elimination. Successful treatment of fatal diseases leaves less room for longevity gains due to effective prevention but more room for health care savings.

There is a growing diversity of views in the Alzheimer's research community regarding mechanisms and future directions, which is probably to be expected given the slow path to results on the consensus approach of removing amyloid β. Here is a representative opinion piece:

Two decades have passed since the discovery of the first proteases that degrade the amyloid β-protein (Aβ), the primary constituent of the amyloid plaques that characterize Alzheimer disease (AD). While significant progress has been made, this is an appropriate juncture to reflect on what has been accomplished and ask which research directions are most likely to bear fruit going forward. Herein, I argue that a renewed focus on intracellular Aβ-degrading proteases (AβDPs) is a highly promising direction for future studies, one that is not only likely to advance our understanding of the fundamental molecular pathogenesis of AD, but also to critically inform the development of effective therapies for use clinically.

To date, most studies of AβDPs have focused predominantly on proteases that act extracellularly. This is not surprising - Aβ is, after all, a secreted peptide, and amyloid plaques form extracellularly. However, there is a growing body of evidence implicating intracellular pools of Aβ in the pathogenesis of AD. Generally speaking, it has been challenging to study specific pools of Aβ in conventional animal models of AD, since most models rely upon overexpression of the β-amyloid precursor protein (APP), which necessarily increases the levels of all pools of Aβ simultaneously. The study of AβDPs, by contrast, offers a unique window into the pathogenic role of Aβ, in no small part because individual AβDPs have unique subcellular localizations and pH profiles, which can be exploited to selectively target different pools of Aβ (e.g., extracellular, lysosomal, etc.). This can be readily achieved by overexpression, genetic deletion or pharmacological manipulation of appropriate AβDPs, either alone or in tandem with APP overexpression.

In conclusion, there is a compelling theoretical and empirical rationale for the field to undertake a renewed focus on intracellular AβDPs. The knowledge we can expect to derive from the study of extracellular AβDPs appears to be, at best, approaching an asymptote and, at worst, revealing that extracellular pools of Aβ may not be involved in the pathogenesis of AD to the extent so widely assumed for so long. The study of intracellular AβDPs, by contrast, seems poised to yield insights into questions that are not merely academic or theoretic, but highly practical - for example, the relative merits of immunotherapies, which only target extracellular Aβ, versus secretase inhibitors or modulators, which affect intracellular Aβ as well. Considering the growing interpersonal, financial and societal impact of AD, and the current lack of therapies, it is wise to pursue any and all avenues that may lead to effective treatments, and the study of intracellular AβDPs seems an especially promising direction for future investigation.

Link: http://journal.frontiersin.org/Journal/10.3389/fnagi.2014.00229/full

SkQ1 is a mitochondrially targeted antioxidant, and there is evidence to show that it can modestly extend life in mice. Mitochondria are important in the aging process, and one of the ways in which they interact with surrounding cell biology is by generating damaging reactive oxygen species (ROS). Too much ROS creation can harm a cell, a state called oxidative stress. Just a little more than usual can be beneficial, as the cell reacts with increased housekeeping for a net benefit - this is probably one of the mechanisms by which exercise improves health, for example.

This signaling is a parallel mechanism to the most important harm likely caused by mitochondrial ROS, however, which is to damage mitochondrial DNA at their point of origin. This can lead to all sorts of persistent dysfunction in a small population of cells, which export harmful molecules to surrounding tissues. Mitochondrial antioxidants probably produce benefits to long term health by reducing the rate of this mitochondrial damage, but that isn't completely certain at this point because of the ROS signaling to other important aspects of cell metabolism. Biology is complex, and as for all small effects on longevity, the actual mechanism could be any one of a number of things.

So these researchers are making use of SkQ1 as a way to better identify what exactly it is that changes in response to ROS levels, with a focus on dysfunction in blood vessel wall tissue (the vascular endothelium) that leads to age-related conditions such as atherosclerosis:

Cardiovascular diseases (CVDs) have a great impact in morbidity and mortality all over the world. One of the major risk factors for development of CVDs is aging. In recent years a vast amount of information has been obtained pointing to a crucial role of endothelium in the development of age-related CVDs. A healthy endothelium fulfils numerous functions in vascular biology including inflammatory responses, as well as vascular tone and permeability. Endothelial dysfunction is typical for many pathological conditions including atherosclerosis, type I and II diabetes, inflammatory processes, and aging. Aging is associated with increased oxidative stress and a proinflammatory endothelial cell phenotype. Excessive or prolonged endothelium activation due to the action of the proinflammatory cytokines underlies endothelium dysfunction.

The "inflammaging theory" postulates that aging phenotype can be explained by an imbalance between inflammatory and antiinflammatory networks, which results in low-grade chronic proinflammatory status. The inflammatory vascular reactions are mediated by complex interactions between circulating leukocytes and the endothelium. Proinflammatory cytokines including TNF increase expression of cell adhesion molecules (CAMs) and leukocyte adhesion followed by invasion through the vascular endothelium.

We have shown that old mice have increased levels of the vascular inflammatory markers in plasma (TNF and IL-6) and in aorta tissues (ICAM1, VCAM, TNF, and MCP1). A significant body of evidence indicates that mitochondrial dysfunction and excessive mtROS production are involved in vascular inflammation and age-related CVDs. Long-term administration of the mitochondria-targeted antioxidant SkQ1 to old mice completely prevented the age-related increase in aortic ICAM1 mRNA expression and attenuated the increase in expression of the other proinflammatory genes. However, SkQ1 did not affect circulatory TNF and IL-6 levels, thus indicating that mtROS are critical for inflammatory signaling downstream from cytokine expression.

Increased expression of CAMs is implicated in early steps of atherosclerosis. The suppression of leukocyte adhesion to endothelial cells by reducing CAM expression prevented development of atherosclerosis and had positive effects on many aseptic inflammatory pathologies. According to our data, mtROS scavenging may attenuate age-related increase in CAM expression and related endothelial dysfunction.

Link: http://www.impactaging.com/papers/v6/n8/full/100685.html

Most research into intervening in the aging process is focused on slowing aging. It is a search for ways to safely alter metabolism in order to reduce the rate at which unrepaired cellular and molecular damage accumulates. This damage is a side-effect of the normal operation of metabolism, and it in turn leads to chains of further changes and damage, and all of that together causes aging - a progressive dysfunction and rising risk of catastrophic system failure in organs and tissues based on growing levels of damage. Working on ways to slow aging is the dominant strategy in the mainstream not because it is the best way forward, but rather because it involves exactly the same research process as is employed in the established drug development pipeline: researchers work on explaining how a tiny slice of metabolism works, find a way to alter it in the existing drug library or develop a new drug for that purpose, and then see if it has a positive enough outcome to move towards trials.

Based on results to date it is highly unlikely that this convenient approach will do much more than add knowledge and consume funding. It is not going to result in ways to greatly extend human life spans in the near future: a decade and at least a billion dollars spent on research of the molecular biology of life extension via calorie restriction has demonstrated just how hard it is to use drugs to replicate even this easily replicated and very well studied method. Despite the time and effort calorie restriction is still not yet fully understood, and there is no reliable drug candidate to mimic even a fraction of its effects on health and longevity at this point. Metabolism is exceedingly complex, and so is the calorie restriction response. Even if a perfect calorie restriction mimetic drug turned up tomorrow, which it won't, then would this drug help old people? From the point of view of extending healthy life, not really. There is little use in a drug that slows down the rate at which damage accrues if you are already elderly, frail, and extremely damaged.

The research community should be focused instead on rejuvenation. Repair the damage in the metabolism we have and restore it to the known good working state it exhibits in youth. Don't slow down the damage, try to fix it: help the elderly and frail by restoring youthful function to their tissues. Metabolism complex and changing it would be enormously challenging, so don't change it. The damage that accumulates in and between our cells due to the operation of metabolism is very simple by comparison. Its effects, the aging process, are only complex because we are complex: simple damage in a complex system produces complex results. Consider this: no-one would rebuild an engine to make it work better when it is very rusted, as it is obviously better to remove the rust and rust-proof that machinery. The former option is enormously complex and ultimately doomed to produce only marginal benefits, while the latter is much simpler and restores the engine to an earlier level of function and a longer expected working life span. Rust is simple, engines are complex.

There is far too much engine rebuilding going on in medical research today, and not enough of a focus on the rust. This must change if we are to see meaningful progress towards bringing aging under medical control in our lifetimes. There is a lot of inertia in the present research community and its establishments, however. I expect to see the drug discovery and metabolic alteration approach to slowing aging continue on its largely futile way for decades, even as the better approach to treating aging gathers support and overtakes it. One of the obvious targets in addition to mimicking the benefits of calorie restriction is to try to enhance cellular housekeeping processes responsible for repairing many forms of molecular and cellular damage. Evidence strongly suggests that many of the ways demonstrated to slow aging in laboratory animals are at least partially due to increased levels of cellular housekeeping. So research results like this paper below appear regularly these days:

Inducing Muscle Heat Shock Protein 70 Improves Insulin Sensitivity and Muscular Performance in Aged Mice

Heat shock proteins (HSPs), named after the observed up-regulation following heat shock, are a family of protective chaperone proteins that maintain normal cellular function when cells are under various stressors. Aging is associated with generally reduced levels of heat shock protein 70 (HSP70), which plays a conserved role in cellular homeostasis in all species. Genetic manipulation to increase generalized HSP70 levels has improved lifespan in invertebrate models, and thus it is the focus of our studies. It has been demonstrated that aged muscle tissue does not increase HSP production in adaptation to normal exercise; however, increases in muscle mass and function can be generated by pharmacological induction or overexpression of HSP70.

Aged C57/BL6 mice acclimated to a western diet were randomized into: geranylgeranylacetone (GGA)-treated (100mg/kg/d), biweekly heat therapy (HT), or control. The GGA and HT are well-known pharmacological and environmental inducers of HSP70, respectively.

HT mice had more than threefold, and GGA mice had a twofold greater HSP70 compared with control. Despite comparable body compositions, both treatment groups had significantly better insulin sensitivity and insulin signaling capacity. Compared with baseline, HT mice ran 23% longer than at study start, which was significantly more than GGA or control. Hanging ability (muscular endurance) also tended to be best preserved in HT mice. Muscle power, contractile force, capillary perfusion, and innervation were not different. Heat treatment has a clear benefit on muscular endurance, whereas HT and GGA both improved insulin sensitivity. Different effects may relate to muscle HSP70 levels. An HSP induction could be a promising approach for improving health span in the aged mice.

Will useful therapies will result from this sort of thing? Likely so: some interesting and fairly dramatic results have been obtained by boosting the operation of cellular housekeeping mechanisms over the years. But this isn't the road to bringing aging under medical control and greatly extending healthy life spans, for the reasons noted above. Slowing aging isn't good enough, being only an expensive path to poor results in terms of healthy years of life gained and the ability to rejuvenate the old.

