Fight Aging! Newsletter, January 26th 2015

January 26th 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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  • Contemplating Fundraising for 2015
  • Is it Different this Time Around?
  • No-one Dies of Old Age
  • Reduced Levels of Myc Extend Healthy Lifespans in Mice
  • Another Step Towards Mass Manufacture of Immune Cells
  • Latest Headlines from Fight Aging!
    • Transferring Calorie Restriction Benefits
    • A Focus on Regulatory Systems in Aging
    • Heart Rate Reduction and Longevity in Mice
    • More Data on the Effects of Sitting on Mortality, Independent of Exercise
    • Aneuploidy and Aging
    • Picking the Wrong Path for Bad Reasons
    • A Look at Parabiosis Research
    • Blood-Brain Barrier Damage in Aging
    • An Interview with Valter Longo on Intermittent Fasting
    • A Novel Method of Telomere Extension


One of the main reasons that we managed to collectively raise a meaningful amount of money at the end of 2014 to assist in expanding ongoing SENS Research Foundation's projects is that the whole process of organization started much earlier in the year, somewhere around June in fact. Preparation is everything. It gave people time to think about how they could help, and many people in fact put in a lot of time and money to make it a success. Thank you all.

At this point in the evolution of rejuvenation biotechnology after the SENS model of damage repair raising money is clearly one of the best things we can be doing. Almost all of the present hurdles involve moving early stage research along to the point of prototypes, or even just close enough for biotech entrepreneurs to pick up the ball. That is a long road for some items, such as telomerase and ALT interdiction, but other areas are much closer to realization, and could get to that point given even modest sustained funding. Early stage research is very cheap in comparison to later development in medicine. In fact we can see this happening at the moment for senescent cell ablation with the recent news that a company has been founded to try one possible approach. Maybe it will work out, maybe it won't, but that isn't the point. The point is that all the various biotechnologies needed for a range of different attempts at senescent cell ablation therapies are within striking distance, and this is the first venture of a number that will arise in the next few years, I'd predict.

So what should the Fight Aging! community do this year? There are a few options to consider, along with all of those I haven't yet thought of.

Stick With What Works, Increase the Goal

We ran an impromptu matching fund to raise tens of thousands for the SENS Research Foundation in 2013, a more planned matching fundraiser last year that raised much more, and we could attempt pretty much the same thing this year for some larger amount. The fundraiser runs via this site, donations are made to the SENS Research Foundation directly, we start by gathering up a matching fund, and the size of that fund determines the goal for later grassroots fundraising. I'll note that at least a third of last year's fund came from one-time sources, so while there are more doors to knock on this year it is still a scary amount of money to raise from the community when you are the one doing the asking. Equally, half-way through the 2014 fundraiser I was fairly convinced I was overreaching and yet that succeeded in the end. So it makes sense to keep raising the target until you fail, as how else can you tell how much the community is willing to provide to help advance research efforts?

Switch to a Science Crowdfunding Platform

Is there a science crowdfunding platform that will give us more than it takes from us? By this I'm skipping over the intangibles to mean that the platform results in more donations than their fee. This could be because of additional audience reach, payment options that are easier for some people than the current PayPal implementation used by the SENS Research Foundation, or some other combination of factors. In the case of Experiment the additional fee is going to be 5% or so and we'd need to find additional donations to cover that.

If I was going to take this approach my contribution would probably be to cover that cost and then help with the materials needed. The real downside of the crowdfunding platform approach is that it is more of a load on the SENS Research Foundation in terms of producing materials: video, glossy PDFs, that sort of thing. Most crowdfunding sites are also going to require some sort of a project specific focus for the fundraiser, and sorting this out and tracking funds later and reporting back on it is a further pain for the Foundation staff. Money always comes with strings, but we want to be helping, not making things harder.

Over the past couple of years my reluctance to engage with science crowdfunding sites has come down to the fact that they really don't have much of a halo of interested users in the same way that Kickstarter does. If you put up a project on Kickstarter you are getting a new audience that wouldn't have otherwise noticed you, but I'm really not seeing that effect in science crowdfunding yet. It is possible that we never will, and that this is an unreasonable expectation. It is also the case that better payment systems don't necessary have a beneficial effect given that the weight of donations to research leans heavily towards a demographic of a few people writing a low five figure check and putting it in the mail rather than a hundred people each sending a more modest amount via PayPal or credit card.

That said I remain optimistic about the field of crowdfunding for research in the mid- to long-term, whether as a platform for better interacting with your community of supporters or as a way to reach out and expand it. I just question whether it is actually better at this point in comparison to the ad-hoc system we've assembled here in the past few years.

Raise for a Specific Research Project

I should start this with the caveat that you should never approach someone to say "I'm going to give you some money, but it will come with annoying reporting requirements, and you'll have to do more tracking internally as well, oh and you'll have to chase up the people you're funding with it to make them do more of this as well." Past fundraising for the SENS Research Foundation has largely been project agnostic for the reasons given above: we trust them to put the money to where it will do the most good based on the detailed annual reports they publish. If we had all of the relevant connections and life science knowledge, we could spend the money ourselves just as well, but we do not. Middlemen can have an important role in some circumstances.

Would it make a difference to our fundraising if we did lay out a specific project, however? Pick something on the SENS wish list roadmap for 2016 that a rough project plan estimates to cost a few hundred thousand and see how far we get towards making it happen. This has many of the downsides noted above for the crowdfunding approach in that it puts the onus on the SENS Research Foundation and the scientists involved to assist in the production of video and other materials. I have to think that this compares favorably with writing grant proposals, but equally it has in the past proven to be blood from a stone to extract this sort of stuff from researchers, especially updates on ongoing research after the fact.

There is also the question of whether people really are more interested in funding specific projects versus funding a cause or a team. There is a view of the future that sees a large disintermediation of the present review and funding function of research non-profits, drive by an increasingly informed public bypassing these gatekeepers to participate in a science crowdfunding industry. Equally this may be unrealistic: people have limited time and attention, and the reason these gatekeepers exist is because supporters of the cause are willing to pay someone else to take the time to figure out how to make things move faster.

