Fight Aging! Newsletter, August 3rd 2015

August 3rd 2015

Fight Aging! provides a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress towards the medical control of aging in order to prevent age-related frailty, suffering, and disease, as well as improvements in the present understanding of what works and what doesn't work when it comes to extending healthy life. Expect to see summaries of recent advances in medical research, news from the scientific community, advocacy and fundraising initiatives to help speed work on the repair and reversal of aging, links to online resources, and much more.

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  • Aubrey de Grey AMA at /r/futurology to be Held on August 4th, 9AM PST
  • The Failing Immune System and Its Role in Pulmonary Disease
  • The Wealthy are Just Like the Rest of Us in that Many Want to Do Good in the World
  • An Update on Spurring Heart Regeneration via PIM-1
  • The Struggle to Find Truth from a Position of Ignorance
  • DRACO Illustrates the Poor Funding Situation for Radical Departures from the Existing Status Quo
  • Latest Headlines from Fight Aging!
    • Proposing a Novel Method to Sabotage Cancer Cells
    • Altering Metabolism to Slow or Override Aspects of Aging
    • Transthyretin Amyloidosis is More Prevalent than Thought
    • More Salivary Gland Engineering
    • Suggesting the Correlation Between Intelligence and Longevity is Mostly Genetic
    • Towards Better Cryoprotectants, With an Eye on Thawing
    • Supercentenarian Research Study
    • Targeting an Improvement in Protein Quality Control
    • Slowing Aging By Restricting Cryptic Transcription
    • The Organoid Stage of the Tissue Engineering Revolution


The futurist Reddit community /r/futurology will be hosting an AMA - Ask Me Anything - event with Aubrey de Grey of the SENS Research Foundation this coming Tuesday August 4th, starting at 9AM PST. If you have questions on progress towards technologies needed for rejuvenation therapies, the goals of the SENS program, the details of the science, how the fundraising situation is changing, or about the Rejuvenation Biotechnology conference to be held later this month, then here is your chance.


In the paper quoted below, researchers review the links between immune system dysfunction in aging and pulmonary diseases - diseases of the lungs, ranging from infections to fibrosis. This is just one of many classes of medical condition that are much more serious and frequent in the elderly.

We all know that the immune system fails in its duties with aging. The elderly are frail in large part because they have little resistance to infection, their healing is impaired, and other functions depending on components of the immune system are similarly diminished. This is partially the result of high levels of various forms of cell and tissue damage, and partially the result of the immune system having evolved into a form that cannot continue to adapt to new threats indefinitely. To oversimplify somewhat, parts of it run out of space, too many cells devoted to memory of pathogens and too few to devoted to the destruction of those pathogens and potentially harmful cells.

The immune system is an enormously complex array of specialized cell populations, and so its progressive failure is similarly complicated. Beyond the disarray within the immune system, we must also consider that immune cells have intricate parts to play in the proper function of many different organs and tissue types, all of which are impacted as the immune system as a whole runs down. Wound healing, for example, falters in the old in part because of dysregulation in the macrophage population. One of the consequences of immune aging is a rising level of chronic inflammation, and it is known that inflammation contributes meaningfully to the development of many age-related conditions. Inflammation grows troublesome in lung tissues for example, the result of changing behavior on the part of immune cells.

The good news is that there are numerous potential ways to adjust the old immune system for more youthful performance, some of which could be realized quite soon, even though none are as yet comprehensive. Any engineering effort that results in more active, useful immune cells in circulation should be beneficial, however. This could be achieved through, for example, restoration of thymic function, or by destroying the clutter of memory cells or other unwanted sections of an experienced immune cell population, or even by using the techniques of stem cell medicine to grow a supply of immune cells and infuse large numbers of them on a regular basis.

The Impact of Immunosenescence on Pulmonary Disease

The shift in global demographics as a consequence of increased life expectancies has given greater clinical and research focus to the physiological process of aging and its impact on chronic disease. Morbidity and mortality from pulmonary illness have interestingly increased while those from other prevalent diseases such as cardiovascular or neurological have remained stable or in some cases decreased. This has led to recognition of the importance of age-related changes to the development and progression of lung disease.

While a multitude of cellular and molecular changes occur with age, their specific impact on the respiratory system, pulmonary physiology, and disease susceptibility remains undetermined. Age-related declines in immune function, termed "immunosenescence," likely play a critical role in the manifestation of age-related pulmonary diseases. Influencing both innate and adaptive components of the immune system, immunosenescence shapes the clinical phenotype observed in many chronic respiratory diseases including asthma and pulmonary fibrosis. This importantly differs from the same disease observed in younger cohorts. Age-related change in immunity additionally predisposes the elderly to pulmonary infection such as influenza and pneumococcus while a poorer vaccine response contributes to poorer outcomes.

Immunosenescence causes age-related declines in immune function at both cellular and serologic levels. Specific responses to foreign and self-antigens ensue promoting an increased susceptibility of the elderly to diseases including infection, cancer, autoimmune, and other chronic processes in addition to a poorer vaccine response. Both innate and adaptive arms of immune function are affected. Autoimmunity, immunodeficiency, and immune-dysregulation are some of the theories put forward to account for this physiological phenomenon; however it is likely that a combination of these takes place in vivo. Aging is associated with a chronic low grade inflammatory state. As such, proinflammatory cytokines including TNF-α, IL-1, and IL-6 are systemically elevated. Such "inflamm-aging" may be part of the aging process itself; however it has been proposed in the pathogenesis of several age-related inflammatory diseases including atherosclerosis, diabetes, and Alzheimer's.

Asthma and Allergy

While the asthmatic phenotype in children is well defined, "late-onset" asthma has lagged behind. This is largely explained by the heterogeneous nature of disease despite the similar treatment approaches. Until recently, phenotypes of "late-onset asthma" were based on aetiology, for instance, aspirin sensitivity, toxic exposures, or occupational influence or alternatively clinical disease characteristics such as mild, moderate, or severe. Consequently, mechanisms associated with late-onset asthma are incompletely understood. Suggestions are that it may occur as a consequence to viral infection that promotes persistent inflammatory change when coupled to the effects of immunosenescence.

Pulmonary Infection

Respiratory infections remain a leading cause of morbidity and mortality worldwide especially in older adults. The increased risk of community-acquired pneumonia in elderly patients ranges from 15 to 30% independent of socioeconomic status or comorbidities. Despite advances in molecular based detection techniques, there is limited evidence addressing specific mechanisms by which immunosenescence predisposes to pneumococcal associated disease. It is very likely that immunosenescence plays a role in increasing susceptibility to respiratory infection in the elderly population. This is likely facilitated by an impaired mucosal barrier, reduced mucociliary clearance, and blunted airway immune and inflammatory responses on exposure to potentially pathogenic microorganisms.

Pulmonary Fibrosis

Several of the affected cellular and molecular mechanisms associated with the aging process are implicated in idiopathic pulmonary fibrosis (IPF). Patients with IPF also demonstrate increased markers of oxidative stress both within the airway and systemically. Abnormal cellular senescence is demonstrated in patients with IPF, particularly from bone marrow derived stem cells such as fibrocytes. Fibrocytes have been shown to traffic into the lungs and to contribute to IPF pathogenesis. Additionally, high levels of circulating fibrocytes have been shown to herald a poor prognosis in IPF. A chronic background inflammatory state occurs in IPF that compares with immunosenescence associated "inflamm-aging."

