$54,000
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Fight Aging! Newsletter, July 27th 2015

FIGHT AGING! NEWSLETTER
July 27th 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.

This content is published under the Creative Commons Attribution 3.0 license. 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!

To subscribe or unsubscribe please visit: https://www.fightaging.org/newsletter/

CONTENTS

  • Announcing the "Longevity for All" Short Film Contest
  • Mortality Risk Analysis in a Dataset of Half a Million People
  • Recent and Ongoing Longevity Advocacy Initiatives
  • Lanosterol versus Cataracts: Promising Initial Results
  • Immune Profiling the Contribution of Cytomegalovirus to Aging
  • Latest Headlines from Fight Aging!
    • "But So Does Aspirin"
    • Calorie Restriction is Feasible and Beneficial for Humans
    • Another Example of Rejuvenation of Cell Characteristics through Induced Pluripotency
    • The Damage Done by Smoking
    • Induced Pluripotent Stem Cells as Kidney Disease Therapy
    • Spurring Complete Liver Regrowth in Mice
    • Treating Cancer as Though It Were an Infectious Disease
    • More on the Work of Researchers at the Buck Institute
    • Arguing that Heat Shock Response Decline is Programmed
    • Thoughts on the Funding Situation in Aging Research

ANNOUNCING THE "LONGEVITY FOR ALL" SHORT FILM CONTEST
https://www.fightaging.org/archives/2015/07/announcing-the-longevity-for-all-short-film-contest.php

The folk behind Heales and the International Longevity Alliance are running a short film contest with a 3,000 first prize. The topic is longevity for all: that progress towards therapies to enable longer and healthier lives is good thing for everyone. The submission deadline is September 21st 2015, so if you or anyone you know is a budding filmmaker, here is your chance to make a statement on the future of rejuvenation biotechnology and the prospects for bringing an end to all of the ills and frailties of aging.

Competition for Best Short Film on Life Extension and Promoting A Longer, Healthier Life (PDF)

Dear citizen, Dear artist, Dear activist,

The scientific community and the media are increasingly telling us that we might enjoy healthier and longer lives thanks to medical progress. This is great and we want more people to be involved to promote longevity. The future can be bright and healthy. However describing something potentially beautiful is not always easy. We think you can help.

You could make a (very) short movie making clear that a longer and healthier life thanks to sustainable medical interventions will be positive for citizens and society alike. Do you want to reach immortality by being famous or by avoiding death? By taking part in this competition, you have a small chance to succeed in both goals :­)

Alexander, Daria, Didier, Sven and Peter.

Rules of the "Longevity for all" Competition 1. The submitted film should show that medical progress for a healthier and longer life is generally a good thing for citizens and society alike. The length of the film should be a minimum of 1 to a maximum 10 minutes (minimum 60 seconds, maximum 600 seconds). The link to the file should be sent, together with the mention of the last name and first name of the competitor and the proposed title of the work, to the address info@heales.org. Videos may also be posted online. The submission deadline is 23:59GMT on 21 September, 2015.

2. Everything is allowed: films, comics, succession of pictures,... It can be science, fiction or science-­fiction, a story, sad or funny, a docufiction or a documentary. However, you cannot use copyrighted documents for which you don't have the rights and of course, you cannot use unlawful documents.

3. The members of the international jury will be Alexander Tietz (Germany), Darya Khaltourina (Russia), Didier Coeurnelle (French speaking Belgium), Peter Wickx (United Kingdom), and Sven Bulterijs (Dutch speaking Belgium). They will communicate their decision the 1st of October 2015 (international day of older persons also often seen as the International Day of Longevity).

4. The language of the video will be English, French or Dutch. Subtitled submissions will be accepted.

5. If your submission is selected for a prize, you agree that Heales and the International Longevity Alliance (ILA) use your movie without restriction to promote life extension. Heales and the ILA can show your work on the internet or by all other means. However, it is prohibited for Heales and the ILA to earn any money with this work and compulsory to mention the authors of the work. Should some organization/person want to pay to have the right to use your work, Heales and the ILA engage themselves to inform you and the possible benefit would be for you.

6. The first prize is 3,000. If the members of the jury unanimously decide to give the first prize to 2 competitors, each competitor will receive 2,000. If the members of the jury unanimously decide so, they can prolong the competition for 3 months. If the work of the winner is a collective work, each person mentioned as a competitor will receive a proportionate part of the prize. If the winner lives in a country where the € is not the current currency, there will be a conversion of the prize in the local currency. The second prize is a stay for 2 persons for two nights in a Spa of the country where the person lives, travel included. (value 400). The third prize is a selection of books related to longevity (value 100).

7. For all issues not mentioned above, the members of the jury will decide. They must decide in equity and with the same rules for all competitors. The competent courts in the event of litigation will be those of Brussels.

MORTALITY RISK ANALYSIS IN A DATASET OF HALF A MILLION PEOPLE
https://www.fightaging.org/archives/2015/07/mortality-risk-analysis-in-a-dataset-of-half-a-million-people.php

The UK mortality risk study I point out below doesn't provide any real surprises when it comes to the risk factors associated with higher mortality rates at a given age, but taken as a whole it is a good example of the present trend towards much more data and far larger study sizes in epidemiology. In this age of databases, with the cost of storage and computation falling rapidly towards numbers barely distinguishable from zero, the quality of epidemiological analysis is increasing. More data and larger study populations bring the possibility of ever better statistical measures, the ability to identify more subtle correlations, and - perhaps of greatest interest for those of us not in the science business - online databases that allow everyone to jump and and look at the results.

So you should head over to the UK Longevity Explorer and take a look at the Association Explorer; it's an interesting tool to tinker with, especially once you start digging down into the weeds of smaller associations. It is a nice view of all the things we'd like to render entirely irrelevant by producing rejuvenation biotechnologies capable of repair of cell and tissue damage. In a world in which the causes of aging can be meaningfully addressed, it no longer matters that you have minor gene variants, or had more or less exposure to infectious diseases in youth, or experienced other circumstances that presently swing life expectancy a year or a few years in either direction. The benefits provided by repair therapies will vastly outweigh all of that when it comes to long term health and life expectancy.