Move Towards Assembling a Tithing Group

This would be more of a radical change, a move away from grassroots fundraising and towards cultivating a smaller group of donors. Much of the success of last year's fundraising came from having a group of people willing to pitch in ten thousand each. It occurs to me that the community of people of unexceptional wealth capable and willing to do this year after year is not well explored at this time. Could Fight Aging! serve as the starting point to build up a group of 100 or so people donating this much apiece to fund research over the next five years? This strikes me as enormously ambitious, especially for someone as little involved in outreach as myself, and would result in big changes to this site and its focus, but the fact that there were a number of people making that leap last year gives me an inkling that this might just be made to work.

Skip to the Chase, Seed Fund a Company

If the Methuselah Foundation can seed fund a new company working on an approach to the SENS-related tactic of senescent cell ablation, why can't we? Seed rounds can be in the low few hundred thousand dollar range for many types of biotechnology nowadays. US law changed not so long ago such that it would be perfectly legal for any group of us to crowdfund a startup's seed round and hand over the equity to the SENS Research Foundation for safekeeping: we'd still be donating to the SENS Research Foundation, but in a more speculative and long-term way.

Ah, but the caveats. Firstly this is highly risky in the same way that funding research is highly risky, but much more so. A majority of the best-looking startup companies vanish into the earth, never to be seen again, and you'll need to go digging to even get some sort of documentation or a published paper out of the effort. Secondly the reason that the Methuselah Foundation can do this is that the organization is headed by a very well connected entrepreneur who has been embedded in the biotech community for some years now: the only reliable way to have the option to fund a seed round at a reasonably price is to know the people who are founding the company in question.

Lastly there is an important element of timing that makes this somewhat challenging. If a company raises a seed round of a hundred thousand (say), then its founders are looking to raise a few million a few months later, or abandon the effort, one or the other. In biotechnology this usually means the seed round is to get you past some version of "does this actually work?" To close the gap between promising research papers and reality, as it were. Crowdfunding is much less rapid, however, or at least around here it is. Last year's process ran from June to December with a short break in the middle to wonder what I'd got myself into. If you tried to sync that up with the breakneck speed of an early stage company then by the time you finished up, you'd find that they are off into the land of raising millions, and thus you are irrelevant, and if they are not then that's probably a compelling sign not to throw good money after bad.

Lastly there just aren't that many people in the position to start companies to do SENS-relevant things at the moment. I was pleasantly surprised to see one turning up now for senescent cell ablation, a most unexpected outcome this year. If wagering, I'd put a little money on the next set of SENS-related startups to emerge from the folk working on glucosepane breakers, assuming they make good progress on their tooling. In the years ahead there will be ever more opportunities to fund SENS-relevant startup biotech companies, but I suspect the process of lining this all up will be something that has to be accomplished via well connected intermediaries and also tend to happen too rapidly when a possible deal finally arises. A better model is to have someone with the funds to spend right now and run the fundraiser to return that money. But that setup doesn't exactly inspire people to donate.

Suggestions Taken

This meandering post by no means covers every possibility that has occurred to me. Suggestions are always taken. Success in past years was largely a matter of people taking it into their own hands to do something to help, after all.


Every culture throughout recorded history had its seekers after agelessness, all of whom were deluding themselves. As science replaced alchemy the seekers remained just as prevalent, but adopted the superficial trappings of science in their futile quest. A few even adopted the scientific method, or emerged from the scientific community of the time, and were thus much more rapidly and reliably disappointed by the results of their experiments. The power of the scientific method lies as much in its ability to close off potential paths ahead as to open up new ones: it clears out wishful thinking and delusion for those willing to adopt its rigors.

Technology and other applications of scientific knowledge have steadily lengthened healthy life spans since the late 1700s, once the positive feedback loop of growth in wealth and knowledge really kicked in. For most of the past few hundred years much of that growth has stemmed from reducing the burden of infectious disease, not just a matter of reducing death rates in the young, but also lowering the damage load carried by those reaching middle age and older. Nowadays the continued growth in life span in the wealthier regions of the world is largely achieved through improvements in treating and preventing age-related disease. As before this is a very incremental process, however, with trends adding a year of life expectancy at 60 in every decade.

In the 1970s futurists were very enthused about the prospects for medicine, and especially in the prospects for their own personal longevity. They are all aged to death or near as gone now. They were absolutely wrong about how much could be achieved with then new and exciting applications of biotechnology. Yet so very much has been achieved. In comparison to the tools of today, 1970s biotechnology is clunky and expensive: halls of manually tended machinery have now shrunk to a single chip, and a graduate student today can accomplish tasks in a few weekends that would have strained the largest laboratory in the country for years back then.

So we're all pretty excited about what can be done today in medicine, and the prospects for our own personal longevity. When it comes to our understanding of biochemistry and ability to manipulate our cells, we are as far beyond the 1970s as the 1970s were beyond the gentlemen-scientists working at the end of the 19th century. Why, however, is it different this time? Why are the seekers after agelessness now rational scientists rather than another crop of self-deluded fools? This is a question that crops up. I can recall numerous conversations over the years in which I was informed that someone knew an older fellow who was, back in the day, quite confident in the forthcoming existence of longevity-enhancing therapies, and yet where are those treatments decades later? Nowhere in evidence, but here I stand telling you that now is the time, that the Strategies for Engineered Negligible Senescence (SENS) are a viable, plausible road to rejuvenation treatments that could indefinitely extend human life, and that given sufficient funding we could make enough progress in the next 20 years to hit actuarial escape velocity, the point at which medicine adds more healthy life faster than aging takes it away.

