Fight Aging! Newsletter, August 19th 2013

August 19th 2013

The Fight Aging! Newsletter is a weekly email containing news, opinions, and happenings for people interested in aging science and engineered longevity: making use of diet, lifestyle choices, technology, and proven medical advances to live healthy, longer lives. This newsletter is published under the Creative Commons Attribution 3.0 license. In short, this means that you are encouraged to republish and rewrite it in any way you see fit, the only requirements being that you provide attribution and a link to Fight Aging!

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  • Mainstream Art Reflects Mainstream Attitudes to Longevity
  • Producing a Beating Mouse Heart Through Recellularization
  • Dear Wealthy Individual, I Have This Great Idea Regarding How to Spend Your Money in a Better Way Than You Seem to Be Managing To Date
  • SENS Research Foundation Releases 2013 Research Report
  • Life Without Ageing: Aubrey de Grey and Tom Kirkwood to Debate Longevity Science at the British Science Festival
  • Latest Headlines from Fight Aging!
    • Mass Production of Patient-Specific Cancer-Targeting T Cells
    • An Example of the Importance of Mitochondrial Membrane Composition
    • The Most Dangerous Pessimists are Those Who Think Themselves Optimists
    • As Expected, Health is About as Heritable as Longevity
    • Curing Leukemia in Mice With Non-Replicating Viruses
    • Why Do Old Flies Die?
    • SENS6 Conference Press Release
    • Targeting Redox Biology to Reverse Mitochondrial Dysfunction
    • Another Way to Improve Memory in Old Mice
    • A Short Overview of 3-D Printing in Tissue Engineering


I'm not convinced by the idea that mainstream art drives attitudes. To my eyes art is simply another form of conversation, and conversations reflect the current distribution of opinions in the melting pot. Pick one thread at random and it will be unusual in its own ways, pick a hundred and the majority will look roughly the same, sharing many commonalities. The more money involved and the larger the conversation the more it will blend to the average, seeking success through being palatable (or at least unoffensive) to as many people as possible, or successful through having already become broadly palatable.

So we should look at mass art for more of what people are thinking now, or at least what people want you to think they think in order to blend in to what they believe are the majority opinions. The largest cultural currents are full of chameleons trying to blend in, even when that goes against their vested interests: we humans like our hierarchies and social acceptance, perhaps too much for our own good. Consider support for longevity science and extending the healthy human life span, for example. The chameleon who supports healthy life extension today can really only blend in by denying it. This is unfortunate on many levels, not least of which being that support is needed to help make rejuvenation therapies a reality sometime soon, and can only be changed by the slow process of convincing people the old-fashioned way: one by one, with articles, with conversation. Advocacy is a matter of changing the environment to become a new normal, repainting the room one small brushstroke at a time.

What reassurances do the community need regarding life extension? Evidence from studies of community attitudes and an analysis of film portrayals

It is increasingly recognised that community attitudes impact on the research trajectory, entry and reception of new biotechnologies. Yet biogerontologists have generally been dismissive of public concerns about life extension. There is some evidence that biogerontological research agendas have not been communicated effectively, with studies finding that most community members have little or no knowledge of life extension research. In the absence of knowledge, community members' attitudes may well be shaped by issues raised in popular portrayals of life extension (e.g. in movies). In order to investigate how popular portrayals of life extension may influence community attitudes I conducted an analysis of 19 films depicting human life extension across different genres. I focused on how the pursuit of life extension was depicted, how life extension was achieved, the levels of interest in life extension shown by characters in the films, and the experiences of extended life depicted both at an individual and societal level.

Mainstream movies will likely be the last of the great mass media to survive our present explosion of diversity in culture. The economics of the business are so gargantuan that it will take greater tides to wash them away that we'll see in the next few decades. But since the population at large are more or less opposed to living longer - at least in public, where the chameleons have to stay dressed up - you can expect to see that same level of opposition expressed in the movies. So it's usually the case that life extension is punished as hubris, given crippling disadvantages, made a curse, and so forth. When you write the story you can do what you want, regardless of the plausibility: it only has to find a receptive audience who have the same incorrect intuitions about the way the world works.

This isn't propagation of ignorance and mistaken attitudes, it's only a reflection of what already exists. If the average fellow in the street was in favor of longevity science, then the average movie plot would support that view.

Monolithic cultural blocks are disintegrating at an increasing pace given the greater ability for people to communicate and organize through the internet. Walk beyond the mass media and you'll find any number of positive portrayals of radical life extension, assumed and issued as a matter of course. In modern written science fiction great longevity is often a non-event - characters live for centuries or millennia because that is the logical outcome of advanced medical technology. We are biological machines, we can be improved, repaired, and rejuvenated, and this is remarked upon to the same degree as the color of the walls: no big deal, a long-accepted trope, let's move on to talk about the interesting new stuff. For examples, you might look at the works of Greg Egan, the late Iain M. Banks, Alastair Reynolds, Vernor Vinge, and so forth.


Decellularization is the process of taking a complex organ or other tissue structure and stripping the cells from it, leaving behind the supporting extracellular matrix. The matrix can then be repopulated by new cells of the appropriate types in order to recreate a functional organ. This is in any case is the end goal of this ongoing line of research: decellularization has been used in recent years to produce tracheas and heart valves for transplantation, populating the tissue with the recipient's own cells so as to eliminate the possibility of rejection.