Autoimmune Disease, Vasculitis, and Other Respiratory Diseases

The elderly have a higher rate of autoimmunity but lower prevalence of autoimmune disease. The explanation for this is uncertain; however, it is postulated to be due to the increased expansion of peripheral regulatory T-cells. Autoimmunity may increase the affinity of T-cells to self-antigens or latent viruses promoting an autoimmune process. Older adults have been shown to possess increased amounts of circulating autoantibodies due to the increased amount of tissue and cell damage coupled with apoptosis. Importantly however higher levels of autoimmunity do not equate with increased autoimmune disease. Thymic T-regulatory cells (Tregs) increase autoimmunity and reduce the CD4 and CD8 response which in turn increases susceptibility to infection and cancers. Recurrent bacterial and viral infections stimulate the release of proinflammatory cytokines which in turn are further expanded by activation of Tregs. Treg expansion is associated with T-helper 17 (Th17) cells and the persistence of chronic inflammation, a phenomenon that occurs during the physiological aging process.


The public echo chamber is often crowded by class warfare sentiments, and they are rarely absent from any discussion of progress in medicine. The green-eyed monster of jealousy dons its best suit and those without power denounce those who have more of it because of their greater wealth. Many believe that the wealthy have greater access to medical technology, while the truth is that those who complain, sitting in the first world, are in exactly the same tier as their wealthier counterparts, with access to exactly the same forms of medicine. The yawning gulf is that which exists between the complainants and the genuine poor in the third world, while the only thing that being first world wealthy buys you is a more handsome, well-dressed set of doctors than the average American will see. Under the hood the drugs are the same, the heart surgery the same, the cancer treatments the same, the outcomes the same. We are all aging to death, and the demographic studies tell us that massive wealth doesn't buy you all that much of an advantage at all.

That is unless the wealthy choose to spend that massive wealth on research and development, the production of entirely new capabilities in medicine. In which case they and everyone else might win together - provided the right research programs are funded. The wealthy who choose to fund medicine with the goal of extended health longevity are, with only a few exceptions, doing it not for their own benefit for but the population as a whole. Most of them believe that they will not live long enough to enjoy more than the first tentative results, as they are either not aware of the potential of SENS-like rejuvenation research programs if fully funded, or not yet convinced by those who advocate that work.

A truly wealthy individual is primarily a figurehead for a process, a life consumed by the demands of maintaining a vast amount of property and business interests. He or she cannot also be a citizen scientist, taking the years to become knowledgeable enough to make their own call about what is the best path forward in research. These high net worth individuals are each the leader of a tribe, beholden to advisers and interests, insulated from views and truth by a layer of people regardless of their desires on that front, and with many ongoing responsibilities that have little to do with philanthropy. Almost all philanthropists in the modern mold of successful businessmen are philanthropists in their snatched spare time, a minute here and a minute there taken hastily around the edges of the all-consuming job of steering their ventures. The exceptions are rare and usually older, retired, focused on spending down their fortunes to get things done: Paul Allen, Bill Gates, Paul Glenn, for example.

The class war voices would have us believe that the evil modern rich have turned to selfishly building longevity technologies for their own use, and to hell with the result of the world. That is simply untrue, not to mention impossible. It takes thousands of people, an entire industry, to build any entirely new class of medical technology. No-one can keep that to themselves: there are no secrets in business and science, and competitors always arise close on the heels of success. Further, the rejuvenation therapies of tomorrow will be infusions, mass-produced, and cheap as today's immune-altering biologics, taken every few years at a cost that after the first few years will settle to a couple of thousand dollars a shot or thereabouts if today's medicines are any guide. A few decades after that and these will be cheap enough for the third world, one step removed from free, like the simpler medicines of past years are today. In the matter of treating aging as a medical condition, we all win together or we all lose together. This is a collaborative game, not a competitive one.

Given this why do we not see the world's wealthy falling over themselves to change the world? Not just in the way we care about, to eliminate aging, but in general? I think it is that many simply do not know how to even begin to do this. Wealth doesn't grant vision, and becoming wealthy only gives you experience in managing your particular process for becoming wealthy. Most people don't look beyond their immediate surroundings, don't think far to the future, and that is just as true of high net worth individuals as it is of the rest of us. They have followed their particular passion, whatever it was that happened - as a side-effect - to mint money. That doesn't give a person any particular insight into how to use that money to change the world for the better. Look at the number of wealthy individuals who go into politics, for example. That is the ultimate public declaration of a lack of vision: it is an admission that you have no ideas on to how to change the world; you can see no further than ordering people around and rearranging the deck chairs that exist today.

So don't snipe at those who are actually trying to use their wealth to make the world a better place. They're figuring it out as they go along, just the same as everyone else has to, new entrants to areas of interest such as aging research and human longevity. Remember when you were first learning about this field of science and the present state of research? A wealthy individual will have just the same issues as you did; it's no easier for them to figure things out. The best that we can do is to help make the signposts better, more clear, and put forward sensible position statements on how newcomers can help to make a revolutionary difference in this field. (Such as by funding SENS research). This is just the same as we'd do for everyone else, as, after all, we're all in this together.

Why are all the tech billionaires chasing 'immortality'?

Although undoubtedly motivated by financial reward, for some investors who have proclaimed their wish to radically extend human lifespan there are also personal factors which can explain each individual's contributions. In this regard, those investing in radical life extension of course want to see the benefits of it themselves. But is it so hard to believe that billionaires really seek to do good with their money? Perhaps these investments can actually be explained as a desire to genuinely improve society by leading the cause of prolonging healthy lifespan.

When Page and Brin formed Calico Labs, Missy Krasner, a Google Health employee declared: "Larry and Sergey have always had this grand vision about how to help society and improve public health." For Sergey Brin this mission has so far manifested itself in over 150 million of personal investments, given primarily to companies that use data to understand DNA. Together with Mark Zuckerberg, he also co-sponsors the 33 million Breakthrough Prize for Life Sciences, awarded to scientists engaged in curing age-related diseases.

Peter Thiel is also driven by the desire to improve public health in the US, a system which he is openly critical of, and one which is increasingly burdened by an aging population. In a Reddit AMA Peter Thiel declared: "We would never design a system like this if we were to start from scratch." As a result, through his two billion capital Founders Fund, Thiel regularly provides money for biotechnology companies and researchers looking at different ways to slow down or stop aging. He has provided Aubrey de Grey's SENS Research Foundation with over six million to help with their mission to find drugs to cure age-related damage.

Similarly Bill Maris has long insisted on a more meaningful purpose for Google Ventures' investments, and moving into the field of healthcare represents a chance for Google money to be used towards developing a more optimistic scenario where people are given the chance to live longer healthier lives. In exclaiming "medicine needs to come out of the dark ages", he plans to use Google Ventures as a primary vehicle for making this happen.