On a slightly different topic, and unlike the study below, I suspect that the largest datasets of interest to aging research that emerge in the decades ahead will be obtained without the consent of study participants. The incentives align with this outcome: (a) all groups with the capability to gather large amounts of data are presently doing so rapaciously, since they can use that data to generate profits in many ways; (b) few organizations are any good at defending large databases from attackers; (c) a dataset released into the wild from legal jurisdiction A is a dataset that researchers in legal jurisdiction B don't have to do the work to assemble or otherwise pay to use.

Given these points, I think that we will see continuing theft and release of large sets of medically relevant data, and that researchers and their boards will concoct ethical justifications for using this data as becomes more widely available. For example, researchers might pay a third party to anonymize stolen datasets available online in a way that prevents records from being associated with individuals without disturbing statistical associations, and then never officially view the original data themselves. There will be a sense that it is a shame to let this all go to waste since it is out there.

5 year mortality predictors in 498,103 UK Biobank participants: a prospective population-based study

Participants were enrolled in the UK Biobank from April, 2007, to July, 2010, from 21 assessment centres across England, Wales, and Scotland with standardised procedures. In this prospective population-based study, we assessed sex-specific associations of 655 measurements of demographics, health, and lifestyle with all-cause mortality and six cause-specific mortality categories in UK Biobank participants using the Cox proportional hazard model. We excluded variables that were missing in more than 80% of the participants and all cardiorespiratory fitness test measurements because summary data were not available. Validation of the prediction score was done in participants enrolled at the Scottish centres. UK life tables and census information were used to calibrate the score to the overall UK population.

Of 498,103 UK Biobank participants included (54% of whom were women) aged 37-73 years, 8532 (39% of whom were women) died during a median follow-up of 4·9 years. Self-reported health was the strongest predictor of all-cause mortality in men and a previous cancer diagnosis was the strongest predictor of all-cause mortality in women. When excluding individuals with major diseases or disorders (Charlson comorbidity index greater than 0; n=355 043), measures of smoking habits were the strongest predictors of all-cause mortality. The prognostic score including 13 self-reported predictors for men and 11 for women achieved good discrimination and significantly outperformed the Charlson comorbidity index.

Measures that can simply be obtained by questionnaires and without physical examination were the strongest predictors of all-cause mortality in the UK Biobank population. The prediction score we have developed accurately predicts 5 year all-cause mortality and can be used by individuals to improve health awareness, and by health professionals and organisations to identify high-risk individuals and guide public policy.

UK Longevity Explorer

Interest into the causes of death and disease is growing, as is our knowledge and understanding. Individuals, healthcare professionals, researchers, health organisations and governments all want to understand more about what might improve or reduce life expectancy, particularly in the middle-aged and elderly.

A large-scale project called UK Biobank was set up, and between 2006 and 2010, it collected 655 measurements from nearly half a million UK volunteers (498,103) aged 40-70. This website presents the two main parts of the researchers' work: the Association Explorer and the Risk Calculator. These are closely connected - the Risk Calculator is based on findings from the Association Explorer.

The Association Explorer is an interactive graph where you can explore how closely 655 measurements (variables) from the UK Biobank study are associated with different causes of death. The results for different associations are presented separately for women and men, and illustrate the ability of each variable to predict mortality. For more detailed results for each specific measurement, you can click on each dot (data point). You can also select groups of measurements, different causes of death, as well as search for a particular variable of interest using the search bar.

As questionnaire-based variables were found to be the strongest predictors, the researchers created a calculator that could use questionnaire answers to predict an individual's risk of dying within five years ('five-year risk'). To do this, they used a computer-based approach to automatically select the combination of questions from UK Biobank that gave the most accurate prediction of death within five years.

RECENT AND ONGOING LONGEVITY ADVOCACY INITIATIVES
https://www.fightaging.org/archives/2015/07/recent-and-ongoing-longevity-advocacy-initiatives.php

There's a lot more going on out there these days in terms of advocacy for longevity science. People are finding it easier to raise funds from the broader community for acts of pure persuasion, which I think is a good sign on the whole. It is one metric by which we can measure support for the cause. Here I'll point out a couple of recent and ongoing projects, the Longevity Cookbook by Maria Konovalenko and allies, and Zoltan Istvan's use of the US presidential election as a platform for raising awareness of long-standing futurist and transhumanist goals such as the defeat of aging.

While you're looking through the materials below, here is something to consider: is it better to fund research or is it better to fund publicity? I suspect that both are needed, striking some sort of balance between (a) science that is within striking distance but effectively invisible to the world and large funding sources, which has been the state for SENS rejuvenation research for quite some time, and (b) advocacy that is so far ahead of technological plausibility that the snake-oil salesmen sneak in and corrupt an entire generation with their nonsense, which is the story of the last quarter of the last century. An argument for the "fund research" side is that meaningful progress in medical science tends to generate its own news. An argument for the "more publicity efforts" side is that there are plenty of historical examples of important scientific progress languishing at the verge of completion for a lifetime or longer. Personally, I'm in favor of funding the research at this time, and one of my main reasons for that is that early stage research has become very cheap over the course of the modern biotechnology revolution, while publicity remains stubbornly expensive. Yes, it is far easier to send your message out into the world, but there is now such a sea of content that making yourself heard is harder than ever.

The Longevity Cookbook managed to raise more than 50,000 via crowdfunding last month, and congratulations to those involved: that certainly surprised me given how much of a challenge it is to pull in that much money for research over at this end of the pool. So far as I can see this will produce a book analogous to Kurzweil and Grossman's Fantastic Voyage from a decade ago: a mix of old school thoughts on diet and health, which will have very little to no determination on the future of your health and longevity, but which are ever popular with the public, merging into discussions of the latest life science research that may lead to therapies to treat aging as a medical condition. I wasn't all that happy with the way in which Fantastic Voyage dwelled upon diet and supplements, things that won't matter in the slightest in comparison to the consequences of success or failure in building SENS rejuvenation therapies or something very similar, and I expect I'll have similar complaints about the Longevity Cookbook. But then I'm not the audience, and there is always an argument for steering people into the topic of a cure for aging softly and by degrees.

