Fight Aging! Newsletter, July 21st 2014

July 21st 2014

The Fight Aging! Newsletter is a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: both the road to future rejuvenation and 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 medicine, news from the longevity science community, advocacy and fundraising initiatives to help advance rejuvenation biotechnology, links to online resources, and much more.

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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  • Fundraising Update: $66,000 Pledged to the Matching Fund
  • SENS Research Foundation Newsletter for July 2014
  • Calorie Restriction Leads to More Very Small Embryonic-Like Stem Cells in Long-Lived Mice
  • Working on Regeneration of Pacemaker Tissue
  • Change for Radical Life Extension Starts from the Bottom Up
  • Latest Headlines from Fight Aging!
    • Making Blood From Stem Cells
    • A Glance at the Russian Network for Longevity Science
    • A Review of Cytomegalovirus in Immune System Aging
    • Beta Cyclodextrins as a Possible Treatment for the Build Up of Lipofuscin
    • Macrophages Needed for Zebrafish Regeneration
    • Can Too Much Exercise Reduce Longevity?
    • Reversing Insulin Resistance in Type 2 Diabetes
    • Developing a Cell Therapy for Alzheimer's Disease
    • Stroke Incidence Reduced 40% in the Last 20 Years
    • An Anti-Deathist FAQ


Starting on October 1st and continuing through to the end of the year we'll be running a grassroots fundraiser for SENS rejuvenation research, with all donations going to the SENS Research Foundation. Initiatives like this help to fund ongoing cutting edge work taking place at noted laboratories around the country, projects that build the foundations for future therapies to reverse the effects of aging and prevent all age-related disease. Aging is just damage to cells and tissue structures, we know what that damage is, and we can envisage the technologies needed to repair it in great detail. All that is lacking for rapid progress is funding: there are any number of researchers who would much rather be working on this exciting initiative than on the projects they can present raise funding to carry out. If you want to work on radical new directions in medicine, or early stage research of any sort for that matter, then you will be reliant on philanthropy, however: there are very few other sources of funding for ambitious rather than incremental work.

Over the next few weeks I and others will be collaborating to raise a matching fund for the October fundraiser, akin to the 3:1 match that we ran successfully last year. I'm pleased to say that a number of individuals and organizations have already answered my call for matching fund founders, and have stepped up to pledge their support:

  • Christophe and Dominique Cornuejols
  • David Gobel (Methuselah Foundation)
  • Dennis Towne
  • Jason Hope
  • Michael Achey
  • Reason (Fight Aging!)

Together we have pledged a total of $66,000 so far, and we hope that some of you will join us. If you are interested in pledging $5,000 to $15,000 dollars to take this matching fund to the next level, then here is your chance to do so. You'll be in the good company of long-standing supporters of SENS rejuvenation research: people with the foresight to see that we must act now if we are to build a better future, in which there is no suffering and no death due to the many medical conditions that accompany aging. One day aging will be looked upon as we see tuberculosis today: a controlled threat from past years, beaten by medical science. If that day is to happen soon enough for us, then we have work to do, however.

It is vitally important for grassroots fundraising to take place year after year: large scale donations from very wealthy sources only arrive after years of proven support and growth from an energetic and enthusiastic community. This is just as true of medical research into aging and longevity as it is for any other endeavor in this world of ours. In this sense, all of the thousands of donors to the SENS Research Foundation and the Methuselah Foundation before it are philanthropic trailblazers, leaders who point the way for those who will come later to put far greater weight behind efforts to develop rejuvenation therapies based on the SENS vision. Without us, the larger donations and next stage of growth will never happen. What we do is essential, but it can't be done without stepping forward, and acting to provide what support you can.

If you can join as a founder to fill out the matching fund, please contact me. I'd be delighted to hear from you.


The latest SENS Research Foundation monthly newsletter turned up in my in-box yesterday, along with a reminder that the 2014 Rejuvenation Biotechnology conference will be held on August 21st in Santa Clara, California. This event has a strong focus on creating the stronger ties between academia and industry that will be needed to speed the development of applied longevity science, building the life-extending therapies of tomorrow to help bring aging under medical control. There's still time to register.

Don't miss this landmark event! Here are 4 reasons to attend RB2014:

1) Meet expert researchers from multiple age-related disease areas in a setting designed to enable true cross-functional learning and partnering.

2) Impact the creation of the emerging Rejuvenation Biotechnology industry by sharing your research, regulatory, finance, academic and industry perspective.

3) Participate in meaningful discussion and productive networking opportunities in the heart of Silicon Valley.

4) Engage with industrial and academic leaders like Eli Lilly, California Institute for Regenerative Medicine (CIRM), Harvard University, GE Healthcare Life Sciences, and Wake Forest Institute for Regenerative Medicine.

Visit our website to view and download our new conference agenda brochure.

The speakers list contains the usual impressive line up characteristic of a SENS conference:

Ajay Royan, Mithril Capital

Ajay Royan co-founded Mithril Capital and heads the firm as its managing general partner. At Mithril, he has led investments in innovative companies located both in Silicon Valley and around the world.

Ajay frequently speaks on technology investing at technology and finance conferences as well as public forums, such as Bloomberg, CNBC, the Financial Times, and The Wall Street Journal. He has been a guest lecturer on macro investing at Yale University and has served as a participant in the Hoover Institution's Working Group on Global Markets and as one of the Churchill Club's Tech Trends experts.