For the newest tech billionaire to enter the arena, Facebook's Mark Zuckerberg the intentions particularly appear to be altruistic and humanitarian. To Stephen Hawking's question in a recent Facebook Q&A on which of the biggest mysteries in science he would like to have an answer to, Zuckerberg wrote an entire list, including "how to cure all diseases" and "what could enable us to live forever?" Also, in 2013, in a status update, the Facebook chief executive wrote: "Our society needs more heroes who are scientists, researchers, and engineers," and "we need to celebrate and reward the people who cure diseases, expand our understanding of humanity, and work to improve people's lives."

Thus, judging by the amounts of money and time these investors are devoting to supporting a range of innovations designed to improve both the human condition and healthcare, one can easily determine that there is genuine interest in making a positive impact on society.


A group of US researchers have demonstrated the potential to induce greater regeneration in heart tissue through overexpression of PIM-1. This is one of many varied approaches to generating greater repair and maintenance of tissues presently under development or in the clinic, ranging from stem cell transplants to the search for signal molecules that spur old tissues into greater activity. The researchers working on PIM-1 have been involved in this program for a number of years now: if you look back in the Fight Aging! archives, you'll find a report from 2012, for example. Sadly, from an outsider's perspective there is little visible difference between the state of this project then and now. The high level outline is the much the same and the expected course ahead is much the same. Benefits have been demonstrated in laboratory animals and human tissues, and the researchers would like to move to clinical trials, but lack the funding needed to take that step.

This is the situation for a lot of medical research these days, stuck at the level of gathering more data and creating more variants on the basic technology demonstration, seeking sufficient funding to enter the path to clinical trials. Thanks to the modern regulatory straitjacket for medical technology it is the case that moving beyond the laboratory has become so enormously and unnecessarily expensive in comparison to building a proof of concept that potential therapies can languish indefinitely in this state of demonstrated promise but lack of meaningful progress. I think this will be a growing class of research program in the future, absent some sort of sweeping change, as the cost of early stage research is falling precipitously while the cost of regulatory compliance for clinical development is steadily rising. Something has to give eventually.

Can We Restart the Heart?

The heart in particular seems to be resistant to developing cancerous cells. "When's the last time you heard of anyone having heart cancer? It's almost unheard of." That's not surprising from an evolutionary standpoint. If heart cells make a grave transcription error during cell division and your ticker ticks its last tock, there's no fixing the problem. So it makes sense that heart cells are incredibly careful when it comes to proliferating. But it's this very meticulousness that makes heart disease such an intractable problem. Over time, the cells burn themselves out. Their ability to repair themselves and generate fresh replacements gets progressively worse. By the time you reach old age and start experiencing symptoms of age-related heart disease, your cardiac cells are running on fumes and aren't able to properly divide into new cells.

Researchers are exploring the results of taking an enzyme, Pim, known to be associated with growth and survival of certain types of cancer cells, and causing it to be overexpressed in cardiac progenitor cells in mice. In healthy cells, Pim helps facilitate chromosome splitting, a key part of the cellular division process. The gene that encodes the production of this enzyme, PIM1, is what's known as a proto-oncogene. That means that by itself, the gene doesn't cause cancer. But when it teams up with another gene, Myc, tumors are likely to form. Fortunately, the Pim/Myc combination isn't an issue in heart progenitor cells, meaning you could tweak those cells to overexpress the PIM1 gene without raising the risk of cancer.

Researchers modified mouse heart progenitor cells to overexpress PIM1 in specific locations within the cell, targeting specific locations with more of the critical Pim enzyme in hopes that it would protect against aging-related heart disease. And it worked. Compared to controls, the mice with overexpressed PIM1 lived longer and showed stronger cell proliferation. But interestingly, the way it worked was different depending on where in the cell the gene was overexpressed. If the researchers caused PIM1 to be overexpressed in the progenitor cell's nucleus, they saw increased proliferation into new cells. If they overexpressed the gene in a different region of the cell, the mitochondria, they found that the enzyme inhibited the cell's natural self-destruct signals, causing them to live longer.

Functional Effect of Pim1 Depends upon Intracellular Localization in Human Cardiac Progenitor Cells

Human cardiac progenitor cells (hCPC) improve heart function after autologous transfer in heart failure patients. Regenerative potential of hCPCs is severely limited with age, requiring genetic modification to enhance therapeutic potential. A legacy of work from our laboratory with Pim1 kinase reveals effects on proliferation, survival, metabolism, and rejuvenation of hCPCs in vitro and in vivo. We demonstrate that subcellular targeting of Pim1 bolsters the distinct cardioprotective effects of this kinase in hCPCs to increase proliferation and survival, and antagonize cellular senescence.


Today I stumbled over a popular press article on the topic of longevity science, in which a fair amount of attention is given to Aubrey de Grey and the SENS Research Foundation vision for rejuvenation biotechnology. Like most such articles it is a view from an individual who, though a scientist himself, stands far outside the field of aging research - just like much of the world he is looking in with limited knowledge, trying to make sense of it all, in search of truth from a position of ignorance.

This struggle, the search for truth in a field in which you will never personally know enough to verify any significant detail for yourself, is one of the defining characteristics of the human condition. We have the urge to know in the moment that we encounter a new assertion, but we cannot justify spending the years it would take to know ourselves, versus accepting a secondhand truth that may or may not in fact be correct. It is frequently a challenge even to understand how great or little is the uncertainty of any claim we come across. This has always been the case, but now that we are all connected in a vast web of communications, superficial summaries of every aspect of human knowledge at our fingertips, the quest for truth is a mouse click away every moment of the day, and we accept all too much of what we see simply because we do not have the time to do otherwise.

This is compounded by the fact that some fields of science are in tumult, experienced researchers in public dispute over vital theories. It is a sign of the times, of accelerating progress. Astrophysics and cosmology were some of the first to benefit from the computational revolution and haven't stood still for long enough to catch a breath in decades; what a student learns in school is out of date within a few years. The life sciences are now in much the same boat, and the study of aging in fact has a great in common with the study of astrophysics in that (a) technology now enables theorizing to proceed far more rapidly than the collection of new and useful data, (b) the problem space is vast, the existing volume of data huge, and the unknown details yet to be filled in even larger, which means that (c) many theories can be made to fit the data that we do have, these theories are multiplying rapidly, and proving or disproving them is a slow process indeed. The junk builds up alongside the specks of gold, and sifting becomes an ever more laborious process.

This all matters far more for aging than for the study of the observable universe beyond the Earth because we are operating under a deadline. We're all aging, and if the research community chases the wrong theories for the next decade or two, meaning those that require expensive work for marginal benefits, that will make the difference between a good life and a painful death in old age for most of us. Pure science is all well and good, but therapies are needed, and pushing for meaningful development as fast as possible requires a slightly different focus from that of the standard scientific model of learning everything there is to know about the system in question before taking action. One other way in which aging research is similar to astrophysics is that very little of it has any connection with development of new technologies: most aging research groups are entirely happy with their focus on gathering data and nothing more.