A trachea is a comparatively simple structure, however. Just as for tissue engineering of organs from scratch, there are hurdles to be overcome in making decellularization a practical option for organs and tissues that are more functional than structural: lungs, livers, hearts, for example While it is certainly the case that decellarization is lot closer to practical application for heart engineering than building a heart from a patient's own stem cells using bioprinting technologies, or other from-scratch strategies, there is work yet to be done. See this latest research, for example, in which a beating mouse heart is produced, but not one that performs well enough to be a transplant candidate:

Decellularized Mouse Heart Beats Again After Regenerating With Human Heart Precursor Cells

For the project, the research team first "decellularized," or removed all the cells, from a mouse heart, a process that takes about 10 hours using a variety of agents. Then, they repopulated the remaining heart framework, or scaffold, with [human] multipotential cardiovascular progenitor (MCP) cells. These replacement cells were produced by reverse engineering fibroblast cells from a small skin biopsy to make induced pluripotent stem cells and then treating the iPS cells with special growth factors to further induce differentiation.

"This process makes MCPs, which are precursor cells that can further differentiate into three kinds of cells the heart uses, including cardiomyocytes, endothelial cells and smooth muscle cell. Nobody has tried using these MCPs for heart regeneration before. It turns out that the heart's extracellular matrix - the material that is the substrate of heart scaffold - can send signals to guide the MCPs into becoming the specialized cells that are needed for proper heart function."

After a few weeks, the mouse heart had not only been rebuilt with human cells, it also began contracting again, at the rate of 40 to 50 beats per minute, the researchers found. More work must be done to make the heart contract strongly enough to be able to pump blood effectively, and to rebuild the heart's electrical conduction system correctly so that the heart rate speeds up and slows down appropriately.

"One of our next goals is to see if it's feasible to make a patch of human heart muscle. We could use patches to replace a region damaged by a heart attack. That might be easier to achieve because it won't require as many cells as a whole human-sized organ would."

Other research teams have prototyped heart patches via decellularization in recent years. It seems to be a popular choice of stepping-stone product for use in medicine, a waypoint on the road to rebuilding hearts completely. There is more competition here from researchers who aim to grow tissues from scratch, however, as they too have demonstrated the ability to create prototype heart patches. So while I don't think that there's any great doubt that decellularization will reach the clinic for whole organs in advance of tissue engineered solutions, it's a different story for smaller and less complex tissue masses.


Why undertake advocacy aimed at persuading wealthy individuals to support your cause? Well, for one, that's where most of the money is. There is the thought that if you have to go to a certain amount of work to persuade a given individual, then why not aim to persuade the individuals who can afford give more as supporters? Why spend a hundred times the effort to persuade a hundred people if you can obtain a thousand times more in the way of resources and publicity by persuading one?

A Letter to Sergey Brin

Dear Mr. Brin,

I've heard you are interested in the topics of aging and longevity. This is very cool, because fighting for radical life extension is the wisest and most humanitarian strategy. I would like to tell you what needs to be done, but, unfortunately, I haven't got your email address, or any other way to be heard. 100,000 people die from aging-related causes every day, but what makes the situation even worse is that the scientists know how to tackle this problem, but don't have clue how to convey their message to those people, who could change the situation and make the creation of human life extension technologies possible. Therefore, I am simply writing in my blog, hoping, that maybe somehow you will read this letter, or that maybe my friends will give me some advice on how it could be delivered to you, or that maybe someone would send it to you.

I think there's a little broken logic in there somewhere, however. Convincing a millionaire to meaningfully support a cause is a long way distant from talking to the average fellow in the street. Moving up another few levels of wealth, convincing a billionaire is more like holding a significant business negotiation with a company: people who have risen to that level are no longer really sovereign individuals with a bank account, but more akin to tribal leaders, with obligations, councils of advisors, processes to follow, and fiefdoms to defend. Even gaining a moment of attention is a tremendous effort.

From a psychological point of view, there is also the hurdle alluded to in the title of this post. No-one really likes to be told to their face that they need to sort themselves out and devote funds to a specific cause. It creates an instinctively defensive reaction. Further, no wealthy person is without a full slate of obligations, long-term plans, and petitioners already. They have put a great deal of thought and energy into have to maintain the processes of their wealth. Why listen to random talking heads who haven't the faintest idea of what it is to take on that work and that responsibility, and why bother to pick out talking head A from talking head B when the likelihood is that they're all full of it? To be wealthy is to have innumerable would-be parasites attracted by the possibility of nibbling away at the edges, and picking out the legitimate causes and honest individuals from the masses is a real challenge. Wealth is a cloud that blinds you in many ways.

This is why I think that while it is certainly tempting to adopt a strategy that consists entirely of persuading high net worth individuals, it's actually far better in the long run to carry though the hard work of persuading as many people as possible, regardless of their wealth and ability to materially support the cause. There is a method to this: what best persuades wealthy individuals and the leaders of funds and companies is (a) social proof and (b) plain old success. The way to open the door to be considered seriously by people who conservatively manage large amounts of money is to already have widespread support: be talked about, have thousands of supporters, have raised millions from the community, have books and films published on the cause, and so on.