Ajay serves as an external adviser to Oak Ridge National Laboratory and the University of Michigan Risk Science Center and also serves on the board of the Thiel Foundation. He was educated at Yale University.

Dr. George Church, Harvard

Dr. George Church is Professor of Genetics at Harvard Medical School and Director of, in addition to being the author of the book, Regenesis: How Synthetic Biology Will Reinvent Nature and Ourselves. His 1984 Harvard thesis work pioneered the first methods for direct genome sequencing, molecular multiplexing and barcoding, which led to the first commercial genome sequence in 1994.

Dr. Church's innovations in "next generation" genome sequencing and synthesis and cell/tissue engineering resulted in 12 companies spanning fields including medical genomics and synthetic biology as well as new privacy, biosafety and biosecurity policies. He is director of the NIH Center for Excellence in Genomic Science, and his honors include election to NAS (National Academy of Sciences), NAE (National Academy of Engineering) and Franklin Bower Laureate for Achievement in Science.

As always the real gem of these newsletters is the scientific question of the month - which this month is actually a question asked in a comment to a recent post here at Fight Aging! The lesson to take away here is that you should always ask questions when you have them, as the world is flat these days and an expert is often closer than you think.

Question Of The Month #5: Must Mitochondrial Mutation Management Account For Humanin?

Q: SENS Research Foundation is working to develop a system of "backup copies" of the genes in the mitochondria that code for proteins as a way to bypass the harmful effects of mutations in mitochondrial DNA. But in addition to these 13 proteins, researchers have found a peptide called humanin that is produced from mitochondrial DNA and that seems to have some physiological functions. How would moving the mitochondrially-encoded genes to the nucleus potentially impact other, less well known, products of mtDNA such as humanin?

A: Humanin is a recent and still somewhat controversial product of mitochondrial DNA. What to do about it as part of generating "backup copies" of the protein-encoding genes in the mitochondrial genome turns on how things ultimately shake out.

First, it's not yet clear whether humanin really is produced by mitochondria to serve a physiological function, or is just a byproduct left over from the of unusual way that mitochondria process their RNA. True, humanin seems to bind to a variety of receptors and to have various functions in models of stress and disease, which some have taken as evidence of function - but of course, the same thing is true of various drugs, including synthetic peptides, and that doesn't mean that they are somehow physiological substances. Also, many of these disease models are very artificial, and may not reflect the real conditions under which cells must respond to stress, or in which humanin would exert any activity. If humanin is just a byproduct of mitochondrial RNA processing, its loss will be harmless.

Second, if humanin is indeed a genuinely physiologically functional peptide, the sequence encoding it may be much less vulnerable to age-associated mutation than the genes encoding the proteins of the electron transport chain. Its putative encoding sequence is located by the minor arc of the mtDNA loop, which is rarely affected by deletions in aging. If that's so, then most of the cells that suffer major deletions in their mitochondrial DNA with age and have to draw on their engineered "backup copies" would still have their native humanin-encoding sequences on which to draw, with no special work on our part.

Third, even if humanin is physiologic and the sequence that encodes it is sufficiently susceptible to mutations as to be problematic for the cell in which that sequence is mutated, the mutation of this sequence isn't necessarily all that big a deal. Remember, only a very small number of cells accumulate large deletions of mtDNA with age. We worry so much about these mutations not so much because of the harm they cause to the individual cells in which they occur, but because such cells appear to adopt an abnormal metabolic regime to continue producing energy, and this abnormal metabolic state seems likely to spread metabolically harmful effects across the rest of the body in turn. So even if we find that a small number of cells do lose the ability to synthesize humanin with age, and even if those cells in isolation might be harmed by its absence, still the dysfunction or death of so small a number of cells will not cause the dysfunction of an entire tissue (or the body generally) in the way that a rising burden of cells unable to produce energy normally probably does. And any cells hypothetically rendered dead or dysfunctional for lack of humanin could be periodically replaced using cell therapy, which is already an essential component of comprehensive human rejuvenation.

Finally: if there turns out to be some really compelling reason why it's important to prevent cells from losing humanin expression with age, we do have the option of developing nuclear "backup copies" of the humanin sequence that can fill in in case of shutdown of translation by age-related mutations.


Very small embryonic-like stem cells (VSELs) are supposed by some researchers to be a population of pluripotent stem cells that support adult tissues throughout life. Pluripotency, the capability to generate most or all of the cell types in the body, makes these stem cells potentially very useful in research and applications of regenerative medicine, where low-cost, reliable sources of large numbers of patient-matched cells for any tissue type are much in demand. The fewer steps along the way to obtaining that supply the better, so the prospect of obtaining pluripotent cells directly from a patient is attractive: that might eliminate the need to generate induced pluripotent stem cells or use some other reprogramming method.

Unfortunately there is some debate over whether VSELs exist at all, or at least in the form proposed by the various groups publishing papers on the topic. VSELs are not the only type of pluripotent stem cell thought to exist in adult tissue, and there are various other names given by various other research groups chasing much the same phenomenon. Independent replication of their work has been patchy however. This may all turn out to be a matter of cells choosing to alter their characteristics in response to circumstances at the end of the day, or the fact that it can sometimes take a few years for techniques in a new field to solidify and standardize. Given the amount of published work on putative pluripotent cells of various sorts in adult tissues I would be surprised to see it all come to nothing in the end, but there are clearly unexplained factors that make it difficult for the community to come to a consensus on this matter.