In any case, the author of this article is some places self-aware of the issue of ignorance and truth, while in others he hasn't looked deeply enough. He could have looked at the scientific advisory board of the SENS Research Foundation today to see the heavy-hitters in the scientific community who are on board rather than simply quoting some of those who opposed SENS as a research strategy in public a decade ago, to pick one example. How do you sift for truth? You look for networks of people who have taken the time to run the analysis, who have the specialized knowledge to say one way or another. There are few who steadfastly claim SENS is the wrong road these days, and they are largely in the programmed aging community, not the same folk as those who turned up their noses more than ten years ago, long before SENS and SENS-like programs had produced numerous confirmations of the potential of this research strategy.

Since then we've seen examples of senescent cell clearance, mitochondrial repair through allotopic expression is in late stage development for the treatment of mitochondrial disease, work on therapies for senile systemic amyloidosis is moving ahead, and so forth. It's a different world now. All this information is out there if you care to look, or ask those who have been following along all this time:

The God quest: why humans long for immortality

Myths live on by disguising themselves in the apparel of modernity. So it is fully to be expected that immortality today is a business offering to tailor clients' diet regimes, that it is expounded at conferences in PowerPoint presentations, that it announces itself with words such as "telomere extension" and "immune regulation". This is distressing to serious biogerontologists, who worry that funding of their careful work on age-related disease and infirmity will seem boring in comparison to supporting folks who promise to let us live for ever. They are right to be concerned but sadly theirs will ever be the fate of scientists working in a field that touches on fabled and legendary themes, where both calculating opportunists and well-meaning fantasists can thrive. Age-related research until recently has been rather marginalised in medicine, and the gerontologist Richard Miller of the University of Michigan suggests one reason for this: "Most gerontologists who are widely known to the public are unscrupulous purveyors of useless nostrums."

It is surprising, perhaps alarming, that we know so little about ageing. We get old in many ways. For instance, some of our cells just stop dividing - they senesce. While this shutdown stops them becoming cancerous, the senescent cells are a waste of space and may create problems for the immune system. Cell senescence may be related to a process called telomere shortening: repeated cell division wears away the end caps, called telomeres, on the chromosomes that contain our genes. Although shortened telomeres seem to be related to the early onset of age-related disease, the ­relationship is complex. It is partly because cancer cells are good at regenerating their telomeres that they can divide and proliferate out of control. Cells also suffer general wear and tear because of so-called oxidative damage, in which reactive forms of oxygen - an inevitable by-product of respiration - attack and disrupt the molecules that sustain life. This has made "antioxidants" such as Vitamins C and E, and the compound resveratrol, found in red wine, buzzwords in nutrition. But the effects of oxidative damage and antioxidants are still poorly understood.

These factors and others can interact with each other in complex ways. A group of UK experts called the Longevity Science Panel, funded by the insurers Legal & General, concluded in a 2014 report: "There is little consensus on which mechanisms of ageing are the most important in humans." Biogerontologists don't even agree about whether the ageing process itself is best considered as a single effect, or many.

Aubrey de Grey genuinely seems to believe not only that he is on to something but that his ideas are of humanitarian importance. He is nothing if not sincere in thinking that to slow and ultimately reverse ageing is an obligation that science is failing dismally to fulfil. He regards old age as a disease like any other: it is scandalous, he says, that it kills 90 per cent of all human beings and yet we are doing so little about it. De Grey calls his quest a "crusade to defeat ageing", which he regards as "the single most urgent imperative for humanity". Death, he says, "is quite simply repugnant", and he equates our acceptance of it in elderly people with our past casual acceptance of the slaughter of other races.

How does de Grey think we will stop our bodies from ageing? He proposes a seven-point plan called SENS (Strategies for Engineered Negligible Senescence) that, in his view, picks off all the processes by which our cells decline, one by one. We can get rid of unwanted cells, such as excess fat cells and senescent cells, by training the immune system or triggering the cells into eliminating themselves. We can suppress cancer by silencing the genes that enable cancer cells to repair their telomeres. We can avoid harmful mutations in the handful of genes housed in our energy-generating cell compartments called mitochondria by making back-up copies, to be housed in the better-protected confines of the cell's nucleus, where the chromosomes reside. We can find drugs that inhibit the degradation of tissues at the molecular level. And so on.

His detractors point out that almost all of these plans amount to saying, "Here's the problem, and we'll find a magic ingredient that fixes it." If you think there are such ingredients, they say, then please find just one. He is looking. With inherited wealth and venture capital backing from the likes of PayPal's co-founder Peter Thiel, de Grey maintains an institution in Mountain View, California, called the SENS Research Foundation, with laboratories to investigate his proposals. But he insists that the criterion of success isn't a steadily increasing longevity in model organisms, because SENS is a ­package, not a series of incremental steps. No one criticised Henry Ford, de Grey says, because the individual components of his cars didn't move if burning petrol was poured on them.

The hope of medical immortality may be false but it raises moral and philosophical questions. Is there something fundamental to human experience in our mortality, or is de Grey right to see that as a defeatist betrayal of future generations? Do we value life precisely because it passes? And is there an optimal span to our time on earth? These are pertinent questions for even the most sober gerontologists, because the truth is that the ageing process can be slowed, and we can expect to have longer lives in the future and to remain well and active for more of that time.

For instance, it has been known for decades that rats and mice live longer, and stay healthy for longer, when given only the quantities of a well-balanced diet that they need and no more. This so-called caloric restriction seems to slow down ageing in a wide range of tissues. No one knows why, but it seems to point to a common mechanism of ageing that extends between species. Some researchers think that with caloric restriction it might be possible to extend mean human lifespans to roughly 110 years. Others aren't persuaded that caloric restriction would be effective at all for slowing ageing in human beings - studies on rhesus monkeys have been inconclusive - and they point out that it is a bad idea for elderly people.

Couldn't we just make an anti-ageing pill? There are candidates. The drug rapamycin, which is used to suppress immune rejection in organ transplants and as an anti-cancer agent, also has effects on ageing. It stops cells dividing and suppresses the immune system - and increases the lifespan of fruit flies and small mammals such as mice. But it has nasty side effects, including urinary-tract infections, anaemia, nausea, even skin cancer. Other researchers think that the answer lies with genetics. The genomics pioneer Craig Venter, whose company Celera privately sequenced the human genome in the early 2000s, recently launched Human Longevity, Inc together with the spaceflight entrepreneur Peter Diamand. It aims to compile a database of genomes to identify the genetic characteristics of long-lived individuals. Whether Venter will find genes responsible for the exceptional longevity of some individuals, and whether they would be of any use for extending average lifespan, is another matter. "His approach has some serious conceptual limitations," the Michigan gerontologist Richard Miller tells me. "I think he's radically overestimating the degree to which the ageing process is modulated by genetic variation."

To read one script, we are on the cusp of a revolution in ageing research. Google has recently created the California Life Company, or CALICO, which seems to be seeking life-extending drugs. The hedge-fund billionaire Joon Yun has launched the Palo Alto Longevity Prize to bring about the "end of ageing", so that "human capacity would finally be fully unleashed". But the Longevity Science Panel, composed of scientists rather than venture capitalists, had a much more sobering message. To get a substantial increase in lifespan - an extra decade or so, say - we would need to find ways of slowing the ageing rate by half (which the panel deemed barely plausible given the current knowledge) and apply that treatment throughout a person's life from an early age. If you're already middle-aged today, even major breakthroughs are barely going to make any difference to how long you will live.