Wealth and the wealthy really only follow success on the large scale. They arrive at the point at which they would have been really helpful a few years back, turning up after the long and painful bootstrapping has been accomplished. It is the rare individual, such as Peter Thiel, who makes a serious effort to buck this trend and create greater progress by taking greater risks, by being less conservative, by not following the herd.

I think that knowledge of and support for radical life extension are on the curve that leads to widespread adoption. It's still very early, though: we haven't even really reached the 10% tipping point at which persuasion becomes an avalanche heading into the cultural mainstream. These are the years in which we keep plugging away at persuasion, fundraising, and education - in the knowledge that we are many millions of dollars further ahead of the game, with far more of the most important rejuvenation research underway, albeit on a small scale, than was the case a decade ago. Keep up the work and ten years from now we'll be even further ahead.


The SENS Research Foundation coordinates and conducts research into the baseline technologies needed for human rejuvenation. We age because we become damaged: cells and the structures between cells accumulate broken proteins, waste products, and other forms of harm. The machines of our cells run down, run amok, and run ragged. Eventually that kills us, as damage overwhelms self-repair, but this ugly process of aging to death could be indefinitely postponed given effective means of repairing the forms of damage that are fundamental, those that result from nothing more than the ordinary operation of human metabolism.

SENS stands for the Strategies for Engineered Negligible Senescence, and is a detailed set of theories and supporting evidence regarding which forms of damage and change identified in the old actually cause aging, combined with research plans to develop the foreseeable means to repair these fundamental forms of damage. SENS is a guide to lead us from today, a time in which the research community finally knows enough to be able to lay out a plan like this in detail, to a tomorrow of realized prototype therapies that can rejuvenate old laboratory animals such as mice.

If fully funded to a level of $100 million / year or so, then SENS is a ten to twenty year project, involving the creation of a large new research community and public support to rival that of the cancer research edifice. It might sound like a massive, unobtainable amount of money, but bear in mind that the National Institute on Aging spends ten times amount that as a yearly budget, a single company engaged in not-so-great-in-the-end research on a single type of drug to slightly slow aging sold for $700 million, and neither of those examples offers any great hope of producing meaningful change in the aging process. To a first approximation the NIA are not funding interventions, only investigations, and much of that work is largely irrelevant in comparison to what might be done by ambitious, funded researchers. Such is life: in large-scale institutions mediocrity rules, and ambitious, high risk work that might produce great change is largely going to go unfunded.

At the end of the SENS road we will have the first form of a medical toolkit to reverse aging - an event that could happen in time to help most of those reading this today. Yet there is still little funding for SENS research: a few million dollars a year, derived from community support and philanthropic donors such as Peter Thiel and Aubrey de Grey. This level of funding will have to increase greatly if we are to see the promise of SENS realized.

In advance of the forthcoming SENS6 conference, the SENS Research Foundation has released their 2013 research report, which as always makes for interesting reading.

SENS Research Report 2013 (PDF)

In May of 2012, a 10-year-old girl was suffering in hospital with a blockage in her portal vein - the major blood vessel that brings nutrients from the digestive tract into the liver. Bypassing the risks of transplantation, Swedish doctors engineered the girl a new, custom replacement. Drawing from earlier human successes with engineered tracheas, a donor's blood vessel was stripped of its cells.The resulting scaffold was seeded with stem cells from the girl's bone marrow, and chemical signals were then used to encourage the cells to grow into a functional portal vein. Thanks to the engineered vessel, the girl's blood tests have normalized, and she is now capable of light gymnastics and mile-and-a-half walks.

This groundbreaking achievement is just one example of what can emerge from a few years of rapid progress in animal models and other precedent-setting tissue engineering projects. It is also an example of the type of work SENS Research Foundation is funding with the goal of applying it to a primary problem of aging: the decline of the immune system. Only a few of us will ever need a new portal vein or trachea - but nearly all of us will need a new thymus, which plays an indispensible role in the immune system. The fine structures and functioning cells of the thymus we were born with will slowly degenerate between our teen years and our sixties; as the organ begins to fail with age, we become increasingly vulnerable to influenza and other common infectious diseases. With SRF support, Wake Forest Institute of Regenerative Medicine researchers are now making rapid progress in work to apply the decellularized-recellularized scaffold method to the thymus in animal models. SRF is excited to be spearheading the adaptation of existing techniques to geriatric medicine, where innovation is so sorely needed. But we know that this alone is not enough to address the emerging health crisis posed by age-related disease, which has surpassed infectious disease as the most pressing health problem facing humanity today.

SENS Research Foundation is currently the only research nonprofit pushing the boundaries of the field toward the molecular level, where much of the damage of aging resides. Treating the symptoms of the resulting pathologies can only take us so far, because the body's repair and maintenance mechanisms continue to deteriorate. SRF's unique dedication to identifying and alleviating the damage that long precedes pathology serves as the basis for much of our work. Our longest-running project in this vein targets age-related macular degeneration, the leading cause of blindness in people over the age of 65. Macular degeneration is caused by the accumulation of a toxic byproduct of the visual cycle called A2E, which builds up in the retinal pigment epithelial (RPE) cells responsible for maintaining the light-sensing cells of the eye. We are working to preserve and restore the health of these cells by fortifying them with new, engineered enzymes capable of clearing A2E deposits. In 2012, scientists in our Research Center identified an enzyme (SENS20) that has since demonstrated efficacy in degrading A2E not only in vitro, but in RPE cells administered an A2E "stress test."