Longevity Cookbook

Aging steals away your most valuable resource: time. The Longevity Cookbook is a strategy guide to help you get more time to experience the joy from everything that you like in life. Take yourself on a journey starting with nutrients and exercise regimes that goes on to explore the usage of genetically modified symbiotic organisms and using gene therapy to boost your own longevity.

Most importantly, we want to draw attention to an overlooked problem whose time has come: aging. In recent decades, we have begun to understand how to use changes in nutrition and lifestyle to extend the healthiest years of life. At the same time, findings in the lab have shown that it may someday be possible to greatly extend our maximum lifespan, and our quality of life as we age. This could happen sooner than you might think!

Any ambition to live longer than the historical human maximum lifespan of ~120 years will require a complex approach, that is not yet fully understood. It's possible that by modestly improving our health, and rolling back the clock using improvements to nutrition and lifestyle, such as those to be outlined in the Longevity Cookbook, we may live long enough to reap the benefits of revolutionary interventions that are currently still in the lab. With this thinking in mind, in the book we'll outline some of the most promising experiments that are currently underway or being proposed.

Zoltan Istvan is a character, and an outspoken transhumanist in a time when it is becoming perhaps a trifle unfashionable to refer to oneself as a transhumanist. Of course we are all transhumanists together here, reading this post while hoping and planning for a future in which fundamental limits of the human condition will be overcome through technological progress, such as this business of aging, suffering, and dying. Istvan has been publishing and speaking relentlessly on the topic of transhumanism for years now, and of late has settled upon the forthcoming presidential race as one of the few opportunities for an activist to make use of the US political system to promote a cause. In Europe starting single issue parties is a viable approach, but not in the US. So Istvan plans a tour and is already attracting attention and giving interviews:

This US presidential candidate doesn't want to be president - he wants to live forever

Zoltan Istvan was among the earliest candidates to declare his bid for the 2016 US presidential elections. But most Americans still won't know about this writer and Transhumanist philosopher by the time they head to the polls. Istvan knows that. Yet, his platform is refreshing: put science first. His ideas are radical, which is not uncommon for third-party candidates, but they are also appealing: make college education mandatory and free; create policies so that everyone can have designer babies, not just the rich; and discover immortality in the next 15-20 years.

Istvan represents the Transhumanist Party, which claims to have its root in philosophical thoughts going back centuries, and has the core aim of building technologies that will give us superhuman powers. The total number of members of Humanity+, the biggest such membership organization, is only 10,000. His campaign - which includes a bus shaped to represent a coffin - is run with help of a group of volunteers in California.

"The reception in the media has been better than anticipated. I think that's because people are really interested in the kinds of questions we ask, such as those about designer babies, artificial intelligence, exoskeleton suits. The big disappointment so far has been the funding."

I have just donated 10,000 to the Immortality Bus, which was the most rational decision of my life

I have non-zero probability to die next year. In my age of 42 it is not less than 1 per cent, and probably more. I could do many investment which will slightly lower my chance of dying - from healthy life style to cryonics contract. And I did many of them. Me and Exponential Technologies Institute donated 10,000 for Immortality bus project. This bus will be the start of Presidential campaign for the writer of "Transhumanist wager". 7 film crews agreed to cover the event. It will create high publicity and cover all topics of immortality, aging research, Friendly AI and extinction risks prevention. It will help to raise more funds for such type of research.

LANOSTEROL VERSUS CATARACTS: PROMISING INITIAL RESULTS
https://www.fightaging.org/archives/2015/07/lanosterol-versus-cataracts-promising-initial-results.php

In the research noted here, scientists have identified a potential treatment for cataracts based on the details of a rare human mutation that causes cataracts to form in young children. These patients lack lanosterol, and for reasons not yet fully understood that causes cataract formation in the lens of the eye. Following on from that finding researchers demonstrated that providing greater than usual levels of lanosterol in tissues and animals causes cataracts to shrink. The initial results are promising, but it remains to be seen how well it does outside the laboratory: too little is yet understood of the underlying mechanism to be sure that it will do well. Still, this is a good example of the very positive side of genetic studies: using mutational differences between individuals to gain enough insight into poorly understood disease mechanisms to enable the production of better treatments.

Most cataracts are age-related, with no meaningful genetic contribution to their progression, at least not to outweigh the damage you do to yourself through becoming overweight or smoking. In later life cataracts of several varieties can form in the lens of the eye to cause progressively worsening blindness. Some types result from changing structural properties of the lens that lead to damage and loss of transparency, while others involve deposition of opaque waste products or damaged and misplaced versions of the proteins that make up the lens. The present state of the art in treating cataracts is surgery to remove the damaged portions and replace them with prosthetic lens material, but some form of drug-like treatment - as proposed here - to clear out the unwanted compounds blocking vision would be a great improvement for some types of cataract.

Looking at the broader picture, a great deal of aging is a matter of the wrong proteins showing up in the wrong places. Protein aggregates feature prominently in neurodegenerative conditions such as Alzheimer's disease, for example. A large segment of the near future of medical science will involve finding ever more sophisticated methods of safely removing specific proteins from specific locations in our tissues. Many of these errant proteins come into existence as a side-effect of the normal operation of cellular metabolism, so it is perfectly feasible to look to periodic clearance as the basis for rejuvenation treatments. Provided that the level of these proteins is kept fairly low, as it is in young people, they should not cause further damage at a pace high enough to cause the emergence of age-related disease, as is the case today.

Eye drops could dissolve cataracts

Though scientists don't fully understand how cataracts form, they do know that the "fog" often seen by patients is a glob of broken proteins, stuck together in a malfunctioning clump. When healthy, these proteins, called crystallins, help the eye's lens keep its structure and transparency. But as humans and animals alike get older, these crystallin proteins start to come unglued and lose their ability to function. Then they clump together and form a sheathlike obstruction in the lens, causing the signature "steamy glass" vision that accompanies cataracts. Researchers came up with the eye drop idea after finding that children with a genetically inherited form of cataracts shared a mutation that stopped the production of lanosterol, an important steroid in the body. When their parents did not have the same mutation, the adults produced lanosterol and had no cataracts.