Researcher Richard Miller is a good example for the complexity of positions in aging research. He is an outspoken opponent of SENS research, yet he and I are basically on the same page when it comes to the poor value of genetic research into variations in human longevity. When you look at a given researcher's position, it isn't just a matter of for and against, or a few large camps of opinion, but rather in a field this complex you really have to make a list of twenty or so nuanced opinions and run through them all to check boxes. Everyone has a slightly different overall take, and while many overlap to a considerable degree, there is always something to disagree on. This state of affairs will continue until good data arrives to support one course forward above the others - which I would expect to happen when the first robust SENS-like repair therapies in mice demonstrate unequivocal extension of healthy life span. We're somewhere near that point for senescent cell clearance, I think, but there is much more to come yet.


DRACO, double-stranded RNA activated caspase oligomerizer, is a broadly applicable antiviral technology that has been under development at a slow pace for quite some time now. You might recall some publicity back in 2011, for example, but that marked the results of years of earlier work. DRACO attacks infected cells, not the viruses themselves, following the principle of finding a common vulnerability to target rather than trying to tailor therapies to every different variety of attacker. Despite technology demonstrations to show effectiveness against a broad range of very different types of virus, and the fact that this technology can in principle be applied to near any type of virus, there is next to no ongoing funding for DRACO. It stands as an example of the fact that you can build a better mousetrap and still have the world ignore you. In this case DRACO is languishing despite grave concerns regarding spreading viral resistance to existing drugs, and billions devoted to constructing new drugs that are just more of the same.

Advocacy and philanthropy are often the only ways forward for a new medical technology that is a radical departure from the present status quo. This is a lesson to keep in mind when we talk about the various branches of longevity science. It is hard to obtain funding in the life sciences in any meaningful fashion, and the organization of funding for any ongoing serious effort has become a baroque effort involving many players, all of whom are operating with perverse incentives that only serve to slow down progress and make funding less effective on a dollar for dollar basis. For example the large funding bodies are extremely risk-averse, and thus almost never fund the most important early-stage and high-risk projects, the science that is actually science, at the forefront and involving new discoveries. These funding bodies only ever put money into ongoing development wherein which the researchers can already demonstrate proof of concept and an understanding of the mechanisms involved. Getting to that point for any new line of research requires creative accounting and the help of philanthropic donations, and even so there is far too little actual science taking place in major laboratories.

I noticed a recent paper, one of the few for DRACO of late, in which the authors provide evidence to show that DRACO is a worthwhile avenue for antiviral therapies in pigs, targeting diseases for which there are no presently adequate therapies. Another of the draws here is that DRACO isn't just an approach for near all viruses but also an approach that should work for near all mammals as well.

DRACO inhibits porcine reproductive and respiratory syndrome virus replication in vitro

Porcine reproductive and respiratory syndrome virus (PRRSV) continues to cause substantial economic losses to the pig industry worldwide. Current vaccination strategies and antiviral drugs against PRRSV are still inadequate. Therefore, there is an urgent need for new antiviral strategies to control PRRSV.

Double-stranded RNA (dsRNA) Activated Caspase Oligomerizer (DRACO) is a synthetic construct consisting of a dsRNA detection domain, an apoptosis induction domain, and a transduction tag. It has been shown to have broad-spectrum antiviral activity, but there have been no reports regarding its effect on PRRSV. Here, we demonstrate that DRACO exhibits robust antiviral activity against PRRSV infection by suppressing virus RNA and protein synthesis in both Marc-145 cells and porcine alveolar macrophages (PAMs). In addition, DRACO still exhibited strong anti-PRRSV activity when viral replication was enhanced by knockdown of interferon-induced protein with tetratricopeptide repeats 3 (IFIT3) in Marc-145 cells. Furthermore, in PAMs, DRACO was capable of inducing IL-6 expression and reducing Hsp70 expression, which might contribute to the inhibition of PRRSV infection.

Collectively, our results imply that DRACO holds promise as a novel anti-PRRSV therapeutic drug.

Yet there is insufficient funding for any meaningful ongoing development of DRACO. Some people have been trying to put together a foundation to raise philanthropic funds, and of late some of their advocacy efforts can be seen at Facebook, but so far there is little progress towards gathering broader support. It is most frustrating; yet another example of the way in which our world is far from ideal.


Monday, July 27, 2015

Some types of cancer produce cells that are not as picky as ordinary, correctly functioning cells in the nucleosides they are willing to incorporate into their DNA during repair and replication. Researchers here propose that by introducing a suitably altered nucleosides into tissues it should be possible to produce DNA in cancer cells that will cause them to destroy themselves. Other cells in the body will be unharmed by the treatment. This is still in the early conceptual stage of development, however; it remains to be seen what hurdles lie ahead in the development of a practical therapy built on the idea:

Normal cells have highly selective mechanisms to ensure that nucleosides - the chemical blocks used to make new strands of DNA - don't carry extra, unwanted chemical changes. But some types of cancer cells aren't so selective. These cells incorporate chemically modified nucleosides into their DNA, which is toxic to them. The findings indicate that it might be possible to use modified nucleotides for specific killing of cancer cells.

Cells are thrifty when it comes to synthesizing new DNA. In addition to making new nucleotides, they recycle chemical parts from the DNA of dying cells, or DNA that we ingest in our diets. However, one of the four types of nucleotides in DNA - the 'C' in genetic sequences - is often chemically modified. These chemical modifications, which are called epigenetic changes, are important for controlling genes and need to be in the correct places in DNA for cells to function normally. If the epigenetic modifications are on the wrong C nucleotides, they could make cells cancerous or kill them.

The enzymes that recycle nucleotides are highly specific. They don't use the modified nucleosides, so the new DNA is epigenetically 'clean.' However, when they looked at the recycling process in cancer cell lines, researchers discovered that some of the cancer cells are able to transform these nucleosides, allowing incorporation into new DNA. This process often kills the cells. It was the cancer cell lines that expressed unusually high levels of a protein called cytidine deaminase (CDA) that made this mistake in recycling. CDA is often overexpressed in certain tumor types, including pancreatic cancer. "It has been suggested that CDA inactivates cytidine analogues that are already used in the clinic to treat some blood and pancreatic cancers. In a strikingly reverse scenario, the nucleosides that we used in our study are relatively harmless until they encounter CDA, which converts them into hostile cytotoxic agents." The researchers will likely continue to investigate this new avenue for 'epigenetic' drugs as cancer therapies.

Monday, July 27, 2015

Below find linked a popular science article on some of the strands of research that aim at safely altering the operation of cellular metabolism to either (a) gently slow aging by reducing the pace at which underlying cell and tissue damage accumulates or (b) override some of the reactions to cellular damage that cause declines in tissue maintenance. Neither strategy aims at repair of that damage, unfortunately, and so is ultimately limited in the quality of results that can be achieved: no true rejuvenation, no indefinite healthspan, just a slowing of the inevitable. Nonetheless, overriding natural mechanisms to restore age-related declines in stem cell activity seems to be on track to produce benefits despite the continued presence of unrepaired cell and tissue damage. The evolved balance between cancer risk and stem cell decline appears to leave more room for action than anticipated.