These two critical-path projects, as well as the others described in this Research Report, reflect our ongoing mission to transform the way the world researches and treats age-related disease. Our commitment to developing the industry of restorative medicine begins with proof-of-concept work - but ultimately rests upon creating the rejuvenation biotechnologies that can actually cure these diseases. To accomplish this, in addition to funding and conducting more research into the health problems of aging, we must realize a shift in how these health problems are conceptualized. We must move from seeing age-related illnesses as discrete entities to acknowledging that as we grow older, we become progressively more vulnerable to every single age related disease that exists, because we are all accumulating damage at levels no form of medicine can presently touch. When we reimagine aging, we envision a world where the damage preceding pathology is recognized as a treatable condition in and of itself, and addressed accordingly. SRF is delighted to share our progress toward this end in this Research Report. We hope you will join us in taking the tremendous opportunity at hand to set the new standard for twenty-first century medical research and development.

SENS and the SENS Research Foundation are the seed for what will become the core, central pillar of medicine in the decades ahead. Nothing will be as important to health as maintaining youth by periodic repair of cellular damage. Just like antibiotics today, that will be the primary barrier that stands between us and the ubiquitous suffering and mortality that preceded it. The greater the support given to SENS and SENS-like research, the faster we get to that point.


The British Science Festival will be held in Newcastle a few weeks from now. One of the events has Aubrey de Grey of the SENS Research Foundation, advocate and coordinator for rejuvenation research, debating Tom Kirkwood, one of the leading figures in the mainstream faction of the aging research community who think that there isn't much hope for rapid progress to rejuvenation. Those researchers see the best available path forward as one of modestly slowing aging through replication of known metabolic or genetic alterations associated with natural variations in longevity, such as those involved in the response to calorie restriction - but even this will be a long time in realization, a slow grind towards incremental improvements.

I agree with the viewpoint that attempts to safely slow aging in humans will be very hard indeed. Success requires a much greater understanding of metabolism and aging than presently exists, and it's not unreasonable to suggest that decades and many billions of dollars lie between us and even the first prototype drugs to slightly slow aging. However, slowing aging by altering genes and metabolism is not the only approach that can be taken - indeed it's probably the worst of viable scientific approaches to extending healthy life. It's exceedingly costly, produces marginal results, and therapies that can slow ongoing aging are of little to no use for people who are already old and frail.

In this Kirkwood represents the old mainstream of standardized drug discovery and marginal, unambitious process in medicine. De Grey represents the disruptive future of medical technology, his SENS vision and ongoing research being one of a number of entirely new paradigms for health and aging that are winning over an increasing fraction of the research community. The times are changing, and every new wave of development is met by skepticism from those in the mature industries it will replace. We should aim for rejuvenation through periodic repair of cellular damage: it will like take no longer, will quite possibly be cheaper than trying alter ourselves to slow aging, and will be very beneficial for people who are already old when these therapies are introduced.

Life Without Ageing - Two Contrasting Visions Of An Ageing World

EVENT: Life Without Ageing - Two contrasting visions of an ageing world DATE: Monday 9th September TIME: 13.00 - 14.30 VENUE: Fine Art Building Lecture Theatre, Newcastle, UK

Is a cure for ageing within reach in our own lifetimes?

Biomedical gerontologist Dr Aubrey de Grey, Chief Science Officer of the SENS Research Foundation will be joining Professor Tom Kirkwood CBE, Associate Dean for Ageing at Newcastle University to debate a 'Life Without Ageing'. In this event, chaired by Dr Sir Tom Shakespeare, Aubrey de Grey will suggest that a "cure" for ageing is within reach in our own lifetimes, while Tom Kirkwood will argue that such a goal is not only unrealistic but distorts what should be the real research priorities of an ageing world.

Dr de Grey's research proposes that eliminating ageing as a cause of debilitation and death in mankind can be achieved within just a few decades through his proposed 'Strategies for Engineered Negligible Senescence'; a term coined by De Grey in his first book The Mitochondrial Free Radical Theory. Countering this is Professor Kirkwood, a former BBC Reith Lecturer, whose research is around healthy ageing and improving life in old age by looking at the prevention of age associated factors, such as frailty, disability and age related disease, and by helping to change society's attitudes towards ageing.

The tantalising idea of living forever is as old as humanity, but can modern science really hope to consign the ageing process to history? Life Without Ageing promises to be a fascinating insight into modern day ageing research and the opposing visions of an ageing world. At the end of the debate the floor will be opened, giving the audience opportunity to put questions to the speakers and take part in what should be a lively discussion.

If you take a careful look at the festival site page for the debate, you'll see that it's possible to submit questions for the speakers. If you intend to go in person, it looks like registration is required, but it's otherwise a free event.


Monday, August 12, 2013

Infusions of massive numbers of immune cells is a promising strategy for treating many conditions, as well as being something that would probably benefit any old person as a periodic compensation for the decline in the aging immune system. The technologies to enable this sort of therapy are falling into place:

Scientists have combined the ability to reprogram stem cells into T cells with a recently developed strategy for genetically modifying patients' own T cells to seek and destroy tumors. The result is the capacity to mass-produce in the laboratory an unlimited quantity of cancer-fighting cells that resemble natural T cells, a type of white blood cell that fights cancer and viruses. In a [recent study] researchers show that the genetically engineered cells can effectively wipe out tumors in a mouse model of lymphoma.