So the researchers wondered: What if lanosterol helped prevent or reduce cataracts? The team tested a lanosterol-laden solution in three separate experiments. First, they used human lens cells to test how effectively lanosterol shrank lab models of cataracts. They saw a significant decrease. Then, they progressed to rabbits suffering from cataracts. At the end of the 6-day experiment, 11 of 13 rabbits had gone from having severe or significant cataracts to mild cataracts or no cataracts at all. Finally, the team moved on to dogs with naturally occurring cataracts. The dogs responded just as the researchers hoped to the lanosterol solution, which was given in the form of both eye injections and eye drops. The dogs' lenses showed the same type of dissolving pattern as the human and rabbit lens cells. The improvement was remarkable - researchers could tell just by looking at the dogs' eyes that the cataracts had decreased. But the exact mechanism of how lanosterol manages to disperse the mass of proteins remains unknown.

Lanosterol reverses protein aggregation in cataracts

The human lens is comprised largely of crystallin proteins assembled into a highly ordered, interactive macro-structure essential for lens transparency and refractive index. Any disruption of intra- or inter-protein interactions will alter this delicate structure, exposing hydrophobic surfaces, with consequent protein aggregation and cataract formation. Cataracts are the most common cause of blindness worldwide, affecting tens of millions of people, and currently the only treatment is surgical removal of cataractous lenses.

The precise mechanisms by which lens proteins both prevent aggregation and maintain lens transparency are largely unknown. Lanosterol is an amphipathic molecule enriched in the lens. It is synthesized by lanosterol synthase (LSS) in a key cyclization reaction of a cholesterol synthesis pathway. Here we identify two distinct homozygous LSS missense mutations (W581R and G588S) in two families with extensive congenital cataracts. Both of these mutations affect highly conserved amino acid residues and impair key catalytic functions of LSS. Engineered expression of wild-type, but not mutant, LSS prevents intracellular protein aggregation of various cataract-causing mutant crystallins. Treatment by lanosterol, but not cholesterol, significantly decreased preformed protein aggregates both in vitro and in cell-transfection experiments. We further show that lanosterol treatment could reduce cataract severity and increase transparency in dissected rabbit cataractous lenses in vitro and cataract severity in vivo in dogs.

Our study identifies lanosterol as a key molecule in the prevention of lens protein aggregation and points to a novel strategy for cataract prevention and treatment.

IMMUNE PROFILING THE CONTRIBUTION OF CYTOMEGALOVIRUS TO AGING
https://www.fightaging.org/archives/2015/07/immune-profiling-the-contribution-of-cytomegalovirus-to-aging.php

Today I thought I'd point out an interesting and very readable open access paper on immune system aging and the contribution of cytomegalovirus to that process. The authors outline the generation of a large set of data on immune aging, sampling a few hundred healthy individuals to obtain a range of measures of immune function, and discuss the results. It makes for interesting reading if you've been following research into cytomegalovirus in immune aging, and there are even online data visualization tools for the results published in this paper.

The immune system grows simultaneously overactive and ineffective in old age, generating chronic inflammation while failing to respond adequately to threats such as pathogens and potentially cancerous cells. A growing consensus in the researcher community sees exposure to cytomegalovirus (CMV) as an important contribution to this dysfunction. CMV is a very prevalent herpesvirus; near everyone has it in their system by the time they are old, and like all herpesviruses it resists clearance, reemerging from hiding to challenge the immune system repeatedly. In the old immune system there is an expansion of memory T cells, and especially memory T cells devoted to CMV. This expansion takes place at the expense of naive T cells needed to respond to new threats.

There is more than just this one form of dysfunction in the aged immune system, but this particular problem might be addressed in the near future in a variety of ways: clear out the useless duplicated memory T cells to free up space, or deliver a much larger supply of new T cells, such as by rejuvenating the thymus, the organ responsible for T cell maturation, or simply culturing new immune cells from a patient's own tissues and periodically delivering them. It is also possible to work towards a reliable way to clear CMV permanently - better ways to treat all herpesviruses are certainly needed. Even if completely successful this won't undo the damage done to the immune system's balance of cell populations, however. It only prevents the accumulation of more damage.

This paper can be taken as one of many that illustrates the magnitude of the effect of CMV on immune aging. It also makes some other interesting points regarding the scale of variations between individuals as compared to variations over the course of aging. It is possible to be old and still have a comparatively effective immune system by some measures: there is considerable overlap in the range of values across a given age and the range across all ages. The trend is still downhill and we need the development of rejuvenation treatments to reverse that, but all is not hopeless.

Large-Scale and Comprehensive Immune Profiling and Functional Analysis of Normal Human Aging

In this study, we describe a large immunological data set based on about 240 individuals from a clinical cohort of 740 healthy aging adults. Data from cellular, protein, and genomic assays are described, with particular emphasis on stimulation-response assays (analysis of cytokine signaling, and cytokine production and gene expression from stimulated peripheral blood mononuclear cells). Our emphasis in this paper was to describe the features of each assay with regard to discovering differences based on age, sex, and CMV status. Further analysis of the data is welcomed, via a parallel coordinates visualization tool.

One common theme among nearly all our immunological readouts is that there is considerable heterogeneity at every age, which is generally greater than the mean change across ages. This is exemplified by the CD27+CD8+ subset of T cells. While the downward trend with age is highly significant, the breadth of values at every age is very high. In this regard, there are essentially no "clock" analytes, which would accurately and independently predict age, since there is so much overlap in the distributions among young and old individuals. The corollary to this is that many, if not most, elderly individuals still fall within the range of the younger adults. In fact, we often observed a broadening of the distribution with age.

In this regard, it is important to note that this study had strict exclusion criteria, such that overt diseases of aging were not clinically present. Although our data provide a relatively clean description of the range of immunological values associated with healthy aging, they represent a cross sectional analysis and as such may include individuals at risk for or developing disease.