The majority of older Americans live out their final years with at least one or two chronic ailments, such as arthritis, diabetes, heart disease or stroke. The longer their body clock ticks, the more disabling conditions they face. Doctors and drug companies traditionally treat each of these aging-related diseases as it arises. But a small group of scientists have begun championing a bold new approach. They think it is possible to stop or even rewind the body's internal chronometer so that all these diseases will arrive later or not at all. Studies of centenarians suggest the feat is achievable. Most of these individuals live that long because they have somehow avoided most of the diseases that burden other folks in their 70s and 80s. Nor does a centenarian's unusual longevity result in an end-of-life decline that lasts longer than anyone else's. In fact, research on hundreds of "super agers" suggests exactly the opposite. For them, illness typically starts later and arrives closer to the end.

Living longer may come with trade-offs. Making old cells young again will mean they will start dividing again. Controlled cell division equals youthfulness; uncontrolled cell division equals cancer. But at the moment, scientists are not sure if they can do one without the other. Figuring out the right timing for treatment is also complicated. If the goal is to prevent multiple diseases of aging, do you start your antiaging therapies when the first disease hits? The second? "Once you're broken, it's really hard to put you back together. It's going to be easier to keep people healthy." So it probably makes more sense to start treatment years earlier, during a healthy middle age. But the research needed to prove that supposition would take decades.

If various diseases can be pushed off, the next obvious question is by how long. It will take at least another 20 years of study to answer that question. Scientists have successfully extended the life span of worms eightfold and added a year of life to three-year-old lab mice. Would these advances translate into an 80-year-old person living five or six centuries or even an extra 30 years? Or would they get just one more year? Life extension in people is likely to be more modest than in yeast, worms, flies or mice. Previous research has suggested that lower-order creatures benefit the most from longevity efforts - with yeast, for instance, deriving a greater benefit in caloric-restriction experiments than mammals. The closer you get to humans, the smaller the effect on life span. And what magnitude of benefit would someone need to justify taking - and paying for - such a treatment? "Do you take a drug your whole life hoping to live 4 percent longer or 7 percent longer?"

I would hope that question never arises in any practical sense for the population at large, as efforts to alter metabolism to slow aging should be quickly overtaken and discarded in the near future by the far better results I'd expect to see achieved through damage repair therapies, such as those proposed in the SENS programs. SENS-like rejuvenation approaches based on repair of cell and tissue damage are slowly advancing to the point of generating meaningful results. That is already the case for senescent cell clearance, but there are numerous other lines of rejuvenation research still at far earlier stages. The sooner this transition happens, the better off we all are.

Tuesday, July 28, 2015

Evidence suggests that transthyretin (TTR) amyloidosis, also known as senile systemic amyloidosis, is the condition that kills the oldest people, those who have survived every other aspect of aging to reach ages of 110 and greater. Here, I'll note a review paper in which the authors point out that TTR amyloidosis in aging is very likely much more prevalent than this: not a condition only seen in the oldest old, but rather also the cause of a small but sizable fraction of some varieties of heart failure across the entire elderly population. It has been misdiagnosed due to lack of adequate testing for the condition, and thus the development of treatments has not been prioritized highly enough.

Numerous types of amyloid appear in tissues with aging, each consisting of a specific misfolded protein that precipitates to form form clumps and fibrils. In the case of transthyretin amyloid, these deposits clog blood vessels and lead to hypertrophy of the heart, ending with something that looks a lot like congestive heart failure.

The obvious path to dealing with amyloids and their contribution to aging and age-related disease is to periodically remove them. This is the approach taken by much of the Alzheimer's research community, but in that case has proven unexpectedly challenging to date even though a large amount of funding is devoted to, for example, the development of immune therapies to achieve this goal. In the case of TTR amyloidosis there is very little work under way, but the SENS Research Foundation has funded a so far successful program into the use of catabodies to degrade transthyretin amyloid. As this paper notes, the need for therapies is there, even if under-appreciated by the medical community at present:

Transthyretin (TTR) amyloidosis is a disease caused by systemic deposition of wild-type (WT) or mutant TTR fibrils, resulting in heart failure when deposition occurs in the heart. Mutant TTR deposition leads to familial TTR amyloid. Accumulation of the normal TTR protein causes WT cardiac amyloidosis (also known as senile amyloidosis).

In recent years, heart failure with preserved ejection fraction (HFpEF) has become increasingly prevalent among individuals hospitalized for acute decompensated heart failure. A recent autopsy series provided pivotal evidence that TTR amyloidosis is more prevalent among HFpEF population. Of the 109 Caucasian patients seen at Mayo Clinic hospitals between 1986 and 2001 with subsequent autopsy, 5% were found to have moderate or severe WT TTR deposits in the left ventricle, consistent with WT systemic amyloidosis as the primary etiology of heart failure. In addition, mild interstitial and/or variable severity of intramural coronary vascular WT TTR deposition occurred in 12% of this cohort. None of these patients carried an antemortem diagnosis of cardiac amyloid.

How TTR amyloidosis contributes to the development of HFpEF is not known. We can only hypothesize that the accumulation of dense TTR amyloid likely worsens diastolic function. Slow accumulation of pathologic TTR amyloid deposits in the heart may initially cause asymptomatic left ventricular (LV) hypertrophy, with relatively late diagnosis because of its gradual progression. The diagnosis of TTR cardiac amyloidosis is often missed until very late in the disease course, as it is an indolent illness affecting the same elderly population with HFpEF. Unlike light chain (AL) amyloidosis, there is no readily available blood test for misfolded TTR protein. Diagnostic algorithms, including non-invasive imaging modalities and endomyocardial biopsy, have been published elsewhere. Yet these algorithms can only be applied if cardiac amyloid is suspected.

Tuesday, July 28, 2015

Here is recent news of another team working to engineer salivary gland tissue, one of many parts of the body typically given little thought until it stops working. This team doesn't seem to be as close to a functional end result as the Japanese group I pointed out last month, but a diversity of approaches is always a good sign:

Saliva is critical to good health. It helps with speaking, swallowing, washing food off teeth, initial food digestion and preventing oral infections. Insufficient saliva can cause chronic bad breath, cavities, gum disease, as well as systemic infections. There is no treatment for low-producing or nonfunctioning salivary glands, and the glands have little regenerative capability.

A research team is the first to use silk fibers as a framework to grow stem cells into salivary gland cells. Silk is a good choice for stem cell scaffolding because it is natural, biodegradable, flexible and porous, providing the developing cells easy access to oxygen and nutrition. It also does not cause inflammation, as other scaffold materials have. The researchers' new process is the first major step toward helping more than 4 million people in the U.S. with a degenerative autoimmune disease called Sjögren's syndrome, in which the body attacks its own tear ducts and salivary glands. Low saliva production also is a devastating problem for thousands of patients who have had radiation treatment for head and neck cancer, as well as about 50 percent of older Americans whose medications can cause dry mouth, also known as xerostomia.