[Researchers] isolated T cells from the peripheral blood of a healthy female donor and reprogrammed them into stem cells. The researchers then used disabled retroviruses to transfer to the stem cells the gene that codes for a chimeric antigen receptor (CAR) for the antigen CD19, a protein expressed by a different type of immune cell - B cells - that can turn malignant in some types of cancer, such as leukemia. The receptor for CD19 allows the T cells to track down and kill the rogue B cells. Finally, the researchers induced the CAR-modified stem cells to re-acquire many of their original T cell properties, and then replicated the cells 1,000-fold.

"By combining the CAR technology with the iPS technology, we can make T cells that recognize X, Y, or Z. There's flexibility here for redirecting their specificity towards anything that you want." Yet questions remain about exactly what kind of cell the researchers created. [The researchers] used gene expression microarrays to compare the mRNA expression profiles of the engineered T cell precursors with several types of natural T cells from the female donor. The analysis revealed that the engineered cells more closely resemble the gd T cell subtype that is involved in an initial broad-spectrum immune response, rather than the αβ subtype, the so-called adaptive subtype, which is slower to respond, but retains a memory of its exposure to various antigens.

Monday, August 12, 2013

The membrane pacemaker hypothesis suggests that longevity is heavily influenced by the composition of mitochondrial membranes, and thus their resistance to oxidative damage. The details of mitochondrial structure and operation correlate strongly with variations in longevity between species, and minor genetic variations between individuals within a species may also correlate with natural variations in longevity, though the evidence for that is less compelling. Damage to mitochondrial DNA is implicated as one of the root causes of degenerative aging, however, and issues with mitochondrial function show up in many of the common age-related diseases.

That mitochondria are so influential in aging means that we should place a high priority on the development of means to repair and replace mitochondria in old tissues, and thus remove whatever contribution to degenerative aging is caused by this damage. Here is a little more evidence that supports the membrane pacemaker hypothesis:

Our studies revealed that lithocholic acid (LCA), a bile acid, is a potent anti-aging natural compound that in yeast cultured under longevity-extending caloric restriction (CR) conditions acts in synergy with CR to enable a significant further increase in chronological lifespan. Here, we investigate a mechanism underlying this robust longevity-extending effect of LCA under CR. We found that exogenously added LCA enters yeast cells, is sorted to mitochondria, resides mainly in the inner mitochondrial membrane, and also associates with the outer mitochondrial membrane.

LCA elicits an age-related remodeling of glycerophospholipid synthesis and movement within both mitochondrial membranes, thereby causing substantial changes in mitochondrial membrane lipidome and triggering major changes in mitochondrial size, number and morphology. In synergy, these changes in the membrane lipidome and morphology of mitochondria alter the age-related chronology of mitochondrial respiration, membrane potential, ATP synthesis and reactive oxygen species homeostasis.

The LCA-driven alterations in the age-related dynamics of these vital mitochondrial processes extend yeast longevity. In sum, our findings suggest a mechanism underlying the ability of LCA to delay chronological aging in yeast by accumulating in both mitochondrial membranes and altering their glycerophospholipid compositions. We concluded that mitochondrial membrane lipidome plays an essential role in defining yeast longevity.

Tuesday, August 13, 2013

A little while back a mainstream media entity published a discussion on longevity between Aubrey de Grey of the SENS Research Foundation, an organization working on the foundation for rejuvenation biotechnology, and Walter Bortz, a long-time advocate for a better approach to health and aging, but a skeptic on the development of new and radically more effective ways to intervene in the aging process. This is a later opinion piece in which Bortz comments on the discussion and de Grey replies in the comments:


We had never met each other, but knew ourselves by reputation. Our interface is similar to one that exists between two senior gerontologists Steve Austad and Jay Olshansky. They have bet $1 million that someone will live to be 150 within their lifetimes. Austad bets "yea," Olshansky, "nay." Jay in fact argues that if we don't get a handle soon on our obesity epidemic we will all live less long than our parents.

De Grey actually pushed back from the immortality label, much preferring the more modest "rejuvenation" tag. His, and Austad's, argument simply put is: Given the rapid progress in molecular biology of the past two decades then it is logical to extrapolate to the conclusion that soon several decades may be added to our current estimate of a 120-year max lifespan.

I follow these various suggestions closely, but find their excitement to be curtailed by realism. My take on all of this is based on my devotion to the Second Law of Thermodynamics that roughly states everything in an open system goes inevitably to greater disorder due to heat loss and entropy. No exceptions allowed. Time has only one direction.

An important codicil to this resides in the fitness advocacy that I favor. This asserts that aging may be slowed but not arrested. Fitness confers a 30 year delay in decay. A fit person of 80 is biologically the same as the unfit person of 50. So De Grey and I agreed to disagree. I am secure in my advocacy of 100 healthy years that I insist is currently within our biologic and political realms. De Grey hopes for more.