Here, for example, a research group are far enough down the road of working with VSELs to be comparing the details of their presence with and without calorie restriction in a long-lived mouse breed:

Positive effects of prolonged caloric restriction on the population of very small embryonic-like stem cells

One of the proposed means of increasing life span is caloric restriction (CR). In support of this notion, it has been demonstrated that CR without malnutrition is an effective means to decelerate the aging process, increase median and maximum lifespan, as well as delay reproductive senescence in a variety of species, including mice.

We recently reported that life span in experimental murine strains (e.g., Laron and Ames dwarf mice) correlates with the number of very small embryonic-like stem cells (VSELs) residing in adult tissues. Specifically, long-living murine strains with low levels of insulin-like growth factor 1 (IGF-1) circulating in peripheral blood (PB) display higher numbers of VSELs in bone marrow (BM) than age-matched normal control animals. The higher numbers of BM-residing VSELs in these animals also correlated with higher numbers of hematopoietic stem progenitor cells (HSPCs) in BM.

We envision that VSELs, which express several markers of pluripotency, are a population of early-development stem cells that, due to epigenetic changes in certain paternally imprinted genes involved in insulin/insulin-like growth factor signaling (IIS), are kept as a quiescent population of cells in adult tissues. Importantly, the epigenetic mechanism that attenuates VSELs responsiveness to IIS has a positive effect on maintaining their number in adult tissues. However, VSELS have the potential to become specified into more-differentiated tissue-committed stem cells (TCSCs) after reversing expression of imprinted genes to the somatic type. We also believe that VSELs most likely overlap with other types of early-development pluri/multipotent stem cells (e.g., spore-like stem cells, multipotent adult stem cells, or multipotent adult progenitor cells) in adult tissues described by other investigators.

Interestingly, a population of small cells corresponding to BM-purified VSELs has also been described in murine ovaries and testes. These ovary- and testis-residing VSELs have been postulated to be precursors of gametes both in mice and humans. We observed that long-living Laron dwarf mice, which we have demonstrated to have higher numbers of VSELs in BM, have the period of active ovulogenesis prolonged to an advanced age, and Laron dwarf mice older than 2 years can become pregnant and deliver healthy offspring.

Based on these observations and the well-known facts that CR lowers IGF-1 levels in PB and has a beneficial effect on life span in mice, we became interested in the effect of CR on the number of murine VSELs and HSPCs as well as on the morphology of ovaries and testes. In our studies, 4-week-old female and male mice were subject to CR by permitting feeding ad libitum (AL) only on alternate days for a period of 9 months.

Our data indicate that mice under CR have a higher number of BM- and spleen-residing as well as PB-circulating VSELs than control mice fed AL. CR also correlated with a higher number of HSPCs in hematopoietic tissues as well as with an increase in the number of primordial and primary follicles in ovaries. At the same time, however, no significant changes were observed in the testes of mice on CR. Thus, our data explain the positive effect of CR on longevity in mice by a novel early development stem cell related mechanism.


Given greater control over cells and tissue growth there are potentially all sorts of ways in which researchers could augment function for healthy people or compensate for loss due to illness and aging. One near term prospects is the ability to reprogram existing superfluous cells in an organ in order to replace small but crucial cell populations that are diminished by aging. Examples include the dopamine-generating neurons lost in Parkinson's disease, but every older individual also suffers a similar loss of these cells due to the damage of aging, just not to the same level. Parkinson's, like many age-related diseases, is a consequence of the rapid progression of a usually slower process that happens to everyone. Other examples include the loss of some of the specialized cell populations in the kidneys, liver, and pancreas. In most of these cases, there are nearby cells in the organ that could in principle be reprogrammed without consequence, as they will either be replaced fairly quickly or their loss is inconsequential.

In the article linked below the heart is the focus, and cardiac pacemakers are the small cell population of interest. One of the near future goals for cell therapy is to eliminate the need for artificial pacemakers and their numerous drawbacks for individuals suffering forms of dysregulation or loss of pacemaker tissue in the heart. Instead the natural population of pacemaker cells would be augmented and guided to better function. This seems a very plausible goal for the next decade, but work similar to that quoted below has been taking place for the past ten years, and there is a way to go yet before human trials will begin:

Next Generation: Biological Pacemakers

Scientists have been investigating ways to biologically recreate the natural pacemaker cells - a collection of specialized impulse-generating heart cells called the sinoatrial node. One approach has been to express the protein TBX18 in heart muscle cells. TBX18 is a transcription factor that drives development of pacemaker cells in the vertebrate embryo, but it can also directly convert adult heart muscle into pacemaker cells. Indeed, such reprogramming has been achieved in the guinea pig heart, where TBX18 expression has been shown to restore pacemaker function. For such an approach to be applicable to humans, however, the technique needed to be scaled up.

Twelve pigs had their own natural pacemakers experimentally destroyed. They then had back-up electronic pacemakers installed, but also received injections of adenovirus vectors containing the TBX18 gene into their heart muscle. The injected cells adopted the morphology and markers of pacemaker cells and, more importantly, acted like them. After just two days, TBX18-injected pigs had higher heart rates compared with control animals, and after five days they had a less than 1 percent reliance on their electronic pacemakers, while control animals relied on their electronic pacemakers between 8 percent and 40 percent of the time.