As a result of quantifying significant readouts by age, sex, and CMV status, one can pose the question, "Which of these three variables has the greatest impact on the immune system as we measured it?" From our data, it seems reasonable to conclude that age, then sex and CMV status, show the greatest effects. Taken another way, it is impressive to see that the changes in the immune system brought about by a single pathogen, CMV, rival the differences seen between the sexes, in terms of the number of significantly affected analytes. Another conclusion from our data is that there is a clear interaction of age, sex, and CMV status. For example, T cell subsets are highly influenced by all three. In this case, the effect of CMV appears to be a downward broadening of the distribution, such that a subset of CMV positive individuals shows markedly lower levels of these cells.

LATEST HEADLINES FROM FIGHT AGING!

"BUT SO DOES ASPIRIN"
Monday, July 20, 2015
https://www.fightaging.org/archives/2015/07/but-so-does-aspirin.php

Every so often along comes a new over-hyped drug candidate with studies showing it extends life in laboratory animals. People throw away common sense and buy the stuff for a few years until the hype wears off in the face of more scientific evidence that throws doubt upon the early claims, and the realization that, like all the preceding drug candidates, this latest one also does next to nothing to impact the progression of aging in humans.

It helps greatly to realize that life span and health are much more plastic in short-lived species than in comparatively long-lived species such as we humans. All sorts of things extend life in lower animals by a large amount yet have no such result in humans. Consider calorie restriction for example, which extends life by 40% in mice, but certainly doesn't do as much in humans. Did you know that ibuprofen use meaningfully extends life in a number of species to a an equal or greater level than metformin, a currently hyped drug candidate to slow aging? Or that aspirin has sizable effects on life span in short-lived species as well? Yet clearly neither of those extends human life span to anywhere near the same degree, despite decades of use and a great deal of data on its effects.

Chasing meaningful effects from drug candidates such as metformin is irrational based on what is known to date. It is not where the research community should be putting time and money. When people point to the effects in animal studies, noting that in some of these metformin is shown to extend life, you can say "but so does aspirin, and that certainly doesn't have the same effect on life span in people."

We examined the impacts of aspirin and metformin on the life history of the cricket Acheta domesticus (growth rate, maturation time, mature body size, survivorship, and maximal longevity). Both drugs significantly increased survivorship and maximal life span. Maximal longevity was 136 days for controls, 188 days (138% of controls) for metformin, and 194 days (143% of controls) for aspirin. Metformin and aspirin in combination extended longevity to a lesser degree (163 days, 120% of controls). Increases in general survivorship were even more pronounced, with low-dose aspirin yielding mean longevity 234% of controls (i.e., health span).

Metformin strongly reduced growth rates of both genders (less than 60% of controls), whereas aspirin only slightly reduced the growth rate of females and slightly increased that of males. Both drugs delayed maturation age relative to controls, but metformin had a much greater impact (more than 140 % of controls) than aspirin (~118 % of controls). Crickets maturing on low aspirin showed no evidence of a trade-off between maturation mass and life extension. Remarkably, by 100 days of age, aspirin-treated females were significantly larger than controls (largely reflecting egg complement). Unlike the reigning dietary restriction paradigm, low aspirin conformed to a paradigm of "eat more, live longer." In contrast, metformin-treated females were only ~67 % of the mass of controls.

Our results suggest that hormetic agents like metformin may derive significant trade-offs with life extension, whereas health and longevity benefits may be obtained with less cost by agents like aspirin that regulate geroprotective pathways.

CALORIE RESTRICTION IS FEASIBLE AND BENEFICIAL FOR HUMANS
Monday, July 20, 2015
https://www.fightaging.org/archives/2015/07/calorie-restriction-is-feasible-and-beneficial-for-humans.php

Here, recently published research adds to the weight of evidence to show that firstly even modest levels of reduced calorie intake produce measurable health benefits over the long term, and secondly it is possible to have a high degree of compliance in the study population. The knee-jerk reaction in many quarters to the practice of calorie restriction with optimal nutrition, meaning fewer calories consumed without reducing the intake of vital micronutrients, is that it is too hard. It is certainly true that most people in this age of cheap calories and ever more enticing foods choose not restrict their intake, but that isn't the same thing as "too hard." If you actually take the time to try it out and experiment with dietary options, you'll find that modest calorie restriction is not all that challenging at all.

Caloric restriction (CR), energy intake reduced below ad libitum (AL) intake, increases life span in many species. The implications for humans can be clarified by randomized controlled trials of CR. To determine CR's feasibility, safety, and effects on predictors of longevity, disease risk factors, and quality of life in nonobese humans aged 21-51 years, 218 persons were randomized to a 2-year intervention designed to achieve 25% CR or to AL diet. Outcomes were change from baseline resting metabolic rate adjusted for weight change ("RMR residual") and core temperature (primary); plasma triiodothyronine (T3) and tumor necrosis factor-α (secondary); and exploratory physiological and psychological measures.

Body mass index averaged 25.1 (range: 21.9-28.0). Eighty-two percent of CR and 95% of AL participants completed the protocol. The CR group achieved 11.7%CR and maintained 10.4% weight loss. Weight change in AL was negligible. RMR residual decreased significantly more in CR than AL at 12 months but not 24 months (M24). Core temperature change differed little between groups. T3 decreased more in CR at 12 and 24 months, while tumor necrosis factor-α decreased significantly more only at 24 months. CR had larger decreases in cardiometabolic risk factors and in daily energy expenditure adjusted for weight change, without adverse effects on quality of life.

We conclude that sustained CR is feasible in nonobese humans. The effects of the achieved CR on correlates of human survival and disease risk factors suggest potential benefits for aging-related outcomes that could be elucidated by further human studies.

ANOTHER EXAMPLE OF REJUVENATION OF CELL CHARACTERISTICS THROUGH INDUCED PLURIPOTENCY
Tuesday, July 21, 2015
https://www.fightaging.org/archives/2015/07/another-example-of-rejuvenation-of-cell-characteristics-through-induced-pluripotency.php

Here researchers show, once more, that the process of creating a line of induced pluripotent stem cells from ordinary cells and then differentiating the pluripotent cells back into the original cell types will repair and reverse measures of cell damage along the way. It makes sense that mechanisms of this nature must exist somewhere in the cellular repertoire, since parents are old but children are young: an embryo undergos a period of intense repair and restoration very early in its development process.