As an aside, there is an unfortunate tendency for successful futurists to be those who predict useful and interesting things to happen soon enough to catch the interest of the audience, regardless of the merits of that claim. Most of the really good communicators have also convinced themselves of their message. It is somewhat challenging for a non-technical person to tell the difference between the self-convinced fraud versus someone who happens to be right about an opportunity for development that happens to be in the near future. Many of these opportunities are in the range of 20-30 years distant, assuming funding goes well at each stage, far beyond the point at which you'll see a lot of corroboration in the form of investment in companies trying to achieve these goals directly.

So why is it different this time? For one there is SENS, a detailed plan of development leading to rejuvenation treatments that could be prototyped in mice given a billion dollars and ten years, give or take. No such plan could have been formed a century ago, and while much of the basic knowledge that informs the SENS viewpoint of aging as an accumulation of cellular and molecular damage existed in the 1970s, SENS could not have been proposed as a serious project at that time even had someone had the realization. There was simply no way to even guess at how much time and money it would have required to build the tools to build the tools to develop the validation of the theories so as to build the tools to build the tools to develop the therapies, and so forth: it would have been a project on the scale of going to the moon, and with far less certainty of success.

More importantly none of the proposed paths to add decades or more of healthy life put forward in past generations, now obviously naive and wrong, were in any way rigorous or supported by large fractions of the scientific community. Only now do we have that, built on the vast body of knowledge of biology accumulated over the last century, and on the new tools of biotechnology of the past few decades. Only now are large numbers of scientists putting their careers and their reputations into the extension of healthy life.

Why is it different this time? The fact that funding for various scientific establishment efforts to extend life is growing rapidly. Most of these are in fact not going to move the needle all that much, but that isn't the point. The point is that the consensus in a significant fraction of the scientific community and its surrounding institutions of funding and review is that the time has come. Investment and interest in any given field are cyclic, and this present cycle will see billions poured into this field, and old narrow views of the implausibility of life extension swept away. Scientists are the arbiters of truth in our culture, though this is sometimes hard to see, and the rest of the world will follow their lead when deciding whether to take something seriously. That will create a feedback loop of funding and progress in which, yes, a lot of less useful work will thrive, but so will significant approaches such as SENS.

None of this was the case for past generations of what turned out to be deluded optimism. It is the case now. The times have changed, and it is different this time around.


This probably doesn't need to be said to anyone who reads Fight Aging! on a regular basis: old people do not die from old age. They die because of specific biological system failures that are caused by a sequence of consequences that can in principle be traced back to an accumulation of cellular and molecular damage, and that damage is a direct byproduct of the normal operation of metabolism. Think of the progression of rust in a complex metal structure as a crude analogy for this situation: simple causes, and a complex progression of structural failure.

Given sufficient time and resources at the time of death it is usually possible to determine with a reasonable degree of accuracy the actual class of system failure responsible. Given a vastly greater knowledge of the exceedingly complex progression of aging in terms of metabolic changes and reactions we could then draw lines of cause and effect all the way back to the fundamental damage. That requires far more effort than the answer is worth, however: the research community will be decades more in making meaningful progress towards that goal, but they will do that work, as the point of science is to gather knowledge. It is fortunate for us that this enormous job can be bypassed on the way to producing treatments for aging; researchers can instead focus on repairing the well-known and well-described fundamental damage resulting from the operation of metabolism. We don't need a full accounting of its progression to effectively treat aging if researchers work on producing ways to periodically repair its causes.

There are other places where people decide that knowledge isn't worth the effort required, and that is in the recording of the cause of death. Statisticians who analyze death records for the old are plagued by the bad habits of pathologists, who in different eras have used various different shorthand notations for "I don't know, I don't have time to find out, this person was old, it happens, moving on now." It used to be the case that "old age" was a fine thing to put on a death certificate, and it still is in many countries, but other more scientific-sounding catch-all categories have come to dominate, giving the appearance of providing information but actually doing nothing of the sort. Some regions are better than others, of course.

Does this matter, really, though? After all, we are interested in repair therapies, which means we are focused on the roots of aging, not its end. Fix the causes and the consequences take care of themselves. Further, the dominant causes of death as a result of the aging process are much more common than the lesser causes, meaning that even with problems in the data is remains fairly clear as to what are the greatest threats to health. Forms of heart disease account for a majority of deaths in the old, for example, and for that collection of age-related diseases you'll find less of the fuzziness in death certificates. Further still, isn't it pedantic and little else to make this distinction between dying from specific things and dying from old age? For regular readers here, maybe. But we still have to convince much of the world, the public at large, that aging is something other than a mysterious process set in stone. I think it makes a difference to talk about dying from specific causes versus "old age." A mystery is something you can't pick apart into jobs to be done and items to be fixed, while a specific cause and mechanism of death invites the question of whether we can do something about it.

The article quoted below is trying, and I think failing, to explain another point of view on why it is that you can't say that people die of old age, via the work of David Gems on aging in model organisms such as nematode worms. If I am following correctly this is the philosophical difference between being killed by accumulating biological damage and its consequences versus being killed by a specific named pathology that could only take hold because you are suffering a high level of damage. To me that's more or less the same thing, damage leading to pathology, but I could envisage situations in which one could frame it the other way. You might look at Gems' recent papers on the evolution of human aging and a definition of longevity enhancing therapies for a better insight into his views.

Can People Really Die Of Old Age?

The answer is no. (Alright, thanks for stopping by!)

Just kidding. But really, people don't die of old age. Though it may seem like a trivial thing to find out, the biology of aging - and the research trailing in its wake - drills down to some pretty profound questions about the nature of existence. But we're getting ahead of ourselves.

"The idea that people die of pure aging, without pathology, is nuts," said Gems, the deputy director of the Institute of Healthy Aging and a professor at the University College London. Here Gems uses "pathology" to refer to something that can kill you - some sort of condition, disease, or ailment - not something so boring and normal as having a lot of birthdays. Something else has to be going on.

"The problem with aging is that it's about the most ghastly and tragic aspect of the human condition. Up until recently, there's been practically nothing one can do about it, so the best thing to do is to lie to oneself about it to make it bearable," said Gems, referring to the relative ease of dying from "old age," rather than crippling pneumonia or the dreaded C-word. "I can't really blame anyone for that, but as a scientist you have to try to understand things as they really are and hope good things come out of that."