I like to see myself as an optimist. Norman Cousins said that "no one is smart enough to be a pessimist," but optimism must be tempered always by reality. To me this means that the Second Law of Thermodynamics rules. Even rejuvenation must obey that law. There is no, and won't be, a perpetual motion machine. We, and everything else, wear out. Sci-fi is sci-fi.

de Grey:

It was indeed an enjoyable conversation. It had a few gaps, though, which didn't make it into the printed piece. One was that I never quite learned how the validity of the second law of thermodynamics as a reason why rejuvenation is fantasy can be reconciled with the fact that babies are born young.

As for Walter being an optimist, yes, that's also how Jay Olshansky likes to label himself. The most dangerous pessimists, in my view, are the ones who think of themselves as optimists, because they infer that anyone more optimistic than themselves is a fantasist and their work unworthy of study detailed enough to deliver accurate evaluation. But I'm sure we will meet again!

The second law of thermodynamics is mentioned, but I think that this is often misunderstood - even by scientists - and has little importance in considerations of aging and rejuvenation. It is perfectly possible to take an open system and impose order so as to reduce its level of entropy. This happens all the time, and we are surrounded by examples of it in practice, both in the natural world and in our technology. Repair is only one form of entropy reduction, but we humans manage well enough in any number of system.

Tuesday, August 13, 2013

Measures of health in old age and measures of mortality and longevity should all stem from the same root causes: the state of cellular damage, the integrity of repair systems, decline in function of organs, and so on. So if one of these general measures is shown to be inherited to a given degree, you'd expect the rest to be similarly heritable.

Longevity-associated genes may modulate risk for age-related diseases and survival. The Healthy Aging Index (HAI) may be a subphenotype of longevity, which can be constructed in many studies for genetic analysis. We investigated the HAI's association with survival in the Cardiovascular Health Study and heritability in the Long Life Family Study.

The HAI includes systolic blood pressure, pulmonary vital capacity, creatinine, fasting glucose, and Modified Mini-Mental Status Examination score, each scored 0, 1, or 2 using approximate tertiles and summed from 0 (healthy) to 10 (unhealthy). In Cardiovascular Health Study, the association with mortality and accuracy predicting death were determined with Cox proportional hazards analysis and c-statistics, respectively. In Long Life Family Study, heritability was determined with a variance component-based family analysis using a polygenic model.

Cardiovascular Health Study participants with unhealthier index scores (7-10) had 2.62-fold greater mortality than participants with healthier scores (0-2). The HAI alone predicted death moderately well and slightly worse than age alone. Prediction increased significantly with adjustment for demographics, health behaviors, and clinical comorbidities. In Long Life Family Study, the heritability of the HAI was 0.295 overall, 0.387 in probands, and 0.238 in offspring.

Wednesday, August 14, 2013

Researchers here demonstrate a way to greatly increase the number of cancer-targeted viruses that can be safely infused into a patient. By disabling the ability of the virus to self-replicate they prevent it from causing dangerous side-effects:

The researchers used a specific method and dose of UV light to transform regular replicating viruses into unique particles that could no longer replicate and spread, but could still enter cancer cells efficiently, kill them and stimulate a strong immune response against the cancer. These particles were able to kill multiple forms of leukemia in the laboratory, including samples taken from local patients who had failed all other therapies. Normal blood cells were not affected. This novel treatment was also successful in mouse models of leukemia. In fact, 80 per cent of the mice that received the therapy had markedly prolonged survival and 60 per cent were eventually cured, while all of the untreated mice died of their leukemia within 20 days.

Rhabdoviruses (RVs) are currently being pursued as anticancer therapeutics for various tumor types, notably leukemia. However, modest virion production and limited spread between noncontiguous circulating leukemic cells requires high-dose administration of RVs, which exceeds the maximum tolerable dose of the live virus. Furthermore, in severely immunosuppressed leukemic patients, the potential for uncontrolled live virus spread may compromise the safety of a live virus approach.

We hypothesized that the barriers to oncolytic virotherapy in liquid tumors may be overcome by administration of high-dose non-replicating RVs. We have developed a method to produce unique high-titer bioactive yet non-replicating rhabdovirus-derived particles (NRRPs). This is the first successful attempt to eradicate disseminated cancer using non-replicating virus-derived particles, and represents a paradigm shift in the field of oncolytic virus-based therapeutics. Through in silico and in vitro testing, we demonstrate that NRRPs, analogous to live virus, are tumor selective, given that they exploit defects in innate immune pathways common to most tumors. However, this platform is unencumbered by the principle safety concern associated with live virus replication, that is, the potential for uncontrolled viral spread in immunocompromised patients. Indeed, the superior safety margin afforded by the NRRP platform was exemplified by the observation that high-titer intracranial NRRP administration was well tolerated by murine recipients.

Here we establish that NRRPs exhibit both direct cytolytic and potent immunogenic properties in multiple acute leukemia models. A peculiar form of programmed cell death involves the induction of adaptive immune responses against the dying cell. This process, commonly referred to as immunogenic apoptosis, is essential to the efficacy of several current chemotherapeutics and is required for host defense against viral infection including live RVs. Our in vivo results indicate that a similar process is induced by NRRPs and is a driving factor for treatment efficacy.