Now that numerous research teams having confirmed this aspect of induced pluripotency and are cataloging the details, the real question is what can be done with this? Producing less damaged patient-matched cells for cell therapies in the old is one immediate possibility, but evidence to date suggests that the problem is the tissue environment as much as the cells - even young and undamaged cells struggle once introduced back into old tissues. So how best to use damage repair via induced pluripotency in therapies remains an open question, I think:

Most neurodegenerative diseases are late-onset and aging-related, and no effective treatments have been developed. The successful generation of induced pluripotent stem cells (iPSCs) and the direct conversion of neurons from patients' specific somatic cells have offered cell resources for disease modeling and potential cell transplantation therapy. However, to date no systematic studies have investigated which approach is more suitable for future cell therapy. Here, using the two approaches mentioned above in parallel we successfully obtained functional neurons from tail-tip fibroblasts (TTFs) of a 1-year-old mouse, which were characterized by specialized morphologies, neuronal marker expressions and electrophysiological properties.

Genome-wide expression analysis revealed that a set of genes related to the stress response and DNA damage were expressed at a much higher level in iNs than in diNs derived from 1-year-old TTFs. Subsequently, significant decreases in mitochondrial dysfunction and DNA damage were observed in diNs compared with iNs derived from aged TTFs. Moreover, the levels of epigenetic markers such as 5hmC, H3K4me3, H3K9me3 and H3K27me3 in iNs were more similar to those in the old TTFs compared with those in diNs, indicating that the iNs converted directly from TTFs may retain some residual epigenetic memories. By contrast, reprogramming to iPSCs not only rejuvenated the cell stages but also erased such epigenetic memories obtained along the aging process. Taken together, the results of our study are instructive and meaningful for future clinical applications.

THE DAMAGE DONE BY SMOKING
Tuesday, July 21, 2015
https://www.fightaging.org/archives/2015/07/the-damage-done-by-smoking.php

Smoking is an effective way to both shorten your life span and suffer ugly medical complications in later life, as this epidemiological study illustrates. Along with being overweight and sedentary it produces one of the larger negative effects on life span that you can achieve through common lifestyle choices. Interestingly, the effects on life expectancy and mortality are about the same size as those resulting from being obese.

Smoking is known to be a major cause of death among middle-aged adults, but evidence on its impact and the benefits of smoking cessation among older adults has remained limited. Therefore, we aimed to estimate the influence of smoking and smoking cessation on all-cause mortality in people aged ≥60 years. Relative mortality and mortality rate advancement periods (RAPs) were estimated by Cox proportional hazards models for the population-based prospective cohort studies from Europe and the U.S. (CHANCES [Consortium on Health and Ageing: Network of Cohorts in Europe and the U.S.]), and subsequently pooled by individual participant meta-analysis. Statistical analyses were performed from June 2013 to March 2014.

A total of 489,056 participants aged ≥60 years at baseline from 22 population-based cohort studies were included. Overall, 99,298 deaths were recorded. Current smokers had 2-fold and former smokers had 1.3-fold increased mortality compared with never smokers. These increases in mortality translated to RAPs of 6.4 and 2.4 years, respectively. A clear positive dose-response relationship was observed between number of currently smoked cigarettes and mortality. For former smokers, excess mortality and RAPs decreased with time since cessation, with RAPs of 3.9, 2.7, and 0.7 for those who had quit less than 10, 10 to 19, and more than 20 years ago, respectively.

Smoking remains as a strong risk factor for premature mortality in older individuals and cessation remains beneficial even at advanced ages. Efforts to support smoking abstinence at all ages should be a public health priority.

INDUCED PLURIPOTENT STEM CELLS AS KIDNEY DISEASE THERAPY
Wednesday, July 22, 2015
https://www.fightaging.org/archives/2015/07/induced-pluripotent-stem-cells-as-kidney-disease-therapy.php

Researchers here investigate the transplant of induced pluripotent stem cells-derived progenitor cells produced from the recipient's tissues as a possible way to spur regeneration of kidney damage, such as the fibrosis characteristic of chronic kidney disease. Like many forms of stem cell therapy, this appears to produce benefits due to the signal molecules generated by the transplanted cells. That in turn suggests that near future therapies emerging from stem cell research will largely involve providing the signals directly, not via cells, in ever more sophisticated efforts to control the behavior of native cells. This present phase of cell transplant development will be used to gain the knowledge needed to build therapies lacking cells but which have the same beneficial effects.

One promising way to treat diseased or damaged kidneys is cell therapies that include the transplantation of renal progenitor cells, which can then develop into the cells needed for full recovery. Acquiring a sufficient number of progenitor cells has been difficult, however, which is why scientists have considered induced pluripotent stem cells (iPSCs), since they can be expanded at significantly high levels and then differentiated into the progenitors.

Researchers transplanted iPSC-derived renal progenitors into the kidney subcapsule, which is at the kidney surface of a mouse model with acute kidney injury. Even though the transplanted cells never integrated with the host, mice that received this transplant showed better recovery, including less necrosis and fibrosis, compared with mice that received transplants of other cell types. One reason attributed to this improvement was the use of cells that expressed Osr1 and Six2. Although these two factors are known markers of renal progenitors, until now researchers had not exclusively used cells that expressed both for cell therapies.

Another conclusion from the study was that because the cells did not integrate into the kidney, their therapeutic effects were the result of paracrine actions that included the secretion of key renoprotective factors. While most stem cell therapies aim for integration, these findings could have important clinical implications. Foremost is that it is one of the first to show the benefits of using human iPS cell-derived renal lineage cells for cell therapy. Second, fibrosis is a marker of progression to chronic kidney disease, suggesting that the paracrine effects could act as preventative therapy for other serious ailments. Finally, these effects could give clues for drug discovery. "There is no medication for acute kidney injury. If we can identify the paracrine factor, maybe it will lead to a drug."