If that conclusion feels anticlimactic, or at best grim, you're not alone. Scientists and sci-fi buffs alike haven't been satisfied knowing why we die. The real question, of course, is how we stop dying. If death is just the result of physical breakdown letting in disease, what if the body never breaks down?


The transcription factor myc has shown up in cancer research over the past decade, and it is possible that reducing its abundance can turn off rapid cellular proliferation in many cancers. Researchers can't get rid of myc entirely, however, as its presence is necessary for a range of fundamental cell processes. Myc is also important in modern stem cell research, as it is one of the factors used in reprogramming somatic cells to become induced pluripotent stem cells, a potentially important source of customized cells for research and therapies. This is one of many examples that illustrate cancer and regeneration to be opposite sides of the same coin from a mechanistic point of view: the same proteins show up in similar roles on both sides of the fence.

Researchers investigating the role of myc in cancer recently stumbled upon an unexpected finding, demonstrating that reduced levels of myc caused improvements in health and longevity in laboratory mice. This was not the result they were looking for at all, but arguably it is far better for everyone involved for their project to be derailed in this fashion:

Benefits of Missing MYC

Compared to wild-type mice, those missing one copy of Myc live longer and suffer less severe aging-associated problems. The mice that we created are long-lived, but they are incredibly normal, and they are incredibly healthy." Myc's apparent broad role in aging comes as a surprise to those who study the gene. "We've been so focused on [MYC's] normal function and its cancer function. I don't think any of us really thought about what happens in terms of longevity."

At first, researchers genetically engineered mice to lack a copy of Myc because they thought this might increase cellular senescence, an aging-associated process in which cells cease to divide. To the researchers' surprise, the mice did not show increased cell senescence but rather increased longevity compared with wild-type animals. As expected given MYC's role in cancer, the loss of one copy appeared to slow progress of the disease. But loss of a Myc copy also reduced hardening of heart muscle, osteoporosis, and age-related decline in immune function. Mice with reduced MYC displayed better motor function, showed reduced age-related changes in lipid metabolism, and had lower cholesterol than control mice. The engineered mice showed reduced levels of insulin growth factor-1. Reduction of this growth factor has also previously been shown to be associated with increased lifespan.

"It's pretty clear that the [Myc-mutant] mice live longer for a variety of reasons, or at least if you look at their overall health, you see effects in a bunch of different organs." Because the Myc-mutant mice were smaller than average, the researchers wondered whether the engineered animals were eating less than the control mice, as caloric restriction has been shown to slow aging. But the researchers found that the engineered mice were in fact eating more than the control animals.

Reduced Expression of MYC Increases Longevity and Enhances Healthspan

MYC is a highly pleiotropic transcription factor whose deregulation promotes cancer. In contrast, we find that Myc haploinsufficient (Myc+/-) mice exhibit increased lifespan. They show resistance to several age-associated pathologies, including osteoporosis, cardiac fibrosis, and immunosenescence. They also appear to be more active, with a higher metabolic rate and healthier lipid metabolism.

Transcriptomic analysis reveals a gene expression signature enriched for metabolic and immune processes. The ancestral role of MYC as a regulator of ribosome biogenesis is reflected in reduced protein translation, which is inversely correlated with longevity. We also observe changes in nutrient and energy sensing pathways, including reduced serum IGF-1, increased AMPK activity, and decreased AKT, TOR, and S6K activities. In contrast to observations in other longevity models, Myc+/- mice do not show improvements in stress management pathways. Our findings indicate that MYC activity has a significant impact on longevity and multiple aspects of mammalian healthspan.

It would be interesting for researchers to now try this in conjunction with some of the other longevity-enhancing genetic alterations that are thought to work through alterations to quality control and repair systems: do they stack? By the sound of it reduced levels of myc work to extend life via many of the same mechanisms as produce the health and longevity benefits of calorie restriction, so there again it would be interesting to see what the outcome is for calorie restriction myc-reduced mice. If there is no or little additive effect there, then perhaps carefully designed drugs capable of suppressing myc levels might prove to be a form of calorie restriction mimetic.


One of the more important ways in which the immune system declines with age is that its composition shifts towards large duplicated collections of comparatively useless cells involved in coordination and memory of threats, and this is at the expense of a shrinking population of cells capable of destroying those threats. The supply of new immune cells is a slow trickle in adults; evolutionary pressures led to a system that starts up very rapidly in youth and generates large numbers of cells at that time. By adulthood the organ responsible for marshaling new T cells of the adaptive immune system, the thymus, has atrophied. The pressures put on the immune system to shift cells into roles other than attacking and destroying pathogens don't let up, however. The end result is an immune system become ever more poorly configured as a whole: too many librarians and bureaucrats, too few warriors. The body is always under attack from pathogens, but the immune system is also responsible for destroying errant cells, such as those become cancerous or senescent. That the immune system falls down on this front is just as bad as the frailty that stems from a growing inability to resist common infectious diseases.

None of this considers the age-related toll of cellular damage or other harms caused to the stem cell populations responsible for generating immune cells. That is also an issue. Putting that to one side for the moment, however, there are several ways in which the aging immune system could be reconfigured. All of them are within reach of modern biotechnology, and have been demonstrated in the laboratory to some extent: all are in that awkward period of being technically feasible but not yet earnestly in development as a therapy. Firstly, the supply of new immune cells cells could be increased by regenerating the thymus such that it behaves as though the patient is young once more. Secondly the population of useless immune cells could be cleared away by targeted cell destruction technologies, which will prompt the body to replace them with new cells capable of attacking pathogens. Lastly large numbers of immune cells could be generated from the patient's own stem cells and delivered via infusion on a regular basis; in theory far more cells than usually present in the body could be provided in this way, greatly increasing the capabilities of the immune system while they survive.