"Salivary gland stem cells are some of the most difficult cells to grow in culture and retain their function. In our process, we purified the silk fibers by removing a number of contaminants. We put stem cells from rat salivary glands on the silk framework with a media to nourish them. After several weeks in culture, the cells produced a 3-D matrix covering the silk scaffolds. The cells had many of the same characteristics as salivary gland cells that grow in the mouth. Until now, retention of salivary gland cell properties has not been possible using other tissue culture techniques. This unique culture system has great potential for future salivary gland research and for the development of new cell-based therapeutics."

Because there are few salivary gland stem cells in the human mouth, the scientists plan to continue using rat salivary glands to refine the process, but eventually hope to use stem cells derived from human bone marrow or umbilical cord blood to regenerate salivary glands for humans.

Wednesday, July 29, 2015

Researchers building on twin study data are suggesting that the well-known correlation between greater intelligence and a little additional longevity is mostly genetic in nature, not a matter of more intelligent people making better lifestyle choices, or tending to be wealthier, or any of the other social or economic factors that are associated with both intelligence and longevity. The size of the effect due to intelligence is small, but a demonstration of it being due to genetics is not the result I would have expected based on past data on human longevity. To date I'm aware of little other research to back this point of view. For one of them, you might look at a paper from a few years back that suggests learning and longevity in bees are both influenced by the same underlying mechanisms of robustness in biological systems, their resistance to stress.

The tendency of more intelligent people to live longer has been shown, for the first time, to be mainly down to their genes. By analysing data from twins, researchers found that 95 per cent of the link between intelligence and lifespan is genetic. They found that, within twin pairs, the brighter twin tends to live longer than the less bright twin and this was much more pronounced in fraternal (non identical) twins than in identical twins. Studies that compare genetically identical twins with fraternal twins - who only share half of their twin's DNA - help distinguish the effects of genes from the effects of shared environmental factors such as housing, schooling and childhood nutrition.

"We know that children who score higher in IQ-type tests are prone to living longer. Also, people at the top of an employment hierarchy, such as senior civil servants, tend to be long-lived. But, in both cases, we have not understood why. Our research shows that the link between intelligence and longer life is mostly genetic. So, to the extent that being smarter plays a role in doing a top job, the association between top jobs and longer lifespans is more a result of genes than having a big desk. However, it's important to emphasise that the association between intelligence and lifespan is small. So you can't, for example, deduce your child's likely lifespan from how he or she does in their exams this summer. It could be that people whose genes make them brighter also have genes for a healthy body. Or intelligence and lifespan may both be sensitive to overall mutations, with people with fewer genetic mutations being more intelligent and living longer. We need to continue to test these ideas to understand what processes are in play."

Wednesday, July 29, 2015

Below find an interesting discussion of one research program aimed at producing a better class of cryoprotectant that enables tissue thawing without damage. The organ storage and cryonics industries have many of the same technical goals: how to preserve complex tissues for the long term at low temperatures while enabling a safe thaw at the far side of storage. Some research companies straddle both industries, such as 21st Century Medicine. The enemy here is ice, as it is crystallization that destroys cells and structures in straight freezing. If near-future thawing is not a concern, then many varieties of cryoprotectant compounds are useful. When infused into tissue the result is vitrification rather than freezing, with minimal ice crystal formation and preservation of even very fine-scale cellular structures, such as synapses and other aspects of brain structure thought to hold the data of the mind.

To date there are very few examples of the successful thaw and use of a vitrified organ, even in the laboratory. It is research programs such as the one noted here that may help to change this state of affairs. Given better cryoprotectants and significant use of long-term organ storage in medicine, one would hope that the public will become more accepting of cryonics as an end of life choice, a shot at living again to see a better future for those who will age to death prior to the advent of rejuvenation therapies.

Researchers have synthesised a polymer that limits ice crystal growth in frozen red blood cells as they thaw. The polymer is set to pave the way for similar synthetic structures that mimic the properties of natural antifreeze proteins. During cryopreservation, cells and tissues are stored at sub-zero temperatures and thawed before use. However, frozen cells can be damaged as they defrost. When ice melts, it can refreeze into larger crystals that puncture cells from the outside. This process, called recrystallisation, is especially damaging for organs and blood bags, which defrost over a long time. "'If you directly freeze cells they don't survive due to ice-induced damage, and the traditional solution is to add antifreeze solvents. Although these work, they involve complex preparation procedures, and transfusing large volumes of solvent is not desirable. Alternatives to the conventional cryoprotectants are urgently required as the fields of regenerative medicine and tissue engineering continue to advance."

Unlike proteins, which need to be extracted or expressed in microorganisms, polymers are more accessible, processable, tunable and cheaper. Researchers modified an already available polymer called a polyampholyte, which is composed of monomers with both positively and negatively charged groups. The polymer functions outside the cells, so it can be washed-off after thawing. This may explain its good compatibility with red blood cells. Up to 60% red blood cell recovery after freezing was observed during slow thawing when the new polymer was used, and this increased to 80% when the cells were thawed quickly. Notably, the polymer was capable of inhibiting ice recrystallisation by 50%.

The mechanism by which the synthesised polymer inhibits ice recrystallisation is still not clear. Although it has been assumed for many years that macromolecules had to bind directly to ice crystal faces to inhibit growth, their work supports the idea that binding to ice crystals is not essential. "It seems that they somehow disrupt the rate exchange of water molecules between ice crystals, via the quasi liquid layer, although we do not have direct evidence for this at the moment. As to why the ampholyte structure works, we are not sure, but we are thinking that it might be a semi-rigid polymer due to charged interactions along the backbone, which helps. Cheap, non-toxic, degradable polymers that inhibit ice recrystallisation may become attractive non-permeating additives for cryopreservation of red blood cells if these boost cell recovery by more than 80% and allow for prolonged post-thaw storage."

Thursday, July 30, 2015

A number of ongoing research programs aim to collect more data on the biochemistry and genetics of the oldest of old people, and here is an example of one of them. I don't believe that these efforts contribute greatly towards building meaningful treatments for aging, for all the same reasons that trying to build calorie restriction mimetic drugs is a dead end: the underlying causes of aging are known, the damage that produces degeneration and loss of function, and researchers should be focused on repairing it to extend healthy life by decades, not on exploring comparatively small differences in how the body adapts to high levels of damage, or how to eke out a few more years while in a diminished and dysfunctional state. From a purely academic perspective, the study of natural variations in human aging is a good way to learn more about the fine details of how exactly aging progresses at the cellular level, however. Just don't expect this to have practical results beyond the production of new knowledge.

Supercentenarians are very rare, very precious individuals, who have lived to at least 110 years of age. Surviving decades longer than their peers -- often in far better health -- supercentenarians may hold the keys to protection from disease, decline, and early death. Our researchers are engaged in an extensive, international study of individuals demonstrating increased or extreme resistance to devastating, age-related diseases -- such as cancer, cardiovascular disease, diabetes, Alzheimer's disease, Parkinson's disease, organ failure, immune system failure, and neurodegeneration -- as well as the illness and injury caused by bone and muscle deterioration, dementia, loss of mobility, and cognitive decline. Supercentenarians have avoided the vast majority of these age-related illnesses, and the study of the protective mechanisms that have ensured their survival may lead to the discovery and development of new treatments and therapies, bringing the good health and great longevity of supercentenarians to the rest of us.