"It's an impressive piece of work that shows proof-of-concept, in a large animal, that we could actually harness the potential to convert one cell to another to cure disease." The reprogrammed pacemakers exhibited natural rises and falls in heart rate over day and night cycles as well as increased heart rate during physical exercise. "We're quite excited about that, because we think we can recreate the normal pacemaker function rather than fixing something artificially. Electronic devices cannot really follow the human physiology."

The team monitored the pigs for two weeks after injections and found that the activity of the induced pacemaker cells peaked at day eight and then slowly declined. This was not a surprise because adenovirus-infected cells tend to be cleared from the body. Such short-term reprogramming would be fine for patients requiring a temporary alternative to electronic devices, such as those undergoing treatment for pacemaker-related infections. But for long-term reprogramming, an alternative vector would be necessary.


Change starts from the bottom up and the top down and meets in the oblivious-to-the-very-last middle. Make no mistake, however, the bottom up initiatives always start well in advance of any top-down efforts, and it is the individuals making up the grassroots of any young movement who do most of the hard work to create growth and success. Their job is to prototype, to take the risks, to forge the path on a shoestring, to spread the word: and eventually those at the top finally notice that there is something to see and put their weight behind the movement.

This is the past fifteen years of the rejuvenation research movement in a nutshell. We're doing pretty well, I think, though of course everyone is impatient for much faster progress. We can point to tens of millions of dollars in philanthropic funding, to dedicated research institutions like the SENS Research Foundation that are now a similar size to many mainstream labs in aging research, and to many online and offline communities whose members take seriously today's efforts to treat and control aging through medical science.

When the public view of of aging research and extending healthy life spans finally slips over into approval and support, so that they feel much the same way about it as they presently do about cancer research in the abstract, it will be a sudden thing. All those years of hammering at the door will suddenly turn into a landslide in which everyone agrees we were right all along. That point is growing close thanks to the advocates, donors, and other supporters of longevity science.

Here is a recent post from Maria Konovalenko; while I don't agree with the specific details of the types of research she tends to champion, I agree with the overall sentiment that it is the time for collaboration, work, and growth in the grassroots of biotechnology to match similar progress in other fields. Costs have fallen tremendously in the past five years, to the point at which biotech startups are blossoming, and open biotechnology and garage biotechnology can have a meaningful influence on the overall pace of development. The future here looks a lot like the recent past of software development. In less regulated parts of the world, that means medical biotech can also experience a renaissance, allowing dozens of distinct attempts to produce solutions for every problem, and may the best win.

What Should Be Done to Achieve Radical Life Extension?

Delivering 5-7 gene vectors simultaneously carrying longevity-associated genes into an old animal could prove to be quite beneficial, because similar approach already works. It is also clear that there are several experiments in the area of therapeutic cloning that should be done immediately. There are about 20 other research directions in the area of radical life extension.

Right now it has become obvious how to find the money for radical life extension. It's crowdfunding. 200-300 campaigns need to be created on various crowdfunding platforms on the topics of fighting aging and regenerative medicine. Of course, we may not be able to find the necessary amounts of money right away, but we will be able to delineate the scope of goals, most importantly not using just the general words, but particular scientists, labs and research plans.

Even by only preparing the campaigns we will influence the society by once again providing the proof of the possibility of significant life extension. Unfortunately, molecular biology is not part of an every day's person background. We will make people more educated, show them how diseases originate, progress, and how they relate to aging. We will also tell the people what can be done.

While working on the crowdfunding campaigns we will mobilize our supporters by giving them a concrete tool and a plan of action. Fighting aging crowdfunding will become a very powerful transhumanist organizational solution. In the end we will gather the money, implement our projects and win!

If you are interested in bringing this plan to live, let's collaborate. Every single project requires a manager, analyst, scientist, director, operator, a guy who owns a car and a guy who writes a lot about this on the Internet. There is work for everybody, so let's do this.


Monday, July 14, 2014

Researchers continue to make progress in understanding how to guide stem cells to a desired outcome:

During development, blood cells emerge in the aorta, a major blood vessel in the embryo. There, blood cells, including hematopoietic stem cells, are generated by budding from a unique population of what scientists call hemogenic endothelial cells. The new report identifies two distinct groups of transcription factors that can directly convert human stem cells into the hemogenic endothelial cells, which subsequently develop into various types of blood cells. The discovery gives scientists the tools to make the cells themselves, investigate how blood cells develop and produce clinically relevant blood products.

The factors identified [were] capable of making the range of human blood cells, including white blood cells, red blood cells and megakaryocytes, commonly used blood products. The method [was] shown to produce blood cells in abundance. For every million stem cells, the researchers were able to produce 30 million blood cells. A critical aspect of the work is the use of modified messenger RNA to direct stem cells toward particular developmental fates. The new approach makes it possible to induce cells without introducing any genetic artifacts. By co-opting nature's method of making cells and avoiding all potential genetic artifacts, cells for therapy can be made safer. "You can do it without a virus, and genome integrity is not affected."

While the new work shows that blood can be made by manipulating genetic mechanisms, the approach is likely to be true as well for making other types of cells with therapeutic potential, including cells of the pancreas and heart.