The open access research quoted below is an example of that third approach. It is worth noting that I have painted with very broad strokes in the description above. The immune system is a city of many different specialized classes of inhabitant, each performing just a few of a very wide range of jobs. It is a very complex and dynamic system of interactions and behaviors. So it is the case that benefits might be obtained just by focusing down on a few specific subtypes of immune cell when generating and delivering large numbers of them as a therapy. The full paper is available in PDF format only at this point, but worth a look.

Genetic engineering of hematopoietic stem cells to generate invariant natural killer T cells

Invariant natural killer T (iNKT) cells comprise a small population of αβ T lymphocytes. They bridge the innate and adaptive immune systems and mediate strong and rapid responses to many diseases, including cancer, infections, allergies, and autoimmunity. However, the study of iNKT cell biology and the therapeutic applications of these cells are greatly limited by their small numbers in vivo (∼0.01-1% in mouse and human blood).

Here, we report a new method to generate large numbers of iNKT cells in mice through T-cell receptor (TCR) gene engineering of hematopoietic stem cells (HSCs). We showed that iNKT TCR-engineered HSCs could generate a clonal population of iNKT cells. These HSC-engineered iNKT cells displayed the typical iNKT cell phenotype and functionality. They followed a two-stage developmental path, first in thymus and then in the periphery, resembling that of endogenous iNKT cells.

When tested in a mouse melanoma lung metastasis model, the HSC-engineered iNKT cells effectively protected mice from tumor metastasis. This method provides a powerful and high-throughput tool to investigate the in vivo development and functionality of clonal iNKT cells in mice. More importantly, this method takes advantage of the self-renewal and longevity of HSCs to generate a long-term supply of engineered iNKT cells, thus opening up a new avenue for iNKT cell-based immunotherapy.


Monday, January 19, 2015

Factors in the blood that affect the behavior of tissues in beneficial ways are a popular topic in aging research at the moment. Researchers are beginning to identify proteins whose amount in circulation changes in reaction to rising levels of damage in aging, and which if altered in old animals can partially reverse some aspects of age-related decline in tissue function. Aging is one set of changes, but what about other differences between individuals such as the beneficial changes to the operation of metabolism brought on by calorie restriction? Researchers would very much like to recreate calorie restriction benefits without the need to eat less, and as a result of findings elsewhere the approach of altering levels of various factors in the blood is now getting a second look. The example quoted here is a study in cell cultures only, but is still somewhat interesting:

The cumulative effects of cellular senescence and cell loss over time in various tissues and organs are considered major contributing factors to the ageing process. In various organisms, caloric restriction (CR) slows ageing and increases lifespan. Here, we use an in vitro model of CR to study the effects of this dietary regime on replicative senescence, cellular lifespan and modulation of the SIRT1 signaling pathway in normal human diploid fibroblasts.

While all of the reported CR-mediated effects in vitro have been observed after incubation of cells for short periods with CR sera from various species, little is known about the long-term effects of CR serum treatment in cultured cells. An important cellular consequence of the process of ageing is replicative senescence, whereby cells lose their replicative capacity and irreversibly exit the cell cycle. Decreased senescence in vivo is believed to contribute to delayed ageing and the increased tolerance to stress observed in organisms subjected to CR regimens; however, the study of this cellular process in vivo (either in animals or humans) is experimentally challenging. Therefore, we decided to test the effects of CR serum on cellular senescence in vitro using normal human diploid fibroblasts, which undergo replicative senescence after several passages in culture.

We found that serum from calorie-restricted animals was able to delay senescence and significantly increase replicative lifespan in these cells, when compared to serum from ad libitum fed animals. These effects correlated with CR-mediated increases in SIRT1 and decreases in p53 expression levels. In addition, we show that manipulation of SIRT1 levels by either over-expression or siRNA-mediated knockdown resulted in delayed and accelerated cellular senescence, respectively. Our results demonstrate that CR can delay senescence and increase replicative lifespan of normal human diploid fibroblasts in vitro and suggest that SIRT1 plays an important role in these processes.

Monday, January 19, 2015

Much of modern aging research, too much in my view, focuses on regulation of aging and the prospects for changing regulatory processes to modestly slow the progression of age-related frailty and disease. Aging is caused by the accumulation of a few types of cellular and molecular damage and so these regulatory processes and their changes in aging are largely reactions to that damage. They are the wrong place to be intervening for best effect, and the focus should instead be on repair of the root cause damage. That remains a minority view at this time, unfortunately, which is why it is so important to raise enough funding to produce definitive proof of its greater effectiveness as a basis for therapies.

This paper is more indicative of how a majority of researchers think about the situation, however. This view explains why those interested in enhancing longevity are most often found working on expensive, marginal ways to alter the very complex reaction to damage rather than addressing the damage itself:

In the consideration of life-extending effects of aging-modulating drugs, a logical error can occur as a result of reductionist thinking peculiar to gerontologists in the middle of the last century when major aging theories including the free radical theory of aging were proposed. From the reductionist point of view, the organism was considered as a sum of relatively independent processes and mechanical components, and interventions designed to prolong life were seen as those being similar to car repairing. If this were indeed the case, then it would be possible to slow the rate of aging by affecting molecular pathways that influence specific aspects of aging, analogous to how antioxidants can slow down the rate of aging of plastic.

However, by summarizing the accumulated information, one can conclude that a reductionist approach in experimental gerontology has proved rather ineffective until now. This is not surprising, since aging is a classic "complex trait," in other words, a trait that is influenced by a plurality of genetic pathways. For example genome-wide research in Drosophila shows that hundreds of genes are involved in the control of aging. Therefore, it seems very difficult, if not impossible, to develop effective pharmaceutical interventions that may slow aging and extend longevity by targeting single genetic pathways.