Wednesday, August 14, 2013

Here is an interesting view on the process of final decline and fatal systems failure due to damage and maladaptive responses to damage that occurs at the end of aging:

As we get older we become more likely to get sick and, eventually, die. Although the underlying pathologies and major causes of death in elderly humans have been well documented, much less is known about the events leading to age-related death in the fruit fly Drosophila melanogaster - one of the premier model systems in aging research. What is the underlying pathology that limits the lifespan of a fly? Is it possible to predict when a fly will die based upon a loss of organ function? What accounts for the enormous variation in lifespan amongst individual flies within a population? Recently, we have identified a physiological phenotype preceding death in Drosophila that allows us to identify, in any given population, individuals that will die in the next few days.

In this work, we show that all individuals show an altered control of intestinal permeability a few days prior to death regardless of chronological age. Interestingly, these same individuals also showed a striking increase in the expression of inflammatory markers (antimicrobial peptides, AMPs) as well as systemic metabolic defects, including impaired insulin/insulin-like growth factor signaling (IIS). Importantly, we observed that chronologically age-matched individuals, from the same population, without altered intestinal permeability do not show major changes in these parameters with age. This discovery suggests that, in Drosophila at least, these different phenotypes are tightly linked to one another and to the end of life. Indeed, we could independently identify flies that would die within a few days by selecting for increased AMP expression, and these flies showed systemic metabolic defects, including impaired IIS, and intestinal barrier failure.

One interpretation of these findings, consistent with the 'hyperfunction theory of aging', is that the overactivity of AMPs is driving pathology and directly leading to death. Alternatively, increased AMP expression may represent a benign marker of impending death, which may result, in large part, from other factors such as a loss of intestinal homeostasis and/or systemic metabolic dysfunction.

As well as highlighting an important link between intestinal aging and organismal aging, this work may be telling us something about the very nature of the aging process itself. Our findings support a model where aging is composed of two consecutive phases, a first phase characterized by a growing likelihood of displaying intestinal barrier failure / inflammation / systemic metabolic dysfunction followed by a second phase leading to death. Remarkably, recent work [has] shown that intestinal cell death precedes organismal death in C. elegans, through a calcium-propagated necrotic wave. Furthermore, a chronic state of inflammation and the development of insulin resistance are key hallmarks of human aging and have been linked to multiple age-onset diseases. Therefore, our findings, in Drosophila, may provide insight into the relationships between intestinal homeostasis, systemic aging and disease susceptibility in mammals.

You might consider this in the context of past research that has shown that altering PGC-1 in intestinal tissues only, thereby apparently increasing stem cell activity and improving mitochondrial function in the intestine, is enough to increase life span in flies by up to 50%.

Thursday, August 15, 2013

The sixth Strategies for Engineered Negligible Senescence conference will be held in September, the latest in a series of conferences devoted to rejuvenation biotechnology, building the means to reverse aging:

The world's leading series of conferences dedicated to the prevention and treatment of the diseases of aging using regenerative medicine will hold its next installment later this year. The conference, entitled "SENS6: Reimagine Aging," will be held from September 3-7, 2013 at Queens' College, Cambridge, UK. As part of the biennial SENS conference series, SENS6 will be presented by SENS Research Foundation (SRF), a biomedical research charity.

"What makes the SENS conferences different is the way they unite experts on every major aspect of aging," said Dr. Aubrey de Grey, SRF's Chief Science Officer. "These conferences are a place where we talk about solutions: repairing the damage that underlies each of these diseases. You won't find that comprehensive, practical approach discussed anywhere else - though, of course, we're doing our best to change that."

Topics covered at the conference will include heart disease, cancer, cellular senescence, age-related dysfunction of lysosomes and mitochondria, and advances in gene delivery. "Based on how far we've already come, as this meeting will show, I'm extremely optimistic about the progress that the scientific community will make in all of these areas in the coming decades," added Dr. de Grey.

The keynote address will be delivered by Harvard's Dr. George Church, a world-leading luminary in genomics. Other top speakers include MIT's Todd Rider, Cambridge's Robin Franklin, Carnegie Mellon's Alan Russell, and the McGowan Institute's Eric Lagasse.

Thursday, August 15, 2013

Mitochondria are the power plants of the cell, generating chemical fuel stores that can be used to power cellular processes. They are important in aging, and this has a lot to do with the generation of reactive oxygen species (ROS) that happens as a side-effect of their operation. Researchers have shown that benefits to health and longevity can be realized in laboratory animals by targeting antioxidants to mitochondria in order to soak up some ROS before they cause harm. Other research focuses on repairing the damage that mitochondria inflict upon themselves this way, so as to stop it from contributing to degenerative aging.

There is general agreement that mitochondria play an important role in the aging process, but the role of mitochondrial oxidative stress remains controversial. Most previous work looking at mitochondrial oxidative stress has focused on damage to DNA, proteins, and lipids with age or in response to manipulation of cellular antioxidants. The interaction between oxidative damage and aging has been called into question in recent years by studies demonstrating little effect on aging and lifespan in mice with genetically modified antioxidant systems. A notable exception is the life extension and protection against multiple diseases in mice that express catalase in the mitochondria, which suggests that the cellular location and type of reactive oxygen species is an important factor.

Our laboratory is interested in whether redox inhibition of mitochondrial function contributes to age-related energy deficits in vivo in mouse and human skeletal muscle. [We] tested this hypothesis using a mitochondrial targeted peptide, SS-31, known to reduce mitochondrial H2O2 production.