Induced pluripotent stem (iPS) cells have been moving towards practical use in medicine quite rapidly since their discovery eight years ago, and here researchers will run a first test in a human patient:

A Japanese patient with a debilitating eye disease is about to become the first person to be treated with induced pluripotent stem cells. Unlike embryonic stem cells, iPS cells are produced from adult cells, so they can be genetically tailored to each recipient. They are capable of becoming any cell type in the body, and have the potential to treat a wide range of diseases. [The] trial will be the first opportunity for the technology to prove its clinical value.

In age-related macular degeneration, extra blood vessels form in the eye, destabilizing a supportive base layer of the retina known as the retinal pigment epithelium. This results in the loss of the light-sensitive photoreceptors that are anchored in the epithelium, and often leads to blindness. [Researchers] took skin cells from people with the disease and converted them to iPS cells. [They] then coaxed these cells to become retinal pigment epithelium cells, and then to grow into thin sheets that can be transplanted to the damaged retina.

[Researchers] have shown in monkey studies that iPS cells generated from the recipients' own cells do not provoke an immune reaction that causes them to be rejected. There have been concerns that iPS cells could cause tumours, but [the] team has found that to be unlikely in mice and monkeys. To counter further fears that the process of producing iPS cells could cause dangerous mutations, [the] team performed additional tests of genetic stability. Guidelines covering the clinical use of stem cells require researchers to report safety testing on the cells before conducting transplants.

Link: http://www.nature.com/news/next-generation-stem-cells-cleared-for-human-trial-1.15897

Type 2 diabetes is for the majority of sufferers a self-inflicted problem. It is usually a consequence of becoming fat and sedentary: if you avoid both of those, then it is unlikely to happen to you. Even in the comparatively late stages type 2 diabetes can be reversed by nothing more than increasingly dramatic diet alterations and consequent loss of excess fat tissue. Here researchers show that the progressive dysfunction leading to diabetes is also raising cancer risk:

Prediabetes is a general term that refers to an intermediate stage between normoglycaemia and overt diabetes mellitus. It includes individuals with impaired glucose tolerance (IGT), impaired fasting glucose (IFG) or a combination of the two. Results to date from prospective cohort studies investigating the link between prediabetes and risk of cancer are controversial. Thus in this new study, the authors did a meta-analysis to evaluate the risk of cancer in association with the impaired fasting glucose and impaired glucose tolerance population.

The researchers found that prediabetes was associated with a 15% increased risk of cancer overall. The results were consistent across cancer endpoint, age, duration of follow-up and ethnicity. There was no significant difference for the risk of cancer with different definitions of prediabetes (IGT or IFG). The authors note that it has been reported that obesity, an important risk factor for diabetes, is also linked to the development of cancer. For this reason, they performed a sensitivity analysis that only included studies that adjusted for BMI in the meta-analysis. They say: "We found that, after controlling for BMI, the presence of prediabetes remained associated with an increased risk of cancer of 22%."

The authors say several possible mechanisms could explain the results. First, chronic hyperglycaemia and its related conditions, such as chronic oxidative stress and the accumulation of advanced glycated endproducts (that are made in conditions of excessively high blood sugar) may act as carcinogenic factors. Second, increased insulin resistance leads to increased insulin secretion, which can in turn allow cancer cells to grow and divide. Third, there could be genetic mutations which predispose individuals to an increased risk of cancer, with one recent study showing that a malfunction in a tumour suppressor gene exposed individuals to increased risk of both cancer and prediabetes.

Link: http://www.sciencedaily.com/releases/2014/09/140908204706.htm

There is an art to writing press releases for large joint ventures, and one part of it involves setting out the largest number you can vaguely justify in terms of dollars that will be spent in the future. You can look at the recent joint announcement of the Calico / Abbvie collaboration on longevity science as a good example of the type: of the $1.5 billion touted everything above the first $100-200 million is basically fuzzy money, a matter of conditional future outlays, a hopeful position statement made far in advance rather than any sort of real commitment. Large numbers are rolled out in this way because the declaration helps the companies involved: it produces free advertising in the media circus, aids in gaining political leverage for tax advantages, and so forth.

But still, that first $100 million is a large chunk of change in the aging research world. The annual budget of one of the noted Buck Institute for Research on Aging is a little more than $30 million, and the National Institute on Aging (NIA) budget is $1.2 billion for 2014. If we take the usual ballpark guesstimate of public funding as about a third of overall research in this field in the US, that gives some idea of the scale of things.

Here is an opinion that I've heard expressed of late: why bother with all the effort and grassroots fundraising and advocacy to fund the rejuvenation biotechnology work at the SENS Research Foundation now that Google is throwing hundreds of millions of dollars into the aging science ring? This sounds like plain old lazy thinking to me. Not all research expenditure is the same, and not everyone who talks about tackling aging is in fact performing useful work likely to have much of an impact on human life spans in the near future. Consider that the organizations coordinating SENS research on repair of the causes of aging have been bootstrapped on philanthropic donations for a decade now, and in an environment in which ten times the amount Google is likely to spend on aging research over the next few years has been expended by the NIA alone - and that is each and every year. The question could just as well be "why bother with SENS when the NIA is spending a river of dollars?"

"But look at the Calico website, right they they say they are tackling aging. That is new and different." That too is something I have heard. But this is really no different from the messaging you'll find at the NIA:

The NIA has been at the forefront of the Nation's research activities dedicated to understanding the nature of aging, supporting the health and well being of older adults, and extending healthy, active years of life for more people.

This story really isn't about dollars. It is about methodology. If everything could be solved by simply ensuring a large inflow of dollars, then the world be a much simpler and possibly much better place as a result. But how those dollars are spent matters far more than the amount. For all the rhetoric and grand budget of the NIA, outside of some cancer and stem cell research, I would be extremely surprised to learn than more than a few million each year out of that vast flow of money actually funds any of the remaining SENS-like lines of research capable of contributing meaningfully to extended healthy life spans. The same is true of the private research and development institutions. The mainstream simply isn't undertaking the needed work, and that is why we need a funded SENS research program.

SENS exists as a disruptive innovation in aging research: it is a conceptually novel way of approaching aging and its treatment, a better approach to using existing capabilities and knowledge to produce longer, healthier lives at the end of the research process. It focuses on repair and root causes, and will ultimately overtake the research community to replace the old way of doing things that is consuming vast sums to no good end. SENS will achieve this goal by producing meaningful results on measures of health and aging where other approaches do not, and at a fraction of the cost; that is the reasonable expectation based on the scientific underpinnings, to my eyes, and to the eyes of a significant minority in the research community. Disruption is a bootstrapping process, a start from nothing but an idea, followed by incremental growth, proof, and persuasion until everyone admits you were right all along and switches to do things your way. This happens constantly in the technology business, and also elsewhere in the sciences, albeit on a slower timeframe because the issues at hand are usually far more complex and - in the case of medicine - far more bound up in regulation.

The deployment of large sums of money in any industry is an extremely conservative business. It is very, very rare for large institutions to head off in new radical directions - or indeed to intentionally take any sort of similarly large risk. They follow and reinforce the mainstream. At this time in aging research the mainstream is still characterized by the NIA and Big Pharma approaches to age-related disease: only treat the complex, late stages of aging; only treat named diseases of aging; only work on proximate causes of dysfunction rather than root causes; only try to repair harm after the fact rather than prevent it; attempt to alter our highly complex metabolism to slow aging rather than repair the damage of aging to reverse aging. The disruptive adoption of a SENS approach of prevention and rejuvenation of aging and age-related disease has not yet happened, for all that it is on the way.

So when you see the emergence of an organization like Calico, well-funded, and headed by establishment figures from the research mainstream, then the odds are good that the organization will prove to be a continuation of the present work of the mainstream. It will most likely start out as a Big Pharma operation trying to make age-slowing candidate drugs work - akin to more of the same failed, expensive work on sirtuins and other aspects of the calorie restriction response, and similar lines of investigation. They are not going to work on SENS-like approaches for all the same reasons that other large groups are not yet doing so. It isn't the mainstream yet, the disruption hasn't happened yet.

As a part of the mainstream, Calico, like all the other existing large entities funding research, can be disrupted in the future, however. They will turn to devote funds to new methodologies demonstrated to be far more effective and cost-effective than the existing very poor paths forward in drug development to slow aging. The best way to have these organizations devote significant funding to rejuvenation research after the SENS model is for the SENS Research Foundation and related groups to be funded well enough over the next few years to be able to prove their case: to make one or more of the detailed proposed treatments work, and show that they results are far better and far less costly than the present dominant approaches to aging. With money that won't be too challenging, but "with money" is the hard part.

That is why we raise funds for SENS research: to ensure that it is adopted as soon as possible by the mainstream, and that in turn is because to our eyes the diverse evidence from the research community paints a very convincing picture that SENS is the best shot at actually defeating aging. There is nothing novel in any of this. This is how change happens in every field: it is an incremental process of persuasion and gathering evidence, it never goes fast enough, and at the start it is always a matter of raising a few dollars in the middle of a river of money heading towards the old, far worse, mainstream ways of doing things.

The cancer research community has developed a wide range of mechanisms that can be used to more accurately target a delivered therapy to specific locations in the body or specific types of cell. Many of these methods are largely independent of the payload being delivered, so why not use them to improve the effectiveness of stem cell treatments?

[Researchers] infused antibody-studded iron nanoparticles into the bloodstream to treat heart attack damage. The combined nanoparticle enabled precise localization of the body's own stem cells to the injured heart muscle. The study, which focused on laboratory rats, [addresses] a central challenge in stem cell therapeutics: how to achieve targeted interactions between stem cells and injured cells. Although stem cells can be a potent weapon in the fight against certain diseases, simply infusing a patient with stem cells is no guarantee the stem cells will be able to travel to the injured area and work collaboratively with the cells already there. "Infusing stem cells into arteries in order to regenerate injured heart muscle can be inefficient. Because the heart is continuously pumping, the stem cells can be pushed out of the heart chamber before they even get a chance to begin to heal the injury."

In an attempt to target healing stem cells to the site of the injury, researchers coated iron nanoparticles with two kinds of antibodies, proteins that recognize and bind specifically to stem cells and to injured cells in the body. After the nanoparticles were infused into the bloodstream, they successfully tracked to the injured area and initiated healing. "The result is a kind of molecular matchmaking. Through magnetic resonance imaging, we were able to see the iron-tagged cells traveling to the site of injury where the healing could begin. Furthermore, targeting was enhanced even further by placing a magnet above the injured heart."