Monday, July 14, 2014

Several distinct networks of researchers, advocates, and funding sources for longevity science have arisen in the past decade. There is some overlap between them, but the backers are different and the scientific strategies largely distinct. The Strategies for Engineered Negligible Senescence (SENS) crowd are I think the most important of these, as they are the only group with a plausible plan to generate rejuvenation rather than just slowing aging, but that network is sadly nowhere near as large yet as the genetics-focused mainstream longevity science network in the US. Most groups working on aging in the US and Europe will probably improve medicine, but are not likely to produce technologies that will lead to considerable extension of healthy life spans.

The topic for today, however, is the Russian network that encompasses the Science for Life Extension Foundation, research institutes in Moscow and elsewhere, a few entrepreneurial types who are launching ventures in other countries, and a few attention-shy high net worth backers. The Russian longevity science community is about as focused on the genetics and metabolism of aging as the US mainstream, but that focus is informed by programmed aging theories rather than a consideration of aging as accumulated damage - which leads to a fairly different emphasis on the development of treatments. I still think that this approach is unlikely to produce meaningful near term results in longevity, however, even while it will generate a great deal of new knowledge and associated improvements to medical technology.

This publicity release should be taken as a sign of the times, and that progress is happening elsewhere. The present growth of interest in serious research on longevity is not limited to the US and Europe, and ours is not the only advocacy and fundraising community.

Deep Knowledge Ventures last week sponsored the inaugural 21st Century Medicine Forum on 'Commercialising Longevity Research' and welcomed a host of London-based investors, scientists and entrepreneurs to the London Bioscience Innovation Center for the event, organised by the UK's Biogerontology Research Foundation and Aging Analytics Ltd. The meeting highlighted the need for both philanthropic support and investment in translational research for age-related disease, as well as the crucial role of social awareness of advances in regenerative and preventative medicine. This point was well made by attending actress, campaigner and international model, Katya Elizarova, who said: "It's clear that the most important thing is to support projects for preventing aging. If researchers are clever enough to develop methods to prevent age-related damage accumulating, it's much more likely that they will have an ability to treat with success. If I, as a media person, can increase the awareness of what you are doing here today and involve as many people as I can, then I shall do it."

Deep Knowledge Ventures investment remit includes artificial intelligence research and robotics, as well as longevity related biotechnology. On the subject of investment in pioneering technologies. Deep Knowledge Ventures Senior Partner Dmitry Kaminskiy said: "According to our estimates we are at an exciting historical point - even with a relatively small amount of investment - hundreds of millions of dollars - but with well-organized and inspired teams, it's possible to accelerate the exponential growth in science and medicine. Our first joint task is now to create a convenient format for investing in this field for conventional investors, who got used to think in very narrow categories. But we need to go beyond this and change the paradigm. Investors in this field stand to gain more valuable results than profit alone. The logic is effective: in case of successful investments, they automatically get direct access to the actual technologies of personalized medicine and life prolongation for themselves and their families. What other business could be better? When you prolong life and still earn a lot of money on this."

Speakers during the event included Dr. Alex Zhavoronkov, CEO of Deep Knowledge Ventures portfolio company In Silico Medicine, who explained "By bringing together class-leading researchers, pensions experts, financial heavyweights and science communicators at meetings like this, we hope to facilitate collaboration across disciplines and produce the next generation of projects that will take longevity science from the bench to the clinic".

Tuesday, July 15, 2014

There is plenty of evidence to suggest that the persistent herpesvirus species cytomegalovirus (CMV) plays an important role in immune system aging. A majority of people carry the virus by the time they reach old age, and its presence causes an ever-increasing number of immune cells to become uselessly specialized to deal with CMV rather than able to respond to new threats. There are other contributing causes to immune system aging, but this seems like a potentially important one, for all that there is still work to be done to definitively prove the case. It is worth chasing this to a conclusion, because a state of too many CMV-specialized immune cells is reversible by the targeted removal of these cells, which will trigger their replacement with new non-specialized cells. This sort of approach has been demonstrated in laboratory animals for similar situations, and so is a possible tool for the rejuvenation toolkit.

As is the case for many potential causes of aging, it would be faster and cheaper to carry out destruction of CMV-specialized cells and then see what happens rather than to fully investigate all of the mechanisms and come to a conclusion without the data from such a prospective treatment. Nonetheless, the research community tends to take the latter rather than the former path. This open access review paper looks over what is known and still unknown about CMV in the context of immune system aging:

Immunosenescence, defined as the age-associated dysregulation and dysfunction of the immune system, is characterized by impaired protective immunity and decreased efficacy of vaccines. An increasing number of immunological, clinical and epidemiological studies suggest that persistent Cytomegalovirus (CMV) infection is associated with accelerated aging of the immune system and with several age-related diseases. However, current evidence on whether and how human CMV (HCMV) infection is implicated in immunosenescence and in age-related diseases remains incomplete and many aspects of CMV involvement in immune aging remain controversial.

After primary infection, CMV is carried for the lifetime of its host. Viral persistence is based on complex interactions between multiple viral and host determinants. These interactions generally result in a carefully negotiated and clinically "innocuous" balance between the virus and the immunocompetent host. Indeed, CMV rarely produces symptoms in the host unless the balance is upset by reduced immune competency of the host.