SS-31 reduced the high mitochondrial H2O2 production from aged permeabilized muscle fibers [but] had no effect on young fibers. In the aged mice, one hour after in vivo treatment with SS-31 the cellular redox status [was] more reduced. This was accompanied by improved mitochondrial [function] in vivo in the skeletal muscle, while there was no effect on the mitochondrial energetics in young skeletal muscle. In addition to the improvements in muscle energetics, one hour and one week of SS-31 treatment resulted in improved muscle performance and increased exercise tolerance, respectively, in the old mice.

This rapid reversal of in vivo energy deficits supports the hypothesis that mitochondrial deficits in aged skeletal muscle are, at least in part, due to reversible redox sensitive inhibition. Thus assessing the role of mitochondrial oxidative stress in aging and disease will require careful attention to changes to the in vivo redox environment and the mechanisms by which these changes can affect cell function.

Friday, August 16, 2013

In recent years researchers have demonstrated a number of ways to improve memory in old laboratory mice. Here is another:

If you forget where you put your car keys and you can't seem to remember things as well as you used to, the problem may well be with the GluN2B subunits in your NMDA receptors. And don't be surprised if by tomorrow you can't remember the name of those darned subunits. They help you remember things, but you've been losing them almost since the day you were born, and it's only going to get worse. An old adult may have only half as many of them as a younger person.

Cognitive decline with age is a natural part of life, and scientists are tracking the problem down to highly specific components of the brain. Separate from some more serious problems like dementia and Alzheimer's disease, virtually everyone loses memory-making and cognitive abilities as they age. The process is well under way by the age of 40 and picks up speed after that. But of considerable interest: It may not have to be that way. "These are biological processes, and once we fully understand what is going on, we may be able to slow or prevent it."

In recent research [scientists] used a genetic therapy in laboratory mice, in which a virus helped carry complementary DNA into appropriate cells and restored some GluN2B subunits. Tests showed that it helped mice improve their memory and cognitive ability. The NMDA receptor has been known of for decades. [It] plays a role in memory and learning but isn't active all the time - it takes a fairly strong stimulus of some type to turn it on and allow you to remember something. The routine of getting dressed in the morning is ignored and quickly lost to the fog of time, but the day you had an auto accident earns a permanent etching in your memory.

Within the NMDA receptor are various subunits, [and] research keeps pointing back to the GluN2B subunit as one of the most important. Infants and children have lots of them, and as a result are like a sponge in soaking up memories and learning new things. But they gradually dwindle in number with age, and it also appears the ones that are left work less efficiently. "The one thing that does seem fairly clear is that cognitive decline is not inevitable. It's biological, we're finding out why it happens, and it appears there are ways we might be able to slow or stop it, perhaps repair the NMDA receptors. If we can determine how to do that without harm, we will."

Friday, August 16, 2013

Technologies derived from rapid prototyping and 3-D printing will likely play an important role in the future of tissue engineering, just as they are coming to do in many fields:

The field of tissue engineering has deployed several fabrication strategies aimed at bringing cells and structure together to generate tissue. Biomaterial scaffolding - which provides structural support and can be formed into biologically relevant shapes - has been combined with cells to generate hybrid 3-D structures for use as tissue surrogates in vitro and in vivo. Protocols have been developed that enable removal of living cells from native tissues, leaving only a natural scaffolding of extracellular matrix, which can then be re-seeded with cells to reconstruct or partially reconstruct 3-D tissues. Another approach to soft tissue reconstruction has been the development of cell-laden hydrogels, which are often cast into a specific shape and placed into a permissive environment in vitro or in vivo that allows maturation and establishment of tissue-specific characteristics. In recent years, with the advancement of 3-D printing technologies for the on-demand fabrication of complex polymer-based objects, efforts have been underway to adapt 3-D printing technologies and engineer bioprinting instruments that can leverage similar 3-D replication concepts and accommodate the incorporation of living cells.

Organovo's NovoGen MMX Bioprinter precisely dispenses "bio-ink" - tiny building blocks composed of living cells - generating tissues layer-by-layer according to user-defined designs. Built for flexibility, the bioprinter enables fabrication of tissues with a wide array of cellular compositions and geometries; side-by-side comparison of multiple tissue prototypes facilitates optimization and selection of specific designs geared toward a particular application. Working within the confines of an object library, bio-ink building blocks of various shapes, sizes and compositions are assembled into architectures that recapitulate the form of native tissue. Tubes, layered sheets and patterned structures have been bioprinted, yielding 3-D tissues that are free of biomaterial scaffolding and characterized by tissue-like microarchitecture, including the development of intercellular junctions and endothelial networks.

In the short-term, 3-D human tissues are being deployed in the laboratory setting as models of human physiology and pathology; cell-based assays are a mainstay of the drug discovery and development process, and multicellular/multitissue systems may serve as more predictive indicators of clinical outcomes. Longer-term applications of 3-D tissue technologies will extend our knowledge of how to build the smallest functional units of a tissue to the fabrication of larger-scale tissues useful for surgical grafts to repair or replace damaged tissues and organs in the body. What are the next steps in the evolution of bioprinting? The first step is scaling up and down - increasing the resolution of specific features while advancing fabrication hardware and techniques to produce larger-scale tissues. The next, enhancing the complexity of designs - building the tool set that enables conceptual or visual inputs to be translated rapidly to executable bioprinting programs that select from a library of bio-ink building blocks to translate the vision into reality.


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