There is a great deal of research to support the theory that supercentenarians' longevity is hereditary. The siblings of supercentenarians are up to 17 times more likely to survive to age 100 than the siblings of non-supercentenarians. Many of these individuals also enjoy increased and lifelong resistance to disease, suffering far less age-related morbidity. Studies reveal a strong link between inherited traits and healthy longevity, as well as mechanisms that protect against a wide variety of illnesses. The careful study of supercentenarians and their families can provide unparalleled insights into the mechanisms of health, aging, and disease.

Thursday, July 30, 2015

A range of research efforts aim at finding ways to improve or enhance the activity of cellular maintenance mechanisms involved in ensuring quality control. Proteins are the building blocks of cell machinery but constantly become damaged or misfolded, which can then cause harm through incorrect function. Thus cells work hard to clear out, break down, and recycle these problem molecules, but all of these mechanisms decline with aging; based on what we know to date, this happens because the repair machinery itself is vulnerable to forms of damage or can be negatively impacted by reactions to damage taking place in other processes, just like the rest of a cell.

So far there is little concrete progress towards therapies based on enhanced protein quality control, though a variety of genetic alterations that extend life in laboratory animals are shown to include enhanced quality control as a part of their effects. I would expect some candidate therapies to emerge in the years ahead, however, as the interest in moving in that direction certainly exists:

Impairment of "protein quality control" in neurons is associated with the etiology and pathogenesis of neurodegenerative diseases. The worn-out products of cell metabolism should be safely eliminated via the proteasome, autophago-lysosome and exocytosis. Insufficient activity of these degradation mechanisms within neurons leads to the accumulation of toxic protein oligomers, which represent a starting material for development of neurodegenerative proteinopathy.

The spectrum of CNS linked proteinopathies is particularly broad and includes Alzheimer's disease (AD), Parkinson's disease (PD), Lewy body dementia, Pick disease, Frontotemporal dementia, Huntington disease, Amyotrophic lateral sclerosis and many others. Although the primary events in etiology and pathogenesis of sporadic forms of these diseases are still unknown, it is clear that aging, in connection with decreased activity of ubiquitin proteasome system, is the most significant risk factor.

We discuss the pathogenic role and intracellular fate of the candidate molecules associated with onset and progression of AD and PD, the protein tau and α-synuclein in context with the function of ubiquitin proteasome system. We also discuss the possibility whether or not the strategies focused to re-establishment of neuroproteostasis via accelerated clearance of damaged proteins in proteasome could be a promising therapeutic approach for treatment of major neurodegenerative diseases.

Friday, July 31, 2015

Researchers have demonstrated slower aging in yeast by increasing H3K36 methylation, which has the effect of restricting certain forms of transcription, the first step in the process of gene expression whereby proteins are generated from their genetic blueprints. It is worth noting that many ways to slow aging in laboratory species, including calorie restriction, have broad effects on observed patterns of transcription, and there is a still a long way to go towards a complete understanding of everything that is taking place in these portions of cellular biochemistry.

Gene expression is regulated by chemical modifications on chromatin - histone proteins tightly associated with DNA. Certain chemical groups on histones allow DNA to open up, and others to tighten it. These groups alter how compact DNA is in certain regions of the genome, which in turn, affect which genes are available to be made into RNA (a process called transcription) and eventually proteins. Researchers have pinpointed specific histone modifications that not only are altered during aging, but also directly determine longevity. "In this study, we found that a type of abnormal transcription dramatically increases in aged cells and that its reduction can prolong lifespan. This longevity effect is mediated through an evolutionarily conserved chemical modification on histones. This is the first demonstration that such a mechanism exists to regulate aging."

In yeast, aging is measured by the number of times a mother cell divides to form daughters before it stops. This number - a mean of 25 divisions - is under tight control and can be either reduced or increased by altering histone modifications, as the researchers found. They showed that when fewer chemical groups of a certain type attach to yeast histones, the abnormal transcription greatly increases in old cells. In contrast, the team found that in yeast strains with a certain enzyme deletion, this abnormal transcription is reduced and lifespan is extended by about 30 percent.

The results reveal that lack of sustained histone H3K36 methylation is commensurate with increased cryptic transcription in a subset of genes in old cells and with shorter life span. In contrast, deletion of the K36me2/3 demethylase Rph1 increases H3K36me3 within these genes, suppresses cryptic transcript initiation, and extends life span. "We show that this aging phenomenon is conserved, as cryptic transcription also increases in old worms. We propose that epigenetic misregulation in aging cells leads to loss of transcriptional precision that is detrimental to life span, and, importantly, this acceleration in aging can be reversed by restoring transcriptional fidelity. We have started investigating whether such a longevity pathway can also be demonstrated in mammalian cells. However, these investigations are confounded by the complexity of the genome in more advanced organisms. One of our long-term goals is to design drugs that can help retain these beneficial histone modifications and extend healthy lifespan in humans."

Friday, July 31, 2015

The first stage for commercially useful tissue engineering is testing and further research, and that is actually well underway. Tissue sections for test and research purposes don't have to be large, and therefore the big problem of how to generate suitable blood vessel networks doesn't have to be solved yet. So researchers have been building organoids and other small sections of tissue, gaining experience and refining techniques. The first tissue types were being sold years ago by companies such as Organovo, and these days many more are being added at an accelerating pace by competing research and development groups. This is a staging ground for the near future construction of organs to order, built from scratch from a patient's own cells:

Efforts to grow stem cells into rudimentary organs have taken off. Using carefully timed chemical cues, researchers around the world have produced three-dimensional structures that resemble tissue from the eye, gut, liver, kidney, pancreas, prostate, lung, stomach and breast. These bits of tissue, called organoids because they mimic some of the structure and function of real organs, are furthering knowledge of human development, serving as disease models and drug-screening platforms, and might eventually be used to rescue damaged organs. "It's probably the most significant development in the stem-cell field in the last five or six years."

The current crop of organoids isn't perfect. Some lack key cell types; others imitate only the earliest stages of organ development or vary from batch to batch. So researchers are toiling to refine their organoids -- to make them more complex, more mature and more reproducible. Still, biologists have been amazed at how little encouragement cells need to self-assemble into elaborate structures. "It doesn't require any super-sophisticated bioengineering. We just let the cells do what they want to do."

Biologists know that their mini-organs are still a crude mimic of their life-sized counterparts. But that gives them something to aim for. "The long-term goal is that you will be able to replicate more and more of the functionality of a human organ." Already, the field has brought together developmental biologists, stem-cell biologists and clinical scientists. Now the aim is to build more-elaborate organs -- ones that are larger and that integrate more cell types. Even today's rudimentary organoids are facilitating discoveries that would have been difficult to make in an animal model, in which the molecular signals are hard to manipulate.


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