SPURRING COMPLETE LIVER REGROWTH IN MICE
Wednesday, July 22, 2015
https://www.fightaging.org/archives/2015/07/spurring-complete-liver-regrowth-in-mice.php

Researchers have found a way to induce complete regrowth of the liver in mice, which intriguing involves inducing far greater cellular senescence than is normally the case. The liver is normally the most regenerative of organs in mammals, capable of regrowing sections of tissue following injury, but this result is somewhat more impressive than that.

Cellular senescence is known to be involved in and promote wound healing, and researchers have shown in past years that senescence in liver cells is both flexible and amenable to manipulation. However clearance of senescent cells is of general interest in the prospective treatment of aging: senescent cells accumulate in all tissues with age and contribute to damage and loss of function through a variety of mechanisms. A more sophisticated control of cellular senescence in tissues may well lead to a range of therapies that alternately encourage it and suppress it at various times and under various circumstances.

Hepatocytes and cholangiocytes self-renew following liver injury. Following severe injury hepatocytes are increasingly senescent, but whether hepatic progenitor cells (HPCs) then contribute to liver regeneration is unclear. Here, we describe a mouse model where the E3 ubiquitin ligase Mdm2 is inducibly deleted in more than 98% of hepatocytes, causing apoptosis, necrosis and senescence with nearly all hepatocytes expressing p21. This results in florid HPC activation, which is necessary for survival, followed by complete, functional liver reconstitution.

HPCs isolated from genetically normal mice, using cell surface markers, were highly expandable and phenotypically stable in vitro. These HPCs were transplanted into adult mouse livers where hepatocyte Mdm2 was repeatedly deleted, creating a non-competitive repopulation assay. Transplanted HPCs contributed significantly to restoration of liver parenchyma, regenerating hepatocytes and biliary epithelia, highlighting their in vivo lineage potency. HPCs are therefore a potential future alternative to hepatocyte or liver transplantation for liver disease.

TREATING CANCER AS THOUGH IT WERE AN INFECTIOUS DISEASE
Thursday, July 23, 2015
https://www.fightaging.org/archives/2015/07/treating-cancer-as-though-it-were-an-infectious-disease.php

Here researchers propose an interesting approach to destroying cancer stem cells via targeted antibiotics. Cancer stem cells have been shown to be the driving force behind many types of cancer: without their presence, tumors would halt their growth or wither. At this point cancer research as a whole is far too slow and expensive. Faster progress towards meaningful treatments will arise from identifying and focusing on common points of attack that are essentially the same in many different types of cancer. However all too many of today's expensive and time-consuming research programs are entirely specific to the genetics and cell metabolism of one very narrow subtype of cancer, and even then individual tumors of that subtype can evolve to remove the vulnerability in question. So it is worth keeping an eye on programs that might blossom into classes of therapy applicable to a broad swathe of cancers:

We propose a new strategy for the treatment of early cancerous lesions and advanced metastatic disease, via the selective targeting of cancer stem cells (CSCs), a.k.a., tumor-initiating cells (TICs). We searched for a global phenotypic characteristic that was highly conserved among cancer stem cells, across multiple tumor types, to provide a mutation-independent approach to cancer therapy. This would allow us to target cancer stem cells, effectively treating cancer as a single disease of "stemness", independently of the tumor tissue type. Using this approach, we identified a conserved phenotypic weak point - a strict dependence on mitochondrial biogenesis for the clonal expansion and survival of cancer stem cells. Interestingly, several classes of FDA-approved antibiotics inhibit mitochondrial biogenesis as a known "side-effect", which could be harnessed instead as a "therapeutic effect".

Based on this analysis, we now show that 4-to-5 different classes of FDA-approved drugs can be used to eradicate cancer stem cells, in 12 different cancer cell lines, across 8 different tumor types (breast, DCIS, ovarian, prostate, lung, pancreatic, melanoma, and glioblastoma (brain)). These five classes of mitochondrially-targeted antibiotics include: the erythromycins, the tetracyclines, the glycylcyclines, an anti-parasitic drug, and chloramphenicol. Functional data are presented for one antibiotic in each drug class: azithromycin, doxycycline, tigecycline, pyrvinium pamoate, as well as chloramphenicol, as proof-of-concept. Importantly, many of these drugs are non-toxic for normal cells, likely reducing the side effects of anti-cancer therapy.

Thus, we now propose to treat cancer like an infectious disease, by repurposing FDA-approved antibiotics for anti-cancer therapy, across multiple tumor types. These drug classes should also be considered for prevention studies, specifically focused on the prevention of tumor recurrence and distant metastasis. Finally, recent clinical trials with doxycycline and azithromycin (intended to target cancer-associated infections, but not cancer cells) have already shown positive therapeutic effects in cancer patients, although their ability to eradicate cancer stem cells was not yet appreciated.

MORE ON THE WORK OF RESEARCHERS AT THE BUCK INSTITUTE
Thursday, July 23, 2015
https://www.fightaging.org/archives/2015/07/more-on-the-work-of-researchers-at-the-buck-institute.php

This is the third in a recent series of local news articles on the work of the Buck Institute for Aging Research in California. Sadly very little of that work is relevant to the SENS vision of rejuvenation biotechnology, targeted repair of the damage that causes aging with the ultimate goal of entirely preventing degeneration and disease. Like much of the field, research at the Buck Institute is almost entirely focused on modest goals; better understanding of the fine cellular details of how aging progresses, and manipulating the operation of cellular metabolism so as to slightly slow the accumulation of damage that causes frailty, suffering, and disease:

Simon Melov, a founding faculty member of the Buck Institute in 1999, trained in molecular biology. Before the 1990s, scientists shunned research on aging as too difficult. "You couldn't do anything about it," Melov said. That attitude persisted for years. "Gordon Lithgow and I would go to conferences. and people would say we were stupid for working on aging. Everyone knows it's ridiculous." A future Nobel prize winner came up to them at a podium where Lithgow was presenting, Melov recalls. "He said we should get out of this and go do something worthwhile. Nothing will ever come of this."