Link: http://www.eurekalert.org/pub_releases/2014-09/cmc-cai090814.php

Here is a little more context for yesterday's launch of the Palo Alto Longevity Prize. Like myself all of the regular readers of Fight Aging! had an awakening at some point in time, a moment in which we suddenly realized that aging could and should be cured with future advances in medicine. With progress in advocacy and research a larger number of fellow travelers will join us, ever more of whom will possess the means to make large strides ahead and the vision to realize that we are entering an age in which wealth can purchase time and an end to suffering if wisely spent:

"We spend more than $2 trillion per year on health care and do a pretty good job helping people live longer, but ultimately you still die," says Dr. Joon Yun, a doctor, investor and the main backer of the prize. "The way we are innovating in health care addresses the consequences of aging, but we're not addressing the root cause. So as a result of that, we ultimately can't save people. Your intrinsic homeostasis erodes at 40. Hangovers that used to last a day now last three days. Coughs drag on for months. You come off a roller coaster, and you feel awful, because you can't self center and your blood vessels don't recalibrate fast enough." The goal with the prize would be to find a way to reverse these degrading processes and return the body to a more youthful state.

Yun says his father-in-law recently passed away at the age of 68, and this, combined with conversations with his friends, inspired him to tackle aging. "I come from an old school Korean farming family where you were just expected to till the farms and die. There was something grand and dignified in that. But after my wife's father died of something pretty preventable, I asked myself, 'Why am I waiting to do something about this?'"

"Based on the rapid rate of biomedical breakthroughs, we believe the question is not if we can crack the aging code, but when will it happen," says Keith Powers, the producer of the prize group. Yun has set aside a large chunk of money to fund not just this initial prize but subsequent attempts at solving the aging puzzle. "The prize is winnable, but I don't think we will hit a grand slam on the first one," he says. "I expect to be writing lots of checks."

Link: http://www.businessweek.com/articles/2014-09-09/silicon-valley-investor-backs-1-million-longevity-prize

In recent years a growing network of supporters of longevity science has emerged in the Bay Area entrepreneurial and venture community. It is a highly networked environment, and visible signs such as the Health Extension meetings are really just the tiniest tip of the iceberg. It is no accident that the SENS Research Foundation and its coordination of rejuvenation biotechnology research is based in the Bay Area: venture capitalist turned philanthropist Peter Thiel was one of the early high net worth donors to SENS research, and folk in the software engineering community have always made up a sizable fraction of the donors and supporters of first the Methuselah Foundation and then the SENS Research Foundation after it was spun off as an independent organization. Medicine is engineering, and aging is an engineering problem asking for a solution: this is something that is perhaps more clearly visible to people who have written code for a living at some point in their careers.

Which is not to skip over the fact that there is a thriving medical biotech venture community in that part of the world as well. It just doesn't get as much press, and the people involved have historically tended to be just as conservative and quiet about the prospects for treating aging as the rest of the life science research community. Sometimes change must come from the outside, which is exactly what happened in this case.

Before funding SENS research the Methuselah Foundation initially focused entirely on the Mprize: a research prize aiming to spur the research community into doing more work and speaking more publicly about efforts to extend healthy life span and produce rejuvenation in the old. At the time the prize launched, the silence of the research community and their unwillingness to push the boundaries, educate the public, and get on with treating aging was a real issue and a cultural roadblock to progress. That this state of affairs has changed dramatically is due in no small part to the efforts of the Methuselah Foundation and the networking that took place as a direct consequence of the existence of a research prize.

The prize continued over the years, and still runs today to encourage researchers to put in more work on extending healthy life spans in mammals. In a different world the Mprize might still be generating meaningful levels of press and attention even now, but it was hampered by an unfortunate happenstance of research, in that one of the first methods discovered to extend life span in mice was so effective that it has yet to be surpassed or even matched, more than ten years later. It is hard to have a contest when there are no new winners emerging on a short enough time frame to interest the public. For my money, I'd wager that producing mice that live longer than growth hormone receptor knockout mutants won't happen without the implementation of SENS rejuvenation treatments, ways to extend life by repairing damage (and thus reversing aging) rather than slowing the progression of damage (and thus slowing aging).

Nonetheless, the Mprize was a successful vehicle to produce change in the aging research community: this is the interesting thing about research prizes, that they don't have to achieve their stated competitive goals or even look like they worked as a contest in order to produce the desired outcome, a revival of effort in a specific field of research and development. Success is all about networking and attention, which in turn leads to fundraising and greater activity where before there was little. The Methuselah Foundation continues to run the Mprize, but is presently more focused on speeding up organ tissue engineering through the New Organ Prize: working to ensure that patient-specific organs built from stem cells exist soon rather than twenty years to thirty years from now.

So perhaps this leaves a space for a next generation of research prizes in longevity science, and it turns out that folk in the Bay Area venture community think that is the case - and if there is one thing that these people are good at, it is networking, the lifeblood of a research prize initiative. So take a little time to peruse the Palo Alto Longevity Prize and note the panoply of advisors and research teams signed up to compete. The actual details of the prize are of technical interest, especially since they lean in the direction of supporting repair over slowing aging, but they are far less important than what is taking place behind the scenes as a result of this initiative:

Palo Alto Longevity Prize

Just six decades after Orville and Wilbur Wright launched the aviation age, President Kennedy pronounced a moonshot: fly people to the moon and back. Eight years later, the mission was accomplished. Now, six decades after James Watson and Francis Crick discovered the code of life, it is time to embark on another historic mission: hack the code of life and cure aging.

The Palo Alto Longevity Prize (the "Prize") is a $1 million life science competition dedicated to ending aging. Ours is one of a growing number of initiatives around the world pursuing this goal - the more shots on goal the better. Through an incentive prize, our specific aim is to nurture innovations that end aging by restoring the body's homeostatic capacity and promoting the extension of a sustained and healthy lifespan.

There are two prizes available and teams may compete for one or both prizes:

1) A $500,000 Homeostatic Capacity Prize will be awarded to the first team to demonstrate that it can restore homeostatic capacity (using heart rate variability as the surrogate measure) of an aging reference mammal to that of a young adult.

2) A $500,000 Longevity Demonstration Prize will be awarded to the first team that can extend the lifespan of its reference mammal by 50% of acceptable published norms. Demonstration must use an approach that restores homeostatic capacity to increase lifespan.

To enable a rapid commercial path forward for the innovations, the sponsor of the Prize will be contributing an existing pool of relevant intellectual property to the Prize effort.

One small step at a time, researchers continue to improve in their attempts to build patient-matched organs for transplantation. An organ constructed with the patient's own cells should have a much lower chance of transplant rejection, and greater odds of success overall. Here work focuses on assembling the necessary techniques to make xenotransplantation feasible:

"Until now, lab-built kidneys have been rodent-sized and have functioned for only one or two hours after transplantation because blood clots developed. In our proof-of-concept study, the vessels in a human-sized pig kidney remained open during a four-hour testing period. We are now conducting a longer-term study to determine how long flow can be maintained." If proven successful, the new method to more effectively coat the vessels with cells (endothelial) that keep blood flowing smoothly, could potentially be applied to other complex organs that scientists are working to engineer, including the liver and pancreas.

The current research is part of a long-term project to use pig kidneys to make support structures known as "scaffolds" that could potentially be used to build replacement kidneys for human patients with end-stage renal disease. Scientists first remove all animal cells from the organ - leaving only the organ structure or "skeleton." A patient's own cells would then be placed in the scaffold, making an organ that the patient theoretically would not reject.

The cell removal process leaves behind an intact network of blood vessels that can potentially supply the new organ with oxygen. However, scientists working to repopulate kidney scaffolds with cells have had problems coating the vessels and severe clotting has generally occurred within a few hours after transplantation.

The [scientists] took a two-pronged approach to address this problem. First, they evaluated four different methods of introducing new cells into the main vessels of the kidney scaffold. They found that a combination of infusing cells with a syringe, followed by a period of pumping cells through the vessels at increasing flow rates, was most effective. Next, the research team coated the scaffold's vessels with an antibody designed to make them more "sticky" and to bind endothelial cells. Laboratory and imaging studies - as well as tests of blood flow in the lab - showed that cell coverage of the vessels was sufficient to support blood flow through the entire kidney scaffold.

Link: http://www.eurekalert.org/pub_releases/2014-09/wfbm-mri090814.php

Intestinal function is especially important in fly aging, and of late a number of ways of extending life in fly studies have involved interventions targeted to intestinal tissue, including altered levels of PGC-1 and improved stem cell function via altered insulin signaling. Further, it was recently established that INDY, an early longevity gene discovery in flies, also works via improved intestinal stem cell function.

The gene AMPK turns up in many studies of methods known to slow aging in laboratory species: you might peruse the Fight Aging! archives for a fair sized selection. AMPK is centrally placed in numerous core mechanisms of metabolism that are altered by these existing ways to slow aging, but it is especially important as an activator of the cellular housekeeping processes of autophagy. More autophagy generally leads to longer life in animal studies for all of the obvious reasons: less damage means less dysfunction. Here researchers show that increased AMPK levels in fly intestines extend healthy life:

Working with fruit flies, the life scientists activated a gene called AMPK that is a key energy sensor in cells; it gets activated when cellular energy levels are low. Increasing the amount of AMPK in fruit flies' intestines increased their lifespans by about 30 percent - to roughly eight weeks from the typical six - and the flies stayed healthier longer as well. "We have shown that when we activate the gene in the intestine or the nervous system, we see the aging process is slowed beyond the organ system in which the gene is activated."

The findings are important because extending the healthy life of humans would presumably require protecting many of the body's organ systems from the ravages of aging - but delivering anti-aging treatments to the brain or other key organs could prove technically difficult. The study suggests that activating AMPK in a more accessible organ such as the intestine, for example, could ultimately slow the aging process throughout the entire body, including the brain. Humans have AMPK, but it is usually not activated at a high level.

"Instead of studying the diseases of aging - Parkinson's disease, Alzheimer's disease, cancer, stroke, cardiovascular disease, diabetes - one by one, we believe it may be possible to intervene in the aging process and delay the onset of many of these diseases. We are not there yet, and it could, of course, take many years, but that is our goal and we think it is realistic. The ultimate aim of our research is to promote healthy aging in people."

"A really interesting finding was when [we] activated AMPK in the nervous system, he saw evidence of increased levels of autophagy in not only the brain, but also in the intestine. And vice versa: Activating AMPK in the intestine produced increased levels of autophagy in the brain - and perhaps elsewhere, too." Many neurodegenerative diseases, including both Alzheimer's and Parkinson's, are associated with the accumulation of protein aggregates, a type of cellular garbage, in the brain. "[We] moved beyond correlation and established causality. [We] showed that the activation of autophagy was both necessary to see the anti-aging effects and sufficient; that [we] could bypass AMPK and directly target autophagy."

Link: http://newsroom.ucla.edu/releases/ucla-biologists-delay-the-aging-process-by-remote-control

Stem cell activity progressively declines with age, leading to lapsed tissue maintenance and increasing dysfunction and frailty. The role of stem cells is after all to replenish tissues, to provide a supply of fresh cells to replace those lost by the normal turnover, as well as issuing signals that spur other cell types into repair and regenerative efforts. Why does stem cell activity diminish? It is most likely an evolved reaction to rising levels of cellular damage, and serves to reduce the risk of cancer: our long life span in comparison to other primates is a balancing act between death by cancer on the one hand and death by tissue failure on the other. This in turn may have came about due to the development of greater intelligence and culture in our species, as when old people can contribute positively to the survival of their descendants there is a selection pressure that leads to a growing number of old people - a lengthening of life spans.