On the contrary, more modern systemic ("holistic") thinking considers the organism as a whole. Taking into account the complexity of the aging process, the systemic approach addressed primarily to central regulation mechanisms seems more appropriate to developing aging-modulating treatments. From a systemic point of view, aging is not a disease in the sense of being caused by disturbance in several specific pathway(s), but is rather an inevitable consequence of realization of some (probably still substantially unknown) central regulatory processes making the organism more vulnerable to disease with age. According to these conceptual frameworks, the aging process is not primarily a result of accumulation of stochastic damage but is rather a co-product of developmentally regulated processes.

One potential mechanism of central regulation of the whole life cycle including aging is a process of epigenetic control of gene expression having important features in the given context. Indeed, it is: (1) potentially adaptive; (2) linking development and aging; (3) generalizing at the whole-organism level.

Tuesday, January 20, 2015

These results suggest that a modest reduction in heart rate leads to a modest increase in life span. The researchers here at least monitored body weight, as I would otherwise immediately suspect inadvertent calorie restriction as a more likely cause of life extension than the proposed mechanisms related to heart rate:

Heart rate correlates inversely with life span across all species, including humans. In patients with cardiovascular disease, higher heart rate is associated with increased mortality, and such patients benefit from pharmacological heart rate reduction. However, cause-and-effect relationships between heart rate and longevity, notably in healthy individuals, are not established. We therefore prospectively studied the effects of a life-long pharmacological heart rate reduction on longevity in mice. We hypothesized, that the total number of cardiac cycles is constant, and that a 15% heart rate reduction might translate into a 15% increase in life span.

C57BL6/J mice received either placebo or ivabradine at a dose of 50 mg/kg/day in drinking water from 12 weeks to death. Heart rate and body weight were monitored. Autopsy was performed on all non-autolytic cadavers, and parenchymal organs were evaluated macroscopically. Ivabradine reduced heart rate by 14% throughout life, and median life span was increased by 6.2%. Body weight and macroscopic findings were not different between placebo and ivabradine. Life span was not increased to the same extent as heart rate was reduced, but nevertheless significantly prolonged by 6.2%.

Tuesday, January 20, 2015

In recent years the data gathered from large epidemiological studies have suggested that more time spent sitting correlates with higher mortality independently of the level of exercise undertaken by an individual. This association seems fairly robust as it has been replicated in a number of different data sets and by different research groups. Here is a survey of these results:

The amount of time a person sits during the day is associated with a higher risk of heart disease, diabetes, cancer, and death, regardless of regular exercise. "More than one half of an average person's day is spent being sedentary - sitting, watching television, or working at a computer. Our study finds that despite the health-enhancing benefits of physical activity, this alone may not be enough to reduce the risk for disease." The meta-analysis study reviewed studies focused on sedentary behaviour. The authors found the negative effects of sitting time on health, however, are more pronounced among those who do little or no exercise than among those who participate in higher amounts of exercise.

"The findings suggest that the health risk of sitting too much is less pronounced when physical activity is increased. We need further research to better understand how much physical activity is needed to offset the health risks associated with long sedentary time and optimize our health." Future research will help determine what interventions, in addition to physical activity, are effective against the health risk of sedentary time. "Avoiding sedentary time and getting regular exercise are both important for improving your health and survival. It is not good enough to exercise for 30 minutes a day and be sedentary for 23 and half hours."

Wednesday, January 21, 2015

Aneuploidy is the state in which a cell has an abnormal number of chromosomes and is dysfunctional as a result. Like all forms of cellular malfunction, there is more of it in old tissues. But is it significant in aging? In recent years researchers demonstrated that one way of reducing aneuploidy is to boost levels of BubR1, which normally declines with age. As a genetic alteration this extends life in mice, but of course has a range of other effects beyond influencing aneuploidy, so the meaningful mechanism in this extension of healthy life isn't clearly defined. This is the case for many ways to slow aging in mice. Here is a piece on another group studying aneuploidy in aging:

Dr. Dunham has recently focused her efforts on the role of aneuploidy in aging. In the last few years, her lab has generated disomic yeast strains, in which each individual chromosome is duplicated, for all the yeast chromosomes (yeast are haploid organisms and normally only have one set of chromosomes). Interestingly, she found that strains with individually duplicated chromosomes had a dramatic decrease in replicative lifespan. Furthermore, her lab identified a suppressor mutation that rescued lifespan decline in these strains. The suppressor mutation was a missense mutation in Bul1, which is part of the Rsp5 E3-ubiquitin ligase complex and is involved in protein quality control. This finding supports a potential mechanism by which aneuploidy effects aging via perturbing protein quality control.

"My lab has already developed tools for studying aneuploidy using genomics and genetics, and the aging phenotype is just another interesting phenotype that we could apply our suite of existing tools too. I've always been interested in aging. I did a rotation in an aging genetics lab in graduate school. What I like about the aging field also is that so much fundamental biology is touched on by aging. And I really like studying metabolism. If you ask who is still interested in studying metabolism...the answer is the aging people! They get that metabolism is really cool and fundamental! I am interested in what happens in general when you have the wrong number of chromosomes: what things go right, and what things go wrong? Can cells tolerate it, and how do they do so if they can? I think that aging is a good phenotype because it's another aspect of what the cell has to do. Being able to look at a cell from birth to death and across environments and phenotypes and determine where aneuploidy and DNA copy number variation can have an effect, this is just one piece of that."

Wednesday, January 21, 2015

As regular readers know, I advocate for the development of treatments for aging based on periodic repair of the low-level cellular and molecular damage that causes aging. There is at least one detailed plan of action on how to produce the necessary treatments, the Strategies for Engineered Negligible Senescence (SENS) research proposals. Enough is known to work on this with a good expectation of success. Outside of factions within the stem cell research community this is still at this time a minority path in the scientific community, however. Most research groups are much more interested in developing a greater understanding of the fine details of metabolism so as to alter it in order to slow down aging. Unfortunately this latter path is nowhere near the point of producing a working plan, and it has proven to be enormously expensive and time consuming to investigate even tiny slices of the necessary reach of knowledge. See the much hyped past decade of research on sirtuins, for example, that has consumed the cost of implementing SENS in the laboratory several times over without producing any meaningful treatment.