The co-existence of human CMV in healthy, and even more so, in elderly individuals is still a poorly understood phenomenon. A number of longstanding questions related to CMV's role as a "driver" or "passenger" in the aging of the immune system, in age-related diseases and in complex comorbidities remain incompletely resolved and rather recalcitrant to being rapidly and conclusively resolved. Part of the obstacle lies in the complexities of longitudinal human studies, with pronounced ethical barriers and genetic and epigenetic variabilities on the one hand, and the imperfect concordance between human infection and more tractable animal models of CMV infection in a specific pathogen-free and genetically homogenized settings, on the other.

Tuesday, July 15, 2014

Liposfucin is the name given to a mix of hardy metabolic waste compounds that build up in long-lived cells over the years, such as the vital cell populations of the retina. Cells are not equipped with suitable tools to remove this gunk, but they try anyway and so it ends up concentrated in the cellular recycling structures known as lysosomes. This leads to bloated, poorly functional lysosomes and a decline in cellular housekeeping, which in turn causes cell dysfunction and loss of tissue function. In the retina this process contributes meaningfully to a number of progressive blindness conditions such as age-related macular degeneration.

Here researchers report on a possible drug candidate that renders harmless some fraction of a few of the important lipofuscin constituent compounds when used on retinal cells:

Lipofuscin accumulation in the retinal pigment epithelium (RPE) is a hallmark of aging. Accumulation of lipofuscin bisretinoids (LBs) in the RPE is the alleged cause of retinal degeneration in genetic blinding diseases (e.g., Stargardt) and a possible etiological agent for age-related macular degeneration. Currently, there is no treatment to prevent and/or revert lipofuscin-driven retinal degenerative changes. Hence agents that efficiently remove LBs from RPE would be valuable therapeutic candidates.

In this study, we report that beta cyclodextrins (β-CDs), cyclic sugars composed of seven glucose units, can bind retinal lipofuscin, prevent its oxidation and remove it from RPE. Computer modeling and biochemical data are consistent with the encapsulation of the retinoid arms of lipofuscin bisretinoids (LBs) within the hydrophobic cavity of β-CD. Importantly, β-CD treatment reduced by 73% and 48% the LB content of RPE cell cultures and of eyecups obtained from [mice], respectively. Furthermore, intravitreal administration of β-CDs reduced significantly the content of bisretinoids in the RPE of [mice].

Thus, our results demonstrate the effectiveness of β-CDs to complex and remove LB deposits from RPE cells and provide crucial data to develop novel prophylactic approaches for retinal disorders elicited by LBs. This study opens an avenue to develop small drugs against, currently untreatable lipofuscin-associated blinding disorders.

Wednesday, July 16, 2014

A fair number of research groups are investigating the low-level mechanisms of regeneration in animals such as salamanders and zebrafish, which are capable of regrowing limbs and even major internal organs. It is possible that the underlying biological machinery of this exceptional regeneration still exists in humans, but is merely dormant. Even if it has been lost over the course of evolutionary time it might be reintroduced if researchers just knew enough of the details. At this stage it is hard to say what the odds are, or how challenging it will be to achieve this goal - but that is what research is for. In recent years scientists have established that the immune cells known as macrophages are required for salamander regeneration to operate, and here a recent open access paper reports that this is the case for zebrafish as well:

Although wound healing has been extensively studied in mammals, we have a limited understanding of the injury-induced cellular response in a regenerative context. In this study, we utilized a combination of cell tracking and genetic cell ablation approaches to detail the course and role of cellular components of inflammation in zebrafish fin regeneration. Neutrophils and macrophages, as key mediators of inflammation, have defined functionally important roles in mammalian tissue repair. Our data suggest that the relative time frame of inflammatory cell movement to and from sites of injury is similar for adult zebrafish and mammals, where neutrophils are attracted to the wound first through 'homing' from the circulation, followed by circulation-based or resident macrophages.

We first tracked neutrophils and macrophages in adult zebrafish following amputation of the tail fin, and detailed a migratory timecourse that revealed conserved elements of the inflammatory cell response with mammals. Next, we used transgenic zebrafish in which we could selectively ablate macrophages, which allowed us to investigate whether macrophages were required for tail fin regeneration. We identified stage-dependent functional roles of macrophages in mediating fin tissue outgrowth and bony ray patterning, in part through modulating levels of blastema proliferation. Moreover, we also sought to detail molecular regulators of inflammation in adult zebrafish and identified Wnt/β-catenin as a signaling pathway that regulates the injury microenvironment, inflammatory cell migration and macrophage phenotype.

Our findings, coupled with recent research detailing pro-repair roles of inflammatory cells in zebrafish brain regeneration, advocate some degree of anatomical conservation of the role of injury components in regenerative process in zebrafish. Finally, macrophages may indeed form part of a cellular bridge between robustly regenerative organisms such as zebrafish and the less regenerative mammals that could potentially be manipulated for mammalian regenerative therapies.

Wednesday, July 16, 2014

There are many animal studies showing that moderate exercise causes extended health and many human epidemiological studies showing a robust correlation between moderate exercise, better health, and extended life expectancy. This should give us confidence in believing that yes, being sedentary is bad for us and the practice of at least moderate exercise is good for us. Showing causation in human studies is a real challenge, however, which is why there is still uncertainty over whether a lot of exercise is better, worse, or no different for longevity than the moderate 30 minutes a day recommended by most physicians. We can point to the fact that exceptional athletes such as Tour de France bicyclists live longer than the rest of the population, but is that because they exercise a great deal, or because only very robust individuals tend to become athletes competing at that level?