The satellite cells that support muscle tissue are one of the most studied stem cell populations. Certainly it is there that most of the really interesting discoveries have been made in recent years. For example that stem cell populations are not greatly diminishing in size, though there is some debate over this point in various different types of stem cell, and that the cells themselves are not becoming incapable of action. Rather the stem cell niche, the supporting tissue environment that houses these cells, changes over time and the stem cells become increasingly quiescent in response to altered levels of circulating proteins. We can speculate as to how these and other changes in the tissue environment are linked to the cellular and molecular damage that accumulates as a side-effect of the normal operation of metabolism. Figuring that out is very much a work in progress. Researchers have identified some of the specific protein signals involved in recent years, and have demonstrated that altering these signal levels can restore aged stem cells to a more youthful level of activity. You might look back in the Fight Aging! archives at work on GDF-11 and muscle stem cell rejuvenation, for example.

Obviously this is of great interest, as putting old stem cells back to work could ameliorate a range of age-related conditions. Just look at the benefits produced today via first generation stem cell therapies used to treated the old and the damaged. As is usually the case, we should expect there to be multiple mechanisms at work and multiple ways to influence any one underlying process in cell biology, however. Nothing is simple in metabolism, and all processes are networks of linked feedback loops and mechanisms. So here researchers report another method of restoring activity in aged muscle stem cells:

Why age reduces our stem cells' ability to repair muscle

[Researchers] found that as muscle stem cells age, their reduced function is a result of a progressive increase in the activation of a specific signalling pathway. Such pathways transmit information to a cell from the surrounding tissue. The particular culprit identified by [the] team is called the JAK/STAT signalling pathway. "What's really exciting to our team is that when we used specific drugs to inhibit the JAK/STAT pathway, the muscle stem cells in old animals behaved the same as those found in young animals. These inhibitors increased the older animals' ability to repair injured muscle and to build new tissue."

What's happening is that our skeletal muscle stem cells are not being instructed to maintain their population. As we get older, the activity of the JAK/STAT pathway shoots up and this changes how muscle stem cells divide. To maintain a population of these stem cells, which are called satellite cells, some have to stay as stem cells when they divide. With increased activity of the JAK/STAT pathway, fewer divide to produce two satellite cells (symmetric division) and more commit to cells that eventually become muscle fibre. This reduces the population of these regenerating satellite cells, which results in a reduced capacity to repair and rebuild muscle tissue.

Researchers discover a key to making new muscles

There are two important processes that need to happen to maintain skeletal-muscle health. First, when muscle is damaged by injury or degenerative disease such as muscular dystrophy, muscle stem cells - or satellite cells - need to differentiate into mature muscle cells to repair injured muscles. Second, the pool of satellite cells needs to be replenished so there is a supply to repair muscle in case of future injuries. In the case of muscular dystrophy, the chronic cycles of muscle regeneration and degeneration that involve satellite-cell activation exhaust the muscle stem-cell pool to the point of no return.

"Our study found that by introducing an inhibitor of the STAT3 protein in repeated cycles, we could alternately replenish the pool of satellite cells and promote their differentiation into muscle fibers. Our results are important because the process works in mice and in human muscle cells. Our next step is to see how long we can extend the cycling pattern, and test some of the STAT3 inhibitors currently in clinical trials for other indications such as cancer, as this could accelerate testing in humans."

Inhibition of JAK-STAT signaling stimulates adult satellite cell function

Diminished regenerative capacity of skeletal muscle occurs during adulthood. We identified a reduction in the intrinsic capacity of mouse adult satellite cells to contribute to muscle regeneration and repopulation of the niche. Gene expression analysis identified higher expression of JAK-STAT signaling targets in 3-week-old relative to 18-month-old mice. Knockdown of Jak2 or Stat3 significantly stimulated symmetric satellite stem cell divisions on cultured myofibers. Genetic knockdown of Jak2 or Stat3 expression in prospectively isolated satellite cells markedly enhanced their ability to repopulate the satellite cell niche after transplantation into regenerating tibialis anterior muscle. Pharmacological inhibition of Jak2 and Stat3 activity similarly stimulated symmetric expansion of satellite cells in vitro and their engraftment in vivo. Intramuscular injection of these drugs resulted in a marked enhancement of muscle repair and force generation after cardiotoxin injury. Together these results reveal age-related intrinsic properties that functionally distinguish satellite cells and suggest a promising therapeutic avenue for the treatment of muscle-wasting diseases.

One concern in this approach of putting old stem cells back to work is the very same that has existed for all stem cell treatments, which is the risk of cancer. If stem cells decline in their activity because it reduces cancer risk, then overriding that behavior in an old body that still has a high level of cellular damage will probably raise the risk of cancer. This is an issue that has been successfully addressed in stem cell treatments to date, and I imagine it will be successfully addressed in future treatments based on making older stem cells act as though they are in young tissue. It is a concern and an additional cost of development, not a roadblock.

Indeed, with reference to this recent work on stem cell rejuvenation you don't have to look far to see that STAT3 levels are associated with cancer stem cells in a variety of cancers, though not in any straightforward fashion. Biology is always far more complicated than we would like it to be for the purposes of medicine.

Mitochondria are the power plants of the cell, a bacteria-like herd of organelles that have an important role in aging. They become damaged as a result of their everyday activities, and that damage ultimately creates malfunctioning cells that harm surrounding tissues. Many of the methods demonstrated to slow aging in laboratory animals involve alterations to mitochondrial function that may impact the pace at which their damage progresses or degree to which it is ameliorated by cellular housekeeping mechanisms. We would like to see a comprehensive way to entirely eliminate this damage, however, a way to completely repair mitochondrial damage and reset the clock on this contribution to degenerative aging. Fortunately there are a range of possible approaches to this goal, such as replacement of mitochondria, replacement of their DNA, moving their DNA into the cell nucleus, and so forth.

This open access paper covers what is known of the numerous ways in which mitochondria are thought to influence the behavior of other important biological systems also linked to aging:

Mitochondria are principal regulators of cellular function and metabolism. In addition, mitochondria play a key role in cell signaling through production of reactive oxygen species that modulate redox signaling. Recent findings support an additional mechanism for control of cellular and tissue function by mitochondria through complex mitochondrial-nuclear communication mechanisms and potentially through extracellular release of mitochondrial components that can act as signaling molecules. The activation of stress responses including mitophagy, mitochondrial number, fission and fusion events, and the mitochondrial unfolded protein response requires mitochondrial-nuclear communication for the transcriptional activation of nuclear genes involved in mitochondrial quality control and metabolism.

The induction of these signaling pathways is a shared feature in long-lived organisms spanning from yeast to mice. As a result, the role of mitochondrial stress signaling in longevity has been expansively studied. Current and exciting studies provide evidence that mitochondria can also signal among tissues to up-regulate cytoprotective activities to promote healthy aging. Alternatively, mitochondria release signals to modulate innate immunity and systemic inflammatory responses and could consequently promote inflammation during aging. In this review, established and emerging models of mitochondrial stress response pathways and their potential role in modulating longevity are discussed.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4143811/

Average telomere length in blood cells tends to decline with advancing age, but it is a dynamic measure that should probably be regarded as an indirect reflection of health and robustness. Consider that telomeres shorten with each cell division, acting as a part of the mechanisms that limit somatic cell life span, so the average telomere length in any given tissue is a function of how rapidly cells divide and how often they are replenished from the supporting population of stem cells in which telomerase activity maintains long telomeres. It isn't clear at all that telomere erosion is an important cause of aging, versus simply a secondary effect of damage taking its toll on stem cell activity and other necessary aspects of tissue maintenance. Given that, it is interesting that telomerase based treatments extend life in mice: the mechanism has yet to be established, however, and there are hints that it may have something to do with the effects of telomerase on mitochondria.

Separately, in recent years researchers have demonstrated that greater time spent sitting, independent of other factors relating to exercise and sedentary behavior, correlates with worse health and a shorter life expectancy. Various researchers are exploring mechanisms that might explain these results. Here this group shows a correlation with telomere length, which would be expected if sitting time does indeed correlate with worse health:

[Researchers] analysed the length of chromosomal telomeres in the blood cells of 49 predominantly sedentary and overweight people in their late 60s, on two separate occasions, six months apart. All 49 participants had been part of a previously reported clinical trial in which half of them had been randomly assigned to a tailored exercise program over a period of six months, and half had been left to their own devices. Levels of physical activity were assessed using a seven day diary and a pedometer to measure the number of footsteps taken every day, while the amount of time spent sitting down each day was gleaned through a validated questionnaire. The time spent exercising as well as the number of steps taken daily increased significantly in the group following the exercise program, while the amount of time spent seated fell in both groups.

Various risk factors for heart disease and stroke also improved in both groups, particularly those on the exercise program, who also lost a great deal more weight than their counterparts left to their own devices. But increases in physical activity seemed to have less of an impact than reductions in sitting time, the findings showed. The number of daily steps taken was not associated with changes in telomere length, while an increase in moderate intensity physical activity was linked to a shortening in telomere length, although this was not significant. But a reduction in the amount of time spent sitting down in the group on the exercise program was significantly associated with telomere lengthening in blood cells.

Link: http://www.sciencedaily.com/releases/2014/09/140903204123.htm

A few weeks from now, on October 1st, advocates for longevity research around the world will hold local events and show their support for the cause. We'd all like to see faster progress towards the control of degenerative aging and elimination of age-related frailty, disease, and aging. Coordinated events are one way to gain greater attention for the staggering cost of degenerative aging and the potential for near future medicine to treat and ultimately reverse the causes of aging. The yearly October 1st events are grassroots efforts encouraged and coordinated by groups such as the International Longevity Alliance and Longecity. A strong grassroots is an essential part of growing the community, generating an environment in which more new ventures launch, more advocates undertake new work, and more seed funding can be raised for early stage research. Big donors only arrive much later in the process, and even then only because a strong grassroots advocacy community has spent years successfully generating growth and public support.

The first step to getting anything done in this world is to make a contribution yourself, and then persuade a few friends to join you in that effort. Enormous, world-changing movements grow from such small roots and successes:

Promoting Longevity Research on October 1 - The International Day of Older Persons

Dear friends,

There are now efforts by longevity activists around the world to organize events (meetings, lectures and publications) dedicated to promotion of longevity research on or around October 1 - the International Day of Older Persons. This symbolic day can be a great opportunity to raise the topic of longevity research in the mainstream (including the media, officials and wide public).

Just about 1 month is left until October 1 - a good time to prepare small events, create publications and distribute materials. Last year, events for that day - ranging from small meetings of friends to seminars and rather large conferences, alongside publications, distributions of outreach materials (petitions and flyers) and media appearances - were held in over 30 countries. Longecity will support these efforts. It will offer small reimbursements for the best events organized by longevity activists around the world toward that day.