In this piece, the author chooses the hard, slow, expensive, largely unknown path of altering the fundamental operation of metabolism as the better way forward for egalitarian reasons - that a one-time alteration that slows aging is better than a frequent treatment to repair aging because it is somehow more equal, or less prone to ongoing costs. This seems silly. For one, even setting aside the much greater difficulty and time required to develop means of altering metabolism, that approach cannot produce rejuvenation as it only slows down the pace of damage accumulation. Thus it cannot help the old, and it cannot extend healthy life indefinitely. Repair therapies can in principle achieve these goals, it's just a matter of how well they repair the damage. When it comes to costs, the mature evolution of SENS-like repair treatments would be a mass-produced infusion given by a bored clinician once every twenty years or so. Mass produced infusions such as TNF inhibitors today cost a few thousand, even in the dysfunctional US medical system. So this seems like another example of death for everyone before even the vague possibility of inequality for someone, a position sadly prevalent in many areas of our society:

Let me give you my nightmare scenario for a world of superlongevity. It's a world largely bereft of children where our relationship to our bodies has become something like the one we have with our smart phones, where we are constantly faced with the obsolescence of the hardware and the chemicals, nano-machines and genetically engineered organisms under our own skins and in near continuous need of upgrades to keep us alive. It is a world where those too poor to be in the throes of this cycle of upgrades followed by obsolescence followed by further upgrades are considered a burden and disposable. It's a world where the rich have brought capitalism into the body itself, an individual life preserved because it serves as a perpetual "profit center".

The other path would be for superlongevity to be pursued along my first model of healthcare focusing its efforts on understanding the genetic underpinnings of aging through looking at miracles such as the bowhead whale which can live for two centuries and gets cancer no more often than we do even though it has trillions more cells than us. It would focus on interventions that were cheap, one time or periodic, and could be spread quickly through populations. This would be a progressive superlongevity. If successful, rather than bolster, it would bankrupt much of the system built around the second model of healthcare for it would represent a true cure rather than a treatment of many of the diseases that ail us.

Yet even superlongevity pursued to reflect the demands for justice seems to confront a moral dilemma that seems to be at the heart of any superlongevity project. The morally problematic features of superlongevity pursued along the second model of healthcare is that it risks giving long life only to the few. Troublingly, even superlongevity pursued along the first model of healthcare ends up in a similar place, robbing from future generations of both human beings and other lifeforms the possibility of existing, for it is very difficult to see how if a near future generation gains the ability to live indefinitely how this new state could exist side-by-side with the birth of new people or how such a world of many "immortals" of the types of highly consuming creatures we are is compatible with the survival of the diversity of the natural world.

I see no real solution to this dilemma, though perhaps as elsewhere, the limits of nature will provide one for us, that we will discover some bound to the length of human life which is compatible with new people being given the opportunity to be born and experience the sheer joy and wonder of being alive, a bound that would also allow other the other creatures with whom we share our planet to continue to experience these joys and wonders as well. Thankfully, there is probably some distance between current human lifespans and such a bound, and thus, the most important thing we can do for now, is try to ensure that research into superlongevity has the question of sustainable equity serve as its ethical lodestar.

Thursday, January 22, 2015

Parabiosis involves joining together the circulatory systems of two individuals. Joining together an old and a young mouse has proved to be very instructive now that researchers can measure quite detailed aspects of cellular biology, and in recent years it has been used to investigate age-related changes that take place in levels of various proteins in the blood. Some of those proteins can alter cellular behavior in important ways, and manipulating them in old individuals can improve degraded tissue function. This article provides a recent history of this research and hopes for the near future:

Experiments with parabiotic rodent pairs have led to breakthroughs in endocrinology, tumour biology and immunology, but most of those discoveries occurred more than 35 years ago. For reasons that are not entirely clear, the technique fell out of favour after the 1970s. In the past few years, however, a small number of labs have revived parabiosis, especially in the field of ageing research. By joining the circulatory system of an old mouse to that of a young mouse, scientists have produced some remarkable results. In the heart, brain, muscles and almost every other tissue examined, the blood of young mice seems to bring new life to ageing organs, making old mice stronger, smarter and healthier. It even makes their fur shinier. Now these labs have begun to identify the components of young blood that are responsible for these changes. And last September, a clinical trial in California became the first to start testing the benefits of young blood in older people with Alzheimer's disease.

"I think it is rejuvenation," says Tony Wyss-Coray, a neurologist at Stanford University in California who founded a company that is running the trial. "We are restarting the ageing clock." Many of his colleagues are more cautious about making such claims. "We're not de-ageing animals," says Amy Wagers, who has identified a muscle-rejuvenating factor in young mouse blood. Wagers argues that such factors are not turning old tissues into young ones, but are instead helping them to repair damage. "We're restoring function to tissues."

Six out of a planned 18 people with Alzheimer's, all aged 50 or above, have already begun to receive plasma harvested from men aged 30 or younger. In addition to monitoring disease symptoms, the researchers are looking for changes in brain scans and blood biomarkers of the disease. Wagers is eager to see the results, but she worries that a failure would be difficult to interpret and so could set the whole field back. Plasma from a 30-year-old donor may not contain factors beneficial to patients with Alzheimer's, for example. She and others would prefer to see testing for a specific blood factor or combination of known factors synthesized in the lab, for which the mechanism of action is fully understood.

There are also lingering concerns as to whether activating stem cells - which is what the young blood most often seems to do - over a long period of time would result in too much cell division. "My suspicion is that chronic treatments with anything - plasma, drugs - that rejuvenate cells in old animals is going to lead to an increase in cancer. Even if we learn how to make cells young, it's something we'll want to do judiciously."