In about 1990, Tom Johnson, in whose University of Colorado lab Lithgow and Melov worked, discovered that aging in worms could be changed by modifying a gene. A few years later, Cynthia Kenyon's paper on her similar research drew acclaim. "When her paper came out, the floodgates opened. It was the aha moment. Cynthia (now at Calico, Buck Institute's Google-funded partner) was a big name." The 2000s brought a shift toward finding drugs that manipulate lifespan. Now the emphasis is on healthspan. "Function is more important than lifespan. The elderly complain about living too long in poor health. Is it easy to put your clothes on every day, reach the top shelf in your kitchen? Is it painful to walk, carry loads? Can you get in and out of the shower easily?"

Melov looks for interventions that improve gene-expression profiling, for instance. In people, he studied resistance exercise as a means to stress bones and help preserve their integrity. "In the mouse, you argue with it for an hour before it goes anywhere. In people, you get a good degree of compliance. We found that repeated resistance exercise over six months reversed many gene expression profiles -- a genetic fingerprint of cellular function in muscle -- associated with aging, back to a more youthful profile. Exercise rejuvenates the tissue." Exercise in the future will be viewed as essential to functioning. "If you don't exercise, you're going to add to the health-care burden. You have to make the time or end up subtracting years from your life." He used to take supplements then realized there's little data to support such intake. "If you exercise and have a good diet. you don't need supplements. It's a very different matter if you have a bad diet and don't exercise."

Lack of substantial federal funding for aging research confounds Melov. "Look at the NIH," he said. "There was an expectation that legislative bodies would recognize that baby boomers were aging," that this is a serious health care crisis "with large-scale financial ramifications for the economy. Unless that investment happens rapidly over the next five years. we are going to be in big trouble. This is a slow-motion train wreck. We're not going to be able to reach into the back pocket of our scientific lab coats and pull out a solution on demand. We need time and money. I'm still optimistic that reality will rear its ugly head."

ARGUING THAT HEAT SHOCK RESPONSE DECLINE IS PROGRAMMED
Friday, July 24, 2015
https://www.fightaging.org/archives/2015/07/arguing-that-heat-shock-response-decline-is-programmed.php

Researchers here present a fairly compelling case that the characteristic decline in the protective heat shock response with age is an evolved program. Compelling but not airtight: one could still argue that the rapid transition from effective to less effective observed in nematode worms is, along with other changes that occur at the same time, a response to rising levels of cellular damage rather than something that will occur regardless of circumstances. It is not too hard to envisage further studies that might add evidence to either side of the argument, and I will be very interested to see the outcome of similar investigations in mammals, but for now the primary point of interest is to see if the signaling that causes this decline can be usefully interfered with. The expectation is that increased levels of heat shock activity should result in more active maintenance and damage repair in cellular machinery, leading to slower aging and longer healthspan, and thus there is some interest in the research community in finding potential approaches to achieve this end.

Knowing more about how the quality control system works in cells could help researchers one day figure out how to provide humans with a better cellular quality of life and therefore delay degenerative diseases related to aging, such as neurodegenerative diseases. "Wouldn't it be better for society if people could be healthy and productive for a longer period during their lifetime? I am very interested in keeping the quality control systems optimal as long as we can, and now we have a target. Our findings suggest there should be a way to turn this genetic switch back on and protect our aging cells by increasing their ability to resist stress."

A genetic switch starts the aging process by turning off cell stress responses that protect the cell by keeping important proteins folded and functional. In C. elegans, the decline begins eight hours into adulthood - all the switches get thrown to shut off an animal's cell stress protective mechanisms. Researchers found it is the germline stem cells responsible for making eggs and sperm that control the switch. In animals, including C. elegans and humans, the heat shock response is essential for proper protein folding and cellular health. Aging is associated with a decline in quality control, so researchers looked specifically at the heat shock response in the life of C. elegans. "We saw a dramatic collapse of the protective heat shock response beginning in early adulthood." Once the germline has completed its job and produced eggs and sperm - necessary for the next generation of animals - it sends a signal to cell tissues to turn off protective mechanisms, starting the decline of the adult animal. "All these stress pathways that insure robustness of tissue function are essential for life, so it was unexpected that a genetic switch is literally thrown eight hours into adulthood, leading to the simultaneous repression of the heat shock response and other cell stress responses."

Using a combination of genetic and biochemical approaches, researchers found the protective heat shock response declines steeply over a four-hour period in early adulthood, precisely at the onset of reproductive maturity. Repression of the heat shock response occurred due to an increase in H3K27me3 marks at stress gene loci, the timing of which is determined by reduced expression of the H3K27 demethylase jmjd-3.1. This resulted in a repressed chromatin state that interfered with HSF-1 binding and suppresses transcription initiation in response to stress. The animals still appeared normal in behavior, but the scientists could see molecular changes and the decline of protein quality control. In one experiment, the researchers blocked the germline from sending the signal to turn off cellular quality control. They found the somatic tissues remained robust and stress resistant in the adult animals.

THOUGHTS ON THE FUNDING SITUATION IN AGING RESEARCH
Friday, July 24, 2015
https://www.fightaging.org/archives/2015/07/thoughts-on-the-funding-situation-in-aging-research.php

Given the potential for producing effective treatments in near all areas of medicine brought about by the ongoing revolution in biotechnology, a growing number of people are coming to see that the present established systems of funding, both public and private, are essentially broken. They are far too conservative, funding next to none of the most important early stage research. All of the most important and risky early stage research programs are funded by either administrative sleight of hand or by visionary philanthropy: established funding sources as a rule never offer grants unless the new science has already been discovered and mapped out with a fair degree of certainty. Thus they fund the process of fleshing out and developing a discovery, not the work needed to create and validate that discovery in the first place. If we want real progress and radical new directions in medicine, it is exactly the early stage and risky research that must be funded with greater confidence, however.

The difference between science and engineering is that scientific research starts without understanding and tries out various hypotheses until one seems to work; while an engineer works with a paradigm that she knows to be reliable enough to be a basis for results of her innovations in advance. A high failure rate is inseparable from good science. But the National Science Foundation (NSF) prefers to fund low-risk work, which is really engineering. One irony is that capitalism is pretty good at allocating funds for engineering. Once the science is well developed, the marketplace isn't a bad model for deciding where to invest engineering resources. We probably don't need NSF to fund the