The criteria for choosing the event to be supported include (but not restricted to):

1) Maximum outreach,
2) Building up the local pro-longevity community,
3) Educational value,
4) A special preference will be given to events organized in countries where little or no longevity activism existed so far.

If you would like to organize an event, please contact us and send us a description. You are welcome to give additional support to these and further local events by longevity activists around the world by donations. This initiative is a part of the general effort to promote Regional Longevity Outreach and Activism around the world, by forming and developing local activist groups.

Coincidentally, October 1st is also the launch of the Fight Aging! 2014 matching fundraiser in support of SENS Research Foundation programs. The Foundation funds ongoing scientific research focused on repairing the cellular and molecular damage that causes aging. All of that funding is provided by charitable donations from people like you and I who feel strongly that this work should move forward rapidly. We're aiming to raise $50,000 before year end, and to help meet that goal have assembled a $100,000 matching fund: every $1 donated will draw down $2 from the fund. Do you want to triple the effect of your charitable donations this year? Then look no further!

If you are considering organizing an event for October 1st, take a look at the full size posters assembled for the fundraiser:

• Fight Aging! 2014 Fundraiser Poster #1
• Fight Aging! 2014 Fundraiser Poster #2

Print them out, and show them off to your circle. Your help in reaching this fundraising goal in support of SENS research would be greatly appreciated: it makes a real difference to the pace of progress.

Senescent cells are those that have removed themselves from the cell cycle in response to damage or a tissue signaling environment that reflects nearby damage. This is an adaptation that serves to reduce cancer risk, at least in the early stages of aging, but it also causes harm as senescent cells accumulate in larger numbers. These cells emit signal molecules that degrade surrounding tissue structures, harm tissue function, and increase the odds of nearby cells also becoming senescent. Thus the accumulation of senescent cells over the years is one of the contributing causes of degenerative aging.

The ideal and simplest approach to removing this issue is to adapt targeted cell killing technologies under development in the cancer research community to periodically clear out senescent cells in the body. Other more complicated paths may be an option, however, such as reprogramming cells to reverse senescence, or as in this case blocking some of the signal molecules released by senescent cells, making them much less harmful to surrounding tissues:

Many age-related diseases are associated with an impaired fibrinolytic system. Elevated plasminogen activator inhibitor-1 (PAI-1) levels are reported in age-associated clinical conditions including cardiovascular diseases, type 2 diabetes, obesity and inflammation. PAI-1 levels are also elevated in animal models of aging.

While the association of PAI-1 with physiological aging is well documented, it is only recently that its critical role in the regulation of aging and senescence has become evident. PAI-1 is synthesized and secreted in senescent cells and contributes directly to the development of senescence by acting downstream of p53 and upstream of insulin-like growth factor binding protein-3. Pharmacologic inhibition or genetic deficiency of PAI-1 was shown to be protective against senescence and the aging-like phenotypes in [mice]. Further investigation into PAI-1's role in senescence and aging will likely contribute to the prevention and treatment of aging-related pathologies.

Link: http://dx.doi.org/10.1055/s-0034-1387883

Mitochondria are the power plants of the cell, generating chemical energy stores used in many cellular processes. A herd of them exists in every cell, dividing like bacteria to keep up their numbers. Mitochondrial damage occurs as a side-effect of the normal operation of metabolism and is an important contribution to degenerative aging, but fortunately there are a wide range of fairly well understood methods by which this issue could be prevented or treated. All that is needed is more funding for research and development.

One possibility is the delivery of replacement mitochondria, and if doing this why not deliver better, more effective mitochondria? Some of the existing mitochondrial haplogroups are objectively better than others, but we could also in theory greatly improve upon what exists based on present knowledge. At the end of this road lies the replacement of mitochondria with optimal synthetic versions, resistant to damage, which influence surrounding cellular mechanisms in beneficial ways, and which minimize the mitochondrial contribution to aging. That isn't a near term prospect, but in the decades ahead it will become very plausible to start replacing more discrete cellular components with designed molecular machinery that is more efficient and less vulnerable, and thus helps to extend healthy life span:

We hypothesize herein that synthetic mitochondria, engineered or reprogrammed to be more energetically efficient and to have mildly elevated levels of reactive oxygen species (ROS) production, would be an effective form of therapeutics against systemic aging. The free radical and mitochondria theories of aging hold that mitochondria-generated ROS underlies chronic organelle, cell and tissues damages that contribute to systemic aging. More recent findings, however, collectively suggest that while acute and massive ROS generation during events such as tissue injury is indeed detrimental, subacute stresses and chronic elevation in ROS production may instead induce a state of mitochondrial hormesis (or "mitohormesis") that could extend lifespan.

Mitohormesis appears to be a convergent mechanism for several known anti-aging signaling pathways. Importantly, mitohormetic signaling could also occur in a non-cell autonomous manner, with its induction in neurons affecting gut cells, for example. Technologies are outlined that could lead towards testing of the hypothesis, which include genetic and epigenetic engineering of the mitochondria, as well as intercellular transfer of mitochondria from transplanted helper cells to target tissues.

Link: http://dx.doi.org/10.1002/cbin.10362

Autoimmunity as a term covers a broad range of ways in which the immune system can run awry to attack healthy tissues. It bears some semblance to cancer in that an autoimmune disorder can occur at any age, there are many, many different types, and the details of the biochemistry involved are enormously complex and comparatively poorly understood. There is no good consensus on why some of the most common autoimmune diseases such as rheumatoid arthritis occur, for example, and the most successful of presently available treatments focus on suppressing the activities of the malfunctioning immune system in as targeted a way as possible rather than addressing the root causes of that malfunction - as the root causes are not yet well enough categorized to identify a point of action. A number of named autoimmune disorders are diagnoses of exclusion: you have the condition because you show some of a grab bag of unpleasant symptoms yet all of the tests for other named autoimmune conditions come back negative. There tend to be no reliable treatments in those cases.

Some autoimmune diseases are not age-related at all, but others are, beyond the assurance of "live long enough and something will go wrong," that is. Certainly the immune system as a whole deteriorates and malfunctions in other characteristic ways with advancing age, becoming increasingly ineffective yet constantly active to generating increased and harmful levels of chronic inflammation. Some researchers have made inroads in a fairly drastic approach to treating autoimmunity: wipe out the entire immune system with chemotherapy and repopulate it with immune cells derived from the patient's own stem cells. This has proven effective in a number of trials for more serious, life-threatening autoimmune conditions, and was even tried for rheumatoid arthritis some years ago before the advent of TNF inhibitors and other immune suppression treatments. The medical community embraced the less drastic approach of partially effective medical control over the more drastic approach of a sometimes cure, however. I suspect the chemotherapy would have to be replaced with a kinder, gentler, and less risky process of stripping the immune system for that approach to gather more funding and attention, or even be considered as a way to reset an age-damaged immune system.

Here is recent news from researchers working on an interesting alternative approach to treating autoimmunity. This has been under investigation for some time, and involves a process of steadily desensitizing key immune cells, training them not to react to certain proteins known to be involved in the autoimmune response. While full details of causation remain to be determined for many autoimmune disorders, researchers do have lists of protein targets to work with in this way in some cases. Note that the paper is open access if you want to delve further:

Scientists discover how to 'switch off' autoimmune diseases

Rather than the body's immune system destroying its own tissue by mistake, researchers have discovered how cells convert from being aggressive to actually protecting against disease. It's hoped this latest insight will lead to the widespread use of antigen-specific immunotherapy as a treatment for many autoimmune disorders, including multiple sclerosis (MS), type 1 diabetes, Graves' disease and systemic lupus erythematosus (SLE).

Scientists were able to selectively target the cells that cause autoimmune disease by dampening down their aggression against the body's own tissues while converting them into cells capable of protecting against disease. This type of conversion has been previously applied to allergies, known as 'allergic desensitisation', but its application to autoimmune diseases has only been appreciated recently. The group has now revealed how the administration of fragments of the proteins that are normally the target for attack leads to correction of the autoimmune response. Most importantly, their work reveals that effective treatment is achieved by gradually increasing the dose of antigenic fragment injected.

Sequential transcriptional changes dictate safe and effective antigen-specific immunotherapy

While progress has been made in developing disease-modifying therapies for the treatment of autoimmunity, it is increasingly clear that successful therapy will need to reinstate long-lasting immunological tolerance to the targeted self-antigens, thereby preventing pathogenic ​CD4+ T-cell responses. This must be achieved without perturbation of normal immune function, leaving anti-microbial and tumour immunosurveillance responses intact. Antigen-specific immunotherapy aims to fulfil these requirements: administration of disease-associated ​CD4+ T-cell epitopes in a tolerogenic form has been shown to restore immune homeostasis and prevent immunopathology in experimental models, as well as in clinical trials of both autoimmune diseases and allergies.

We have developed a dose escalation strategy for efficient self-antigen-specific tolerance induction and characterized sequential modulation of ​CD4+ T-cell phenotype at each consecutive stage of escalating dose immunotherapy (EDI). We show that self-antigen-specific tolerance can be effectively induced via the subcutaneous (s.c.) route. We demonstrate that antigen dose plays a critical role in determining the efficacy of immunotherapy, and that a dose escalation protocol is imperative to allow safe s.c. administration of the high antigenic doses required for efficient tolerance induction. We reveal that EDI minimizes ​CD4+ T-cell activation and proliferation during the early stages of immunotherapy, preventing excessive systemic cytokine release.

The end goal for tissue engineering is not the generation of organs and tissues outside the body for transplantation, but rather to direct the rebuilding of complex tissue structures in situ inside the body:

What if repairing large segments of damaged muscle tissue was as simple as mobilizing the body's stem cells to the site of the injury? [Researchers have] demonstrated the ability to recruit stem cells that can form muscle tissue to a small piece of biomaterial, or scaffold that had been implanted in the animals' leg muscle. The secret to success was using proteins involved in cell communication and muscle formation to mobilize the cells. "This is a proof-of-concept study that we hope can one day be applied to human patients."

The current treatment for restoring function when large segments of muscle are injured or removed during tumor surgery is to surgically move a segment of muscle from one part of the body to another. Of course, this reduces function at the donor site. Several scientific teams are currently working to engineer replacement muscle in the lab by taking small biopsies of muscle tissue, expanding the cells in the lab, and placing them on scaffolds for later implantation. This approach requires a biopsy and the challenge of standardizing the cells. "Our aim was to bypass the challenges of both of these techniques and to demonstrate the mobilization of muscle cells to a target-specific site for muscle regeneration."

Most tissues in the body contain tissue-specific stem cells that are believed to be the "regenerative machinery" responsible for tissue maintenance. It was these cells, known as satellite or progenitor cells, that the scientists wanted to mobilize. The scientists tested the effects of several proteins known to be involved in muscle formation by designing the scaffolds to release these proteins. The protein with the greatest effect on cell recruitment was insulin-like growth factor 1 (IGF-1). After several weeks of implantation, lab testing showed that the scaffolds with IGF-1 had up to four times the number of cells than the plain scaffolds and also had increased formation of muscle fibers. Next, the scientists will evaluate whether the regenerated muscle is able to restore function and will test clinical feasibility in a large animal model.