Thursday, January 22, 2015

Like all tissues, those of the blood-brain barrier in blood vessel walls deteriorate due to the cellular and molecular damage of aging. Researchers here correlate that deterioration with progressive cognitive impairment, further reinforcing existing data on the contribution of blood vessel functional decline to age-related damage in the brain:

The blood-brain barrier (BBB) limits entry of blood-derived products, pathogens, and cells into the brain that is essential for normal neuronal functioning and information processing. Post-mortem tissue analysis indicates BBB damage in Alzheimer's disease (AD). The timing of BBB breakdown remains, however, elusive. Using an advanced dynamic contrast-enhanced MRI protocol with high spatial and temporal resolutions to quantify regional BBB permeability in the living human brain, we show an age-dependent BBB breakdown in the hippocampus, a region critical for learning and memory that is affected early in AD.

The BBB breakdown in the hippocampus and its CA1 and dentate gyrus subdivisions worsened with mild cognitive impairment that correlated with injury to BBB-associated pericytes, as shown by the cerebrospinal fluid analysis. Our data suggest that BBB breakdown is an early event in the aging human brain that begins in the hippocampus and may contribute to cognitive impairment.

Friday, January 23, 2015

Researcher Valter Longo is presently working on, among other things, packaging up intermittent fasting as a treatment with the sort of rigor needed to get it through clinical trials with the FDA. The work leading up the clinical trials involved putting numbers to the short term term benefits provided by fasting: how often and how long must someone fast in order to achieve specific changes in biomarkers of health, and how long do those effects last? The data will be useful for people who practice intermittent fasting as a health strategy, moving the state of scientific support for this strategy closer to that existing for the practice of calorie restriction with optimal nutrition.

Calorie restriction is a very wide-ranging word. We focus more on periodic fasting - we're not really big believers in having people be on special diets or restrictions all the time. We just believe in interventions that are short and lasting, that can last a long time and protect from aging and age-related diseases. But also the use of these in improving disease treatment.

It has been very effective. Originally we did this in simple organisms to understand the molecular basis for it, and then moved to mice, and now we're finishing a number of clinical trials. The effects have been very, very promising. Most of it is not published in humans yet but a lot of it is already finished. So in the next year or so we're going to have at least 3 papers and clinical trials showing normal subjects, cancer subjects and also other diseases, showing the efficacy of these techniques, but also the high compliance that we get in doing this. So it's really something that we've found that most people can do.

As soon as the clinical trial is over basically that's it - people can start doing it. Now for the cancer one people could do it, but not to treat the cancer, only to reduce the side effects of chemotherapy. The cancer itself is regulated by the FDA so we'll have to continue our trials until these are FDA approved if we want to have the treatment included in therapy for delaying cancer progression. But of course people will do it anyway, because if you can use it with chemo obviously you're already using it to treat cancer but you just can't say.

The reduction of IGF-1 is really key in the anti-aging effects of some of the interventions. Both the dietary ones and the genetic ones. We've been putting a lot of work into mutations of the growth hormone receptor that are well established now to release IGF-1 and also cause a record life span extension in mice. So we know for example with chemotherapy resistance if you fast mice and inject IGF-1 you reverse a lot of the protective effects of fasting. So it's important; it's not the only factor, but it's certainly one of the key ones.

Friday, January 23, 2015

Telomeres are the protective caps of repeated DNA sequences found at the end of chromosomes. Telomere length is a part of the regulatory system that prevents cells from dividing indefinitely: a little length is lost with each cell division, and a cell destroys itself or otherwise ceases to divide when its telomeres become too short. In stem cell populations, responsible for delivering fresh batches of long-telomere daughter cells into tissues to replace those lost due to reaching the limits of replication, the enzyme telomerase is active to maintain lengthy telomeres by adding extra repeating sequences to the ends. Cancer cells also make use of telomerase or other methods of lengthening telomeres in order to maintain their ability to rapidly and continually divide, but this process isn't normally active in the majority of the cells in the body. Average telomere length in white blood cells tends to decrease with age and illness, and this is really a proxy measure that blurs some combination of cell division rates and stem cell activity.

Researchers have lengthened healthy life in mice by boosting the activity of telomerase via genetic engineering, though it is still the case that there is no definitive experiment to show which of the possible mechanisms causes this life extension. Is it a matter of more stem cell activity, some secondary effect of having long telomeres such as increased cell life span, or another aspect of telomerase, such as its influence on mitochondrial biology? There is considerable interest in the research community in continuing to explore what might happen when telomeres are lengthened, and so it is inevitable that better methods of lengthening will be developed:

A new procedure can quickly and efficiently increase the length of human telomeres, the protective caps on the ends of chromosomes that are linked to aging and disease. The procedure, which involves the use of a modified type of RNA, will improve the ability of researchers to generate large numbers of cells for study or drug development. Skin cells with telomeres lengthened by the procedure were able to divide up to 40 more times than untreated cells. The research may point to new ways to treat diseases caused by shortened telomeres.

The researchers used modified messenger RNA to extend the telomeres. RNA carries instructions from genes in the DNA to the cell's protein-making factories. The RNA used in this experiment contained the coding sequence for TERT, the active component of a naturally occurring enzyme called telomerase. Telomerase is expressed by stem cells, including those that give rise to sperm and egg cells, to ensure that the telomeres of these cells stay in tip-top shape for the next generation. Most other types of cells, however, express very low levels of telomerase.

The newly developed technique has an important advantage over other potential methods: It's temporary. The modified RNA is designed to reduce the cell's immune response to the treatment and allow the TERT-encoding message to stick around a bit longer than an unmodified message would. But it dissipates and is gone within about 48 hours. After that time, the newly lengthened telomeres begin to progressively shorten again with each cell division. "We were surprised and pleased that modified TERT mRNA worked, because TERT is highly regulated and must bind to another component of telomerase. Previous attempts to deliver mRNA-encoding TERT caused an immune response against telomerase, which could be deleterious. In contrast, our technique is nonimmunogenic. Existing transient methods of extending telomeres act slowly, whereas our method acts over just a few days to reverse telomere shortening that occurs over more than a decade of normal aging. This suggests that a treatment using our method could be brief and infrequent."


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