Separately, there is also the question of whether extremely high levels of exercise actually shorten life expectancy when practiced across a broader slice of the population, once you go on to consider more than just professional athletes. Again here we don't have much to go on in terms of causative relationships, but a brief tour of some of the relevant research is provided in this article:

All runners have heard about the tragedies. The marathoner Alberto Salazar, at the age of forty-eight, suffered a heart attack and lay dead for fourteen minutes before a stent opened up a blocked artery and saved his life. Hundreds of studies, as well as our own intuition, associate exercise with cardiac health. But, in recent years, a small group of cardiologists have advanced a hypothesis that suggests these tragedies may not be so shocking, after all: they believe that an excess of exercise actually damages the heart.

For those of us who believe that the "everything in moderation" rule applies to, well, everything, this argument makes sense. Exercise remains one of the best things you can do to improve your cardiovascular health, but you certainly do not need to run marathons to achieve the benefits. Moderate amounts of exercise throughout life are perfectly adequate. Athletes who exercise in extremes generally do so for reasons other than their health - competitiveness, professional requirement, compulsion. But recognizing that exercising more than a certain amount reaps no greater cardiovascular benefits is quite different than suggesting that this level of exercise causes cardiovascular harm.

After reviewing the data and interviewing experts in the field, my own impression is that among people without known cardiovascular disease there is no compelling data to suggest that mortality significantly differs between moderate and extreme exercisers. There is thus no way to precisely define an upper limit of exercise for an average healthy individual. I suspect, though, that part of what sustains the "too much exercise can kill you" myth is the widespread recognition of the so-called exercise paradox. That is, while consistent exercise decreases the likelihood that you will have a heart attack, if you are destined to have one it is more likely to happen while you are exercising. That's why no one can issue a blanket statement that extreme exercise is safe. It's also why so many researchers have attempted to figure out how to make extreme exercise as safe as possible.

Thursday, July 17, 2014

Type 2 diabetes is largely something that you inflict on yourself. If you don't let yourself get fat and sedentary, the odds are you won't suffer metabolic syndrome or other precursor dsyregulation of metabolism until very late in life, if at all. If you do walk down that road, the progression of the condition can be reversed even quite late by drastic dietary changes and weight loss. But we live in an age of convenience at all cost, and a great deal of research funding goes towards finding treatments that will reverse the effects of type 2 diabetes without asking people to care about managing their health:

In mice with diet-induced diabetes - the equivalent of type 2 diabetes in humans - a single injection of the protein FGF1 is enough to restore blood sugar levels to a healthy range for more than two days. The team found that sustained treatment with the protein doesn't merely keep blood sugar under control, but also reverses insulin insensitivity, the underlying physiological cause of diabetes. Equally exciting, the newly developed treatment doesn't result in side effects common to most current diabetes treatments.

Diabetes drugs currently on the market aim to boost insulin levels and reverse insulin resistance by changing expression levels of genes to lower glucose levels in the blood. But drugs which increase the body's production of insulin, can cause glucose levels to dip too low and lead to life-threatening hypoglycemia, as well as other side effects.

In 2012, [researchers] discovered that a long-ignored growth factor had a hidden function: it helps the body respond to insulin. Unexpectedly, mice lacking the growth factor, called FGF1, quickly develop diabetes when placed on a high-fat diet, a finding suggesting that FGF1 played a key role in managing blood glucose levels. This led the researchers to wonder whether providing extra FGF1 to diabetic mice could affect symptoms of the disease.

[The] team injected doses of FGF1 into obese mice with diabetes to assess the protein's potential impact on metabolism. Researchers were stunned by what happened: they found that with a single dose, blood sugar levels quickly dropped to normal levels in all the diabetic mice. "Many previous studies that injected FGF1 showed no effect on healthy mice. However, when we injected it into a diabetic mouse, we saw a dramatic improvement in glucose. With FGF1, we really haven't seen hypoglycemia or other common side effects. It may be that FGF1 leads to a more 'normal' type of response compared to other drugs because it metabolizes quickly in the body and targets certain cell types."

Thursday, July 17, 2014

Delivering new neurons to replace those lost in Alzheimer's disease isn't an ideal approach in isolation: it is a patch therapy, something that doesn't attempt to address the root causes of the condition in any way, and thus can have only limited short-term benefits while those causes are still churning away. However this sort of treatment may be needed for people that have advanced Alzheimer's disease at the time a cure is finally deployed. The clinical community will need some way to restore function in those who have suffered irreversible damage in the late stages of the condition.

Scientists transplanted inhibitory neuron progenitors - early-stage brain cells that have the capacity to develop into mature inhibitory neurons - into two mouse models of Alzheimer's disease, apoE4 or apoE4 with accumulation of amyloid beta, another major contributor to Alzheimer's. The transplants helped to replenish the brain by replacing cells lost due to apoE4, regulating brain activity and improving learning and memory abilities. "This is the first time transplantation of inhibitory neuron progenitors has been used in aged Alzheimer's disease models. Working with older animals can be challenging from a technical standpoint, and it was amazing to see that the cells not only survived but affected activity and behavior."