Link: http://www.wakehealth.edu/News-Releases/2014/Research_in_Rodents_Suggests_Potential_for_%E2%80%9CIn_Body%E2%80%9D_Muscle_Regeneration.htm

This news from Calico is not unexpected; deals of this nature were a given at some point in the process of building out the company. It does reinforce current views on the direction that will be taken in their research and development, however. It is my hope that Calico turns out to be something other than a hybrid of the Ellison Medical Foundation and a continuation of the past ten years wasted on sirtuins, rapamycin, and other exceedingly expensive investigations aimed at slowing aging, efforts that can do no more than produce marginal benefits even if completely successful, and which despite years and billions spent have not even advanced to the point at which a realistic timeframe or cost for that success can be proposed. Metabolism is too complex and too little is known of its detailed relationship with aging to have a firm plan of action at this point.

We shall see, but I suspect that the only way to make Calico effective by diverting it from the current mainstream is for groups like the SENS researchers, people working on much more promising means of treating aging by repairing the damage that causes degeneration, where there is enough existing knowledge to have a plan and a projected cost and timeline for success, to demonstrate that they can produce better results at far less cost than the mainstream of longevity science. That in turn requires funding: the chicken and the egg issue for making significant progress towards the treatment of aging these days.

Calico, a Google-backed biotech company run by the former Genentech chief executive Arthur D. Levinson, said it would build a new Bay Area-based facility that will research diseases that afflict the elderly, such as neurodegeneration and cancer. The facility, which doesn't have a precise location just yet, is being built in partnership with AbbVie, a Chicago-area pharmaceutical company that has a research facility in Redwood City, Calif., just a few miles from Google's Mountain View headquarters. The companies will put up equal money - $500 million at first, and up to $1.5 billion if things go well - and split any profits down the middle.

The partnership is a standard biotech deal in which, more or less, one company deals with the early phases of drug development while the other takes responsibility for testing and making whatever gets discovered. You could say that Calico will look for drugs in test tubes and, if they're successful, AbbVie will test them out and make them in factories. "Calico will set up a world-class research and development facility in the San Francisco Bay Area, where we will explore the basic biology of aging and develop new medicines for patients with aging-related diseases," said Mr. Levinson, Calico's chief executive. "AbbVie will use its deep pharmaceutical expertise to provide scientific and clinical development support and its commercial expertise to ensure these therapies are widely available."

The AbbVie partnership seemingly makes it clear that Calico will be a drug discovery and development company, which is what many observers expected based on Mr. Levinson's background in drug development.

Link: http://bits.blogs.nytimes.com/2014/09/03/googles-anti-aging-company-announces-new-research-facility

The Methuselah Foundation is presently partnering with the SENS Research Foundation to put out a quarterly update on ongoing research for members of the 300. This focuses on work relevant to the end goal of bringing aging under medical control, preventing and curing age-related frailty and disease. Members of the 300 are largely long-standing donors who have pledged to give at least $1000 each year for the next 25 years to fund the work of the Methuselah Foundation. Many of the 300 were early backers and signed up when SENS research was coordinated by the Methuselah Foundation, prior to the SENS Research Foundation spinning off as an independent organization. Their donations still go towards SENS programs even today. Members of the 300 will see their names inscribed on a lasting monument to be raised in the US Virgin Islands, and perhaps more pertinently have access to perks such as glossy updates on SENS research and other insider news from ongoing Methuselah Foundation initiatives.

There are still a very small number of positions left in the 300 - give it some thought. Given just how important funding and public support are for longevity science at this juncture, and the scale of what will be possible with rejuvenation treatments in the future, I'd argue that the 300 is probably the most influential organization that I belong to. The growth in membership was the spur to Methuselah Foundation success a decade ago, and thus the existence of the SENS Research Foundation, as well as a web of other influences on the aging and longevity research community over recent years. This in turn paves the road to a welcome future in which aging no longer causes suffering and death, bringing that era closer than would otherwise be the case. We all make a difference, and every last action counts.

Rejuvenation Biotechnology Update

The Methuselah Foundation is thrilled to partner with SENS Research Foundation in order to bring out the most recent advancements in tissue engineering, regeneration, and rejuvenation research for members of The 300. Because it doesn't take a scientist to understand the vital importance of investing in healthy life extension, these news-letters attempt to frame three significant studies from the past 3-6 months as accessibly and approachably as possible, describing how each one fits into the broader landscape of longevity research.

Regeneration of the aged thymus by a single transcription factor

In this study, the researchers used a genetic switch to induce FOXN1 expression in the thymic epithelial cells of mice, and compared them with mice that did not have FOXN1 induced. They observed that with FOXN1 induction, the thymus was regenerated from progenitor thymic epithelial cells that were still present in the aged thymus. They found that when FOXN1 was induced, the size of the thymus was larger, the expression of genes associated with a young, active thymus was increased, and the production of native T cells was boosted.

Thymic involution is one of the main contributors to declining immune system function with age. In the SENS paradigm, it could be categorized in the class of damage known as "cell loss and tissue atrophy." SENS Research Foundation is currently collaborating with the Wake Forest Institute of Regenerative Medicine on thymic regeneration research. The fact that induced expression of a single transcription factor could have such profound effects on thymic function and T-cell output in aged mice makes this study very interesting. Wouldn't it be nice if we could find a single transcription factor for each organ that, when upregulated, would restore the organ to a "youthful" state?

However, there are some caveats to consider, as one always should with scientific research. One is that, although the researchers did measure T-cell output from the regenerated thymuses of aged mice, they did not test their overall immune function. The quantity of T-cells produced by the regenerated thymuses was increased, but did these T-cells function similarly to young, normal T-cells? It is also prudent to be cautious about the idea of "robust thymus regeneration." In some autoimmune diseases, such as myasthenia gravis, thymic hypertrophy is observed. This kind of autoimmunity might also happen with an approach similar to FOXN1, because the thymus itself, being old, may have other dysfunction besides its reduction in size. Contrast this approach with genuine tissue engineering, where one would receive a new, youthful thymus. More research about thymic regeneration will be needed to determine whether FOXN1 overexpression will contribute to immune hyperreactivity and autoimmunity.

Physiological IgM class catalytic antibodies selective for transthyretin amyloid

TTR amyloidosis is a canonical example of "extracellular junk" - one of the fundamental types of aging related damage that SENS Research Foundation (SRF) attempts to treat. This work was partially funded by SRF, with the goal of finding a reliable way to break down misfolded TTR.

In Alzheimer's disease research, similar strategies of "vaccination" or treatment with antibodies against amyloid plaques have been tried. These treatments yielded some promising results but also some dangerous side effects in a few patients (inflammation of the protective membrane covering the brain). However, there are a few important distinctions between the catabody strategy and the immunization strategy. Perhaps the most notable difference is that catabodies actually break down the target protein (in this case, amyloid aggregates of TTR) themselves, without the requirement for other immune or blood components. Conversely, in previous studies on Alzheimer's disease, the antibodies did not break down ß-amyloid themselves but merely encouraged its clearance through the recruitment of other immune proteins and cells, which also initiates tissue-damaging inflammatory processes. Catabodies may prove to be less inflammatory, since they do not require other immune components to work. Additionally, the dose required for therapeutic effects may be smaller, and potentially less costly to produce.

Most very early stage medical research is funded by philanthropy, even in labs that largely depend on grants from established institutional sources of funding. Obtaining public and other private funding is usually impossible until a researcher can provide a proof of concept, which is only the case after most of the high risk early stage work is accomplished. In larger labs this results in a juggling of funds from government and industry, trying to squeeze out enough time and money from existing projects to actually work on new things, and patching over the gap with philanthropic donations from supporters. Any group that is entirely focused on early stage work must rely almost entirely upon philanthropy, and thus have patrons with deep pockets. This is the case for the establishment of the Glenn Consortium laboratories, for example, and for the ongoing work of the SENS Research Foundation.

Philanthropist Jason Hope is a patron for SENS rejuvenation research aimed at repairing the cellular and molecular damage that is the root cause of aging. He funds ongoing work organized by the SENS Research Foundation and does more than most patrons to help publicize and explain the science involved:

When it comes to age-related illness, the direction of modern medicine seems more reactive than proactive. In other words, what type of research is being done to prevent conditions like Alzheimer's disease and diabetes from happening in the first place? Enter people like Jason Hope, an Arizona-based Internet entrepreneur who's using his money and influence to advance anti-aging initiatives. Much of Hope's philanthropy efforts are concentrated on the SENS Research Foundation, a non-profit formed in 2009 to tackle age-related disease head on. Since its inception, SENS has been a driving force in what's known as rejuvenation biotechnology. This line of research focuses specifically on addressing age-related disease.

Hope's involvement with SENS began in 2010, when he donated half a million dollars to the organization. Because of these funds, the group was able to establish its Cambridge SENS laboratory and implement new research initiatives. Since then, he's gone on to contribute over $1 million of his own money to the cause. "I'm invested in the SENS Research Foundation for a number of reasons. In simplest terms, I believe in their work and understand how essential it is in terms of advancing human medicine. It has the power to completely redefine the healthcare, pharmaceutical and biotech industries."

In addition to lending his financial support to SENS, Hope also plays an active role in the group's outreach efforts. According to Hope, rejuvenation biotechnologies represent the future of human health. This approach to anti-aging is geared less toward treating diseases, and more toward understanding prevention as a way to create a longer, better quality of life. Over time, normal metabolism gradually damages the body. This, in turn, leads to the ravaging diseases associated with old age. To combat this, the SENS approach specifically works to repair this kind of damage before the body develops deadly pathologies.

Link: http://www.metro.us/newyork/lifestyle/wellbeing/2014/09/02/jason-hope-helps-push-anti-aging-efforts-forward/

The expected result emerges from the study results noted below, joining the mountain of evidence linking exercise and long term health. In human studies it is challenging to prove causation, but the evidence for regular moderate exercise to cause enhanced healthy longevity in animal studies is extensive, although unlike the practice of calorie restriction it apparently doesn't extend maximum life spans.

Why care about exercise when we are a few steps away from radical advances in medical science? Because we are still a few steps away. In terms of interaction with medicine your life to date is likely little different from that of your parents, and you will continue to age and decline like them until new medical technologies of rejuvenation arrive. That could be decades from now, even in this present age of revolutionary progress in biotechnology, so why shorten your odds of living long enough to benefit?

Researchers say more than an hour of moderate or half an hour of vigorous exercise per day may lower your risk of heart failure by 46 percent. Heart failure is a common, disabling disease that accounts for about 2 percent of total healthcare costs in industrialized countries. Risk of death within five years of diagnosis is 30 percent to 50 percent. Swedish researchers studied 39,805 people 20-90 years old who didn't have heart failure when the study began in 1997. Researchers assessed their total and leisure time activity at the beginning of the study and followed them to see how this was related to their subsequent risk of developing heart failure. They found that the more active a person, the lower their risk for heart failure.

The group with the highest leisure time activity (more than one hour of moderate or half an hour of vigorous physical activity a day) had a 46 percent lower risk of developing heart failure. Physical activity was equally beneficial for men and women. Those who developed heart failure were older, male, had lower levels of education, a higher body mass index and waist-hip ratio, and a history of heart attack, diabetes, high blood pressure and high cholesterol. "You do not need to run a marathon to gain the benefits of physical activity - even quite low levels of activity can give you positive effects. Physical activity lowers many heart disease risk factors, which in turn lowers the risk of developing heart failure as well as other heart diseases."

Link: http://newsroom.heart.org/news/an-hour-of-moderate-exercise-a-day-may-decrease-heart-failure-risk

As I noted in a recent post on naked mole rats, there are at least two good reasons to study the comparative biology of aging, which is to say how and why aging differs between species. Why are some species long lived, some short lived, and some very few exhibit negligible senescence, a near absence of age-related changes across their life spans? Why do whales live longer than humans, humans longer than other primates, primates longer than horses, and naked mole rats nine times as long as standard issue rats? Firstly, isolating small but important differences between similar species with different life spans may help to conclude debates over which of the possible causes of aging are more important. (Though to my eyes less time spent debating and more time spent trying to repair all known forms of cellular damage associated with aging is the better, faster way to figure out what is and isn't important). Secondly, some researchers see the potential to generate therapies or enhancements for humans from the biological differences present in other species. There are several lines of research here funded to varying degrees, including identification of the basis for exceptional regeneration in salamanders, or the roots of longevity and cancer resistance in naked mole rats, to pick two examples from the crowd.

It is hard to say whether or not the quest for ways to alter human biochemistry to produce effects seen in other species is going to lead to meaningful results in the near term. On the one hand, it is clear that there is a lot of shared biology between even comparatively distant species such as humans and lizards. On the other hand there is no reason to expect that even a fully understood mechanism would be easy or even possible to bring to humans as enhancement or therapy: the devil is in the details, and the answer will probably vary widely mechanism by mechanism. So it is too early to say what will come of all of this. That said, I think the odds of beneficial outcomes in the near term shrink the further away from our species you go. When investigating the biology of tiny possibly ageless organisms such as the highly regenerative hydra, I suspect that the end result will be knowledge and little more. Hydra are just too different, and their regenerative prowess is based on constant aggressive reconstruction that is simply impractical in a higher organism that must keep the fine structure of its central nervous system basically intact. Nonetheless some researchers are optimistic that hydra studies will teach us some things that we can use to produce regenerative treatments in humans:

In Swiss Lakes, Scientists Search For The Source Of Immortality

"Since the mid-20th century, scientists have been interested in the longevity of this animal," Galliot explains. "When it's maintained in satisfactory conditions, hydrae reproduce asexually. They bud. We could observe them for years, and we wouldn't see any decline. They stay in shape." One day, Belgian researcher Paul Brien decided to plunge one of his group of hydrae into 10° C. "In that species, cold is a natural stimulus that tells them 'Oh, life is going to become harder,' because they don't survive very low temperatures." The result was incredible. Although they lived until then without partners, hydrae suddenly started looking for other hydrae to mate. They developed oocytes or testicles. "The animal started a sexual cycle. It reproduced. Then parents died and only their offspring survived in a small gangue that allowed them to survive the winter at the bottom of the water."

In 2000, a Japanese team renewed the experiment and confirmed the result. Then Brigitte Galliot came along, but something wasn't quite right. "The first year, the poor student who was checking on the hydrae was going nowhere. We were working with the same species, the very common Hydra oligactis, but the animals remained super happy. We maintained them for over a year at 10°. They were fine, they were still budding. So we thought ... drat!" The solution to this mystery was simple and ideal for the scientists. "There are, in the same species, different strains. One can resist, the other can't, and it ages. So by comparing the molecular and cellular processes of these two strains, we can understand what induces aging and what enables hydrae to resist it."

In practical terms, there could be two ways to take advantage of these findings to stop our own aging. "One of the approaches consists in telling ourselves that with evolution, these species developed all sorts of small molecules, some peptides and lipids that could be used as a source for new pharmacological agents," she says. The other approach, on which Galliot and her team are currently focusing, centers on autophagy, "a process through which cells digest their own content." A temporary survival strategy when faced with a lack of food but also a self-cleaning method to evacuate toxic waste, autophagy is controlled by very similar molecular tracks in animals that could not be more different, hydrae and mice.

Therefore, if this cellular process survived through millennia of evolution, it might still be triggered. The stakes are immense. "It's about understanding how to promote an efficient autophagy, which would enable our cells to digest the increasing number of aggregates we produce as we age, and which are at the root of Alzheimer's disease, as well as other neurological pathologies," Galliot explains. To achieve this, the comparison between "immortal" hydrae and those that age is illuminating. "The two strains seem to have different efficiencies in the way they get rid of these toxic aggregates." Galliot, however, remains cautious. "I'm not saying that we'll have a ready-to-use molecule in five years. What we're doing is very basic, but the implications can be very relevant. We do have, at the moment, a molecular candidate that is most interesting."

If you are going to try to slow down aging, which isn't the best approach to the problem at all, then it has long seemed to me that artificially upregulating the cellular housekeeping mechanisms of autophagy is a more promising approach than trying to more blindly mimic other aspects of the calorie restriction response that enhances health and longevity. Upregulated autophagy is present in many slow-aging animal models, and there are very good reasons to believe it is a cause rather than an effect of this outcome. Despite a fair number of researchers including this sort of work in their portfolio not much has come of it in the past decade, however. I don't see much going on today to convince me that we are closer to a generation of practical, effective autophagy-inducing treatments than we were at the turn of the century. Want more autophagy? Either practicing calorie restriction or regular moderate exercise will get you further in terms of upregulated autophagy than what was has emerged from the labs to date - and neither of those options will do much for your longevity in the grand scheme of things. Thus it isn't surprising to see that these hydra researchers are still at a fairly early stage in their studies:

Hydra, a powerful model for aging studies

H. oligactis is a model that has numerous features that complement the drawbacks of existing invertebrate model systems used for aging research, namely hundreds of human orthologs that were lost in nematode and fruit fly ancestors. To identify the putative aging genes present in Hydra but missing in C. elegans and D. melanogaster, we analysed the hydra-human orthologs associated with aging. Among 259 human aging genes retrieved from The Human Ageing Genomic Resources, we found that 207 (80%) were conserved in Hydra. Interestingly, some of these genes are missing or poorly conserved in D. melanogaster and C. elegans, such as the p53 regulator MDM2 or the TGFβ inhibitor noggin. The aging-induced regulation of these genes is currently under investigation.

As an alternative approach to aging studies, several studies aimed at dissecting the mechanisms that underlie the lack of senescence in Hydra focused on FoxO, an evolutionarily conserved transcription factor. In bilaterian organisms, FoxO regulates the response to stress, the proliferation of stem cells, and modulates lifespan. In nematodes and fruit flies, the knockdown of FoxO significantly shortens lifespan. In Hydra, FoxO is expressed in stem cells, and appears to respond to stress. Reduction in FoxO levels in the H. vulgaris AEP strain negatively affected the proliferation of stem cells, the speed of the budding process, the growth of Hydra population, and the production of immune peptides. However, no mortality was observed in FoxO deficient polyps, suggesting that other factors contribute to negligible senescence in H. vulgaris.

Senescent cells rise in number with aging, in an evolved adaptation of developmental machinery that at least initially reduces cancer risk by removing potentially damaged cells from the cycle of division and replication. Many senescent cells are destroyed by the immune system, at least until the immune system begins its own age-related decline in earnest. More than enough senescent cells remain to cause issues, however: they export proteins that degrade surrounding tissues and promote chronic inflammation in a process known as the senescence-associated secretory phenotype (SASP). When many senescent cells are present in tissue SASP becomes a serious issue, causing enough harm and inflammation to promote the development of cancer and many other serious age-related conditions. This is more readily apparent and measured where external factors such as smoking are at work to provide the sort of toxicity that strongly promotes cellular senescence:

Chronic obstructive pulmonary disease (COPD) is a major disease of the lungs. It primarily occurs after a prolonged period of cigarette smoking. Chronic inflammation of airways and the alveolar space as well as lung tissue destruction are the hallmarks of COPD. Recently it has been shown that cellular senescence might play a role in the pathogenesis of COPD.

Cellular senescence comprises signal transduction program, leading to irreversible cell cycle arrest. The growth arrest in senescence can be triggered by many different mechanisms, including DNA damage and its recognition by cellular sensors, leading to the activation of cell cycle checkpoint responses and activation of DNA repair machinery.

Senescence can be induced by several genotoxic factors apart from telomere attrition. When senescence induction is based on DNA damage, senescent cells display a unique phenotype, which has been termed "senescence-associated secretory phenotype" (SASP). SASP may be an important driver of chronic inflammation and therefore may be part of a vicious cycle of inflammation, DNA damage, and senescence. This research perspective aims to showcase cellular senescence with relevance to COPD and the striking similarities between the mediators and secretory phenotype in COPD and SASP.

Link: http://dx.doi.org/10.1165/rcmb.2013-0382PS

Proteostasis is a shorthand term used to mean that the balance of proteins in cells remains steady and correct over time: proteins are produced and destroyed at more or less the same pace, relative levels of different proteins in different places in cells remain the same, levels of damaged proteins are low and consistent, and so forth. There are always ongoing variations in the amounts of some proteins in some places, as this is how the machinery of metabolism works, but overall you'd expect to see much the same thing tomorrow as you do today. Aging disrupts proteostasis, however. It changes the picture of what is going on inside cells through both an increased level of damaged proteins and altered rates of production of many proteins: cellular machinery reacts to local damage directly and remote damage through signaling networks and altered levels of circulating proteins outside cells.

By way of following on from yesterday's post on proteostasis in naked mole rats, a species that shows only comparatively small changes in the machinery of metabolism over much of the course of its life span, here is a paper on the role of the endoplasmic reticulum in proteostasis. Much of it is in the context of genetic conditions unrelated to aging, and their effects on proteostasis, but it is still relevant and interesting material:

The endoplasmic reticulum (ER) is an intracellular compartment dedicated to the synthesis and maturation of secretory and membrane proteins, totalling about 30% of the total eukaryotic cells proteome. The capacity to produce correctly folded polypeptides and to transport them to their correct intra- or extracellular destinations relies on proteostasis networks that regulate and balance the activity of protein folding, quality control, transport and degradation machineries. Nutrient and environmental changes, pathogen infection, aging, and, more relevant for the topics discussed in this review, mutations that impair attainment of the correct 3D structure of nascent polypeptide chains may compromise the activity of the proteostasis networks with devastating consequences on cells, organs and organisms' homeostasis.