A balance of excitatory and inhibitory activity in the brain is essential for normal function. However, in the apoE4 model of Alzheimer's disease - a genetic risk factor that is carried by approximately 25% of the population and is involved in 60-75% of all Alzheimer's cases - this balance gets disrupted due to a decline in inhibitory regulator cells that are essential in maintaining normal brain activity. The hippocampus, an important memory center in the brain, is particularly affected by this loss of inhibitory neurons, resulting in an increase in network activation that is thought to contribute to the learning and memory deficits characteristic of Alzheimer's disease. The accumulation of amyloid beta in the brain has also been linked to this imbalance between excitatory and inhibitory activity in the brain.

In the current study, the researchers hoped that by grafting inhibitory neuron progenitors into the hippocampus of aged apoE4 mice, they would be able to combat these effects, replacing the lost cells and restoring normal function to the area. Remarkably, these new inhibitory neurons survived in the hippocampus, enhancing inhibitory signaling and rescuing impairments in learning and memory. In addition, when these inhibitory progenitor cells were transplanted into apoE4 mice with an accumulation of amyloid beta, prior deficits were alleviated. However, the new inhibitory neurons did not affect amyloid beta levels, suggesting that the cognitive enhancement did not occur as a result of amyloid clearance, and amyloid did not impair the integration of the transplant.

Friday, July 18, 2014

Reduction in mortality due to various forms of heart disease is one of the larger recent past drivers of the slow upward trend in adult and elderly life expectancy. A reduction in the incidence of Stroke is most likely due to many of the same underlying advances in medical practice. It is welcome, but worth remembering that the technologies and approaches that have created the present trend in life expectancy have very little to do with what lies ahead. The whole approach to aging is changing, and future trends will be very different from the present ones, because researchers will be trying to actually treat the causes of aging and all age-related disease rather than only patching the symptoms.

A new analysis of data from 1988-2008 has revealed a 40% decrease in the incidence of stroke in Medicare patients 65 years of age and older. This decline is greater than anticipated considering this population's risk factors for stroke, and applies to both ischemic and hemorrhagic strokes. Investigators also found death resulting from stroke declined during the same period. The team identified more than one million stroke events from 1988 to 2008, of which 87.3% were ischemic and 12.7% hemorrhagic strokes. The analysis showed a reduction in ischemic strokes from 927 per 100,000 in 1988 to just 545 per 100,000 in 2008. Hemorrhagic strokes decreased from 112 per 100,000 to 94 per 100,000 over the same time period, primarily among men. Data indicated that stroke mortality also declined. The risk-adjusted 30-day mortality rate for ischemic strokes fell from 15.9% in 1988 to 12.7% in 2008. For hemorrhagic stroke, the mortality rates declined slightly from 44.7% in 1988 to 39.3% in 2008.

The study was constructed to analyze stroke cases over the past two decades, not to investigate causation; however, researchers did find evolving patterns in the risk factors associated with strokes. Although the prevalence of diabetes mellitus increased over time, other risk factors, such as cigarette smoking, measured systolic blood pressure, and total cholesterol values, decreased.

The decline in stroke rates paralleled increasing use of antihypertensive and statin medications and might explain the reduction in stroke rates. "Antihypertensive medications reduce the risk of stroke by approximately 32% and statins by approximately 21%. Stroke rates seem to decrease most sharply after year 1998, approximately when statin use became more prevalent. If true, then this illustrates how medical interventions have resulted in significant improvements in health on a population level."

Friday, July 18, 2014

As used in the longevity science community, deathism is a catch-all term for philosophies and viewpoints that encourage relinquishment of medical progress and acceptance of death by aging rather than the infinitely better alternative of medical research to extend healthy life and prevent age-related disease. If you have ever tried to persuade people that it is in fact a great plan to try to cure aging by controlling its root causes, you will have found that deathism is in fact very prevalent. Strangely, most people march towards a slow and painful death due to degenerative aging with little to no intent of doing anything about it.

Here is a great short post to show to those of your friends and family who think this way:

Q: What is Deathism?

A: Deathism is the belief that everyone should die.

Q: What is Anti-Deathism?

A: Anti-Deathism is the belief that death should not be mandatory.

Q: How the hell is that supposed to work?

A: Medical research. Aging has biological causes which we grow ever closer to unraveling.

Q: What happens when the earth is full of people because the population never stops increasing?

A: Space colonization is one possible answer, as is introducing disincentives for childbearing (like China did, though they went a bit overboard). But the earth's population is increasing regardless, so banning life-extension would only be a delaying tactic.

Q: Poor people already have much lower life expectancies than rich people. Won't life-extension technology just make this gap worse?

A: At first, probably, yes. That's how new technologies work. Two decades ago cell phones were only owned by rich people. Now they're transforming sub-Saharan Africa. Technologies (unlike wealth) trickle down.

Q: But it's wrong to focus on improving the lives of rich people when we could be helping the less fortunate!

A: Why don't you apply this standard to other types of medical research? Should we abandon all research into aging-related diseases like Alzheimer's, and instead use that money on charitable work abroad? I'm in favor of continuing to pursue many goals simultaneously, like humans do.

Q: The rarer something is, the more precious. So too for years. Life extension would devalue human experience.

A: Rarity is one source of value, but there are others. My favorite novel would not be improved just because I was the only one to ever read it.

Q: Extending human lifespans is unnatural!

A: So is polyester.

Q: But I don't want to live forever!

A: Okay. You don't have to.


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