Production and maintenance of a functional proteome is crucial for cells, tissues and organisms viability. Highly efficient folding, quality control and transport machineries located in specific intracellular compartments such as the ER convert the genetic information stored into the cell nuclei into functional proteins and protein complexes that fulfil the wide array of functions required for life. Paradoxically, mutations that do not affect the function of a given polypeptide may result in debilitating and life threatening diseases if they introduce small structural defects. In fact, the quality control devices that prevent exit of aberrant polypeptides from the biosynthetic compartment and insure their clearance from cells are alerted by non native features such as exposure at the polypeptide surface of hydrophobic patches, unpaired cysteine residues or otherwise unstructured determinants, independent of the capacity of the mutant polypeptide to fulfil its biological activity.

This "quality control paradox" highlights the importance of basic research in cell biology aiming at understanding the molecular basis of retention- and degradation-based mechanisms operating in our cells. Characterisation of these processes at the molecular level is required to develop therapeutic interventions that promote selective export of functional mutant proteins inappropriately segregated for architectural biases or to sustain "unfolded protein responses" that must intervene when misfolded polypeptides start to accumulate in or outside cells. This becomes even more important for aging-related diseases such as many neurodegenerative disorders, which result from gradual impairment of the proteostasis network, as the increased life expectancy is a fact in our society, and the number of patients will ineluctably raise.

Link: http://www.smw.ch/content/smw-2014-14001/

Comparative study of the biology of aging in species with widely divergent life spans is undertaken by a number of groups in the broader research community. The idea here is that, especially in the case of similar species that nonetheless have very different life spans, chasing down the root causes of these differences will help identify the most important aspects of the biology of aging in our species. This is a very different approach to the problem of aging to the strategy I favor, which is to skip over much of this investigation of the details in favor of focusing on ways to repair known differences between old tissue and young tissue, as exemplified by the SENS research programs.

In any case, it turns out that a great deal of the interaction between metabolism and aging is very similar in many species, and the specific mechanisms present today are inherited from a common but distant evolutionary past, such as the response to calorie restriction that increases health and longevity. Given this, a better understanding of differences in aging between various types of mammal should in turn help to inform research aimed at understanding or treating human aging. In the most optimistic viewpoint the study of aging in diverse species may yield treatments based on importing or mimicking beneficial aspects of non-human biochemistry. Whether or not that turns out to be an effective path forward is up for debate. It depends greatly on the details of any specific attempt and it is really far too early in this process to do more than speculate on that front.

Naked mole rats are one of the better studied species with respect to the comparative biology of aging. From a taxonomic point of view they are not so very distant from mice of a similar size and yet live up to nine times longer. Why? Further, and of perhaps greater interest to today's medical research community, where funding is very biased towards treatment of specific named diseases and there is comparatively little money for aging research, naked mole rats appear to be essentially immune to cancer. Thus there is a growing interest in this species in many quarters. The research group run by João Pedro de Magalhães, who you might recall published a call to action on life extension research earlier this year, recently released an open online database for the naked mole rat genome:

The Naked Mole Rat Genome Resource: facilitating analyses of cancer and longevity-related adaptations.

The naked mole rat (Heterocephalus glaber) is an exceptionally long-lived and cancer-resistant rodent native to East Africa. Although its genome was previously sequenced, here we report a new assembly sequenced by us. We analyzed the annotation of this new improved assembly and identified candidate genomic adaptations which may have contributed to the evolution of the naked mole rat's extraordinary traits, including in regions of p53, and the hyaluronan receptors CD44 and HMMR (RHAMM).

Furthermore, we developed a freely-available web portal, the Naked Mole Rat Genome Resource, featuring the data and results of our analysis, in order to assist researchers interested in the genome and genes of the naked mole rat, and also to facilitate further studies on this fascinating species. This resource is open source and the source code is available at: https://github.com/maglab/naked-mole-rat-portal.

Meanwhile, other researchers are looking for mechanisms to explain how it is that naked mole rats maintain relative levels of undamaged proteins, or proteostasis, far more efficiently throughout their life spans than other rodent species. Aging is characterized by the accumulation of damage and change in cell structures and relative levels of circulating proteins, and slower or more negligible aging is associated with more effective maintenance of proteostasis over time. This doesn't say too much about cause and effect when stated at the high level in this way: it is just what can be observed.

In the research quoted below scientists are on the trail of a noteworthy difference in naked mole rat damage control mechanisms, structures called proteasomes within the cell responsible for breaking down damaged or otherwise unwanted proteins. In naked mole rats the proteasome is more effective at its job as well as being more resilient to interference and damage, and these researchers have found that they can cause proteasomes from other mammalian species to perform just as well by importing a grab bag of proteins and structures from naked mole rat cells. At this point it remains to be seen as to what the crucial factors are, but I can't imagine it'll take long to pin that down:

Factor in naked mole rat's cells enhances protein integrity

A factor in the cells of naked mole rats protects and alters the activity of the proteasome, a garbage disposer for damaged and obsolete proteins. The factor also protects proteasome function in human, mouse and yeast cells when challenged with various proteasome poisons, studies showed. These proteasomes usually rapidly stop functioning, leading to the accumulation of damaged proteins that further impair cell function, contributing to the vicious cycle that leads to cell death. "I think this factor is part of an overall process or mechanism by which naked mole rats maintain their protein quality."

Generally, as an organism ages, not only are there more damaged proteins in need of disposal, but the proteasome itself becomes damaged and less efficient in clearing out the damaged proteins. As a result, protein quality declines and this contributes to the functional declines seen during aging. Enhancement of protein quality, meanwhile, leads to longer life in yeast, worms, fruit flies and naked mole rats.

A cytosolic protein factor from the naked mole-rat activates proteasomes of other species and protects these from inhibition

The naked mole-rat maintains robust proteostasis and high levels of proteasome-mediated proteolysis for most of its exceptional (~ 31 years) life span. Here, we report that the highly active proteasome from the naked mole-rat liver resists attenuation by a diverse suite of proteasome-specific small molecule inhibitors. Moreover, mouse, human, and yeast proteasomes exposed to the proteasome-depleted, naked mole-rat cytosolic fractions, recapitulate the observed inhibition resistance, and mammalian proteasomes also show increased activity.

Gel filtration coupled with mass spectrometry and atomic force microscopy indicates that these traits are supported by a protein factor that resides in the cytosol. This factor interacts with the proteasome and modulates its activity. Although HSP72 and HSP40 (Hdj1) are among the constituents of this factor, the observed phenomenon, such as increasing peptidase activity and protecting against inhibition cannot be reconciled with any known chaperone functions. This novel function may contribute to the exceptional protein homeostasis in the naked mole-rat and allow it to successfully defy aging.

There is a range of evidence to suggest infection by various fungi, bacteria, and viruses might contribute to the development of Alzheimer's disease (AD), all of this being somewhat unrelated to evidence suggesting that Alzheimer's is a lifestyle disease created by many of the same root causes as type 2 diabetes, such as obesity and lack of exercise. It may yet turn out to be the case that Alzheimer's is better considered as a collection of discrete conditions that happen to have the same end point. In this open access paper researchers look over what is known of the relationship between the ubiquitous persistent herpes simplex virus 1 (HSV-1) and Alzheimer's:

Among the multiple factors concurring to Alzheimer's disease (AD) pathogenesis, greater attention should be devoted to the role played by infectious agents. Growing epidemiological and experimental evidence suggests that recurrent herpes simplex virus type-1 (HSV-1) infection is a risk factor for AD although the underlying molecular and functional mechanisms have not been fully elucidated yet.

Herpes simplex type 1 virus primarily infects epithelial cells of oral and nasal mucosa. The newly produced viral particles may enter sensory neurons and, by axonal transport, reach the trigeminal ganglion where usually establishes a latent infection. The virus undergoes periodic reactivation cycles in which the newly formed viral particles are transported back to the site of primary infection through the sensory neurons, causing the well-known cold sores and blisters. However, the bipolar trigeminal ganglion neurons also project to the trigeminal nuclei located in the brainstem. From here, neurons project to the thalamus to finally reach the sensory cortex. This is the path through which the reactivated virus may reach the central nervous system (CNS), where it may cause acute neurological disorders like encephalitis or a mild, clinically asymptomatic, infection, or establish life-long latent infection. The weakening of immune system occurring during aging may favor this process. In addition to the neuronal route, HSV-1 may enter the CNS through the blood stream. Experimental evidence suggest that accumulation of intracellular damage caused by repeated cycles of viral reactivation may concur to neurodegeneration.

Some reports suggest that during infection herpes virus interacts with several human proteins that it uses to enter the cell and to move from plasma membrane to the nucleus and back. HSV-1 also uses the host's transcriptional machinery to replicate and binds to proteins that control immune surveillance or apoptosis. Noteworthy, in the attempt to eliminate the virus, host may even cause cell damage via immune and inflammatory responses targeting the virus-containing cells. If this happens in the CNS, HSV-1-induced inflammatory response may result in cell death and neurodegeneration.

Epidemiological, immunological and molecular evidence link HSV-1 infections to AD pathogenesis. HSV-1 is a ubiquitous virus that affects more than 80% of people over 65 worldwide. The first evidence suggesting the involvement of HSV-1 in AD dates back to 1982 and is based on the observation that people surviving HSV-1 related encephalitis showed clinical signs reminiscent of AD (i.e., memory loss and cognitive impairment), and that brain regions primarily affected were the same regions compromised in AD. During the last 30 years several research groups have conducted many studies providing solid support to the involvement of HSV-1 infection in AD pathogenesis. Here we will briefly summarize the main results of these researches.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4019841/

Aubrey de Grey is cofounder of the SENS Research Foundation, one of the few groups presently coordinating and funding serious scientific work on ways to repair the root causes of aging:

Marty Nemko: You claim that the public is indifferent to, even resistant to, efforts to extend lifespan. Isn't there strong evidence to the contrary, for example, people's commitment to exercise and the massive dietary supplement industry?

Aubrey de Grey: The public is terminally conflicted about life extension. Yes, they desperately try to stave off the ill-health of old age by already available means but are scared by the idea that we might some day have anti-aging medicine that actually delivers. This irrationality arises from fear: fear of the unknown and of getting one's hopes up prematurely. So they put the issue out of their mind.

MN: What about people who oppose extending longevity because they believe overpopulation is bad for the environment?

AD: That fear is based on a misconception: that the defeat of aging would occur without other progress. We are already addressing issues such as overpopulation by developing renewable energy, nuclear fusion etc. Birth rates are falling and maternal age at birth is rising as women become more educated and emancipated worldwide.

MN: You and those at your foundation and allied scientists believe there's a 50 percent chance that your proposed strategies for repairing age-related cell damage will come to fruition within 20 to 25 years. What's your evidence for that?

AD: It's the same kind of evidence that any pioneering technologist has: We have a concrete idea of what real anti-aging medication would consist of plus detailed knowledge of what technology already exists that constitutes the starting-points for developing that medication. So we have a reasonable sense of how hard it is to get from here to there and thus how long it will probably take.

Link: http://www.psychologytoday.com/blog/how-do-life/201408/the-present-and-future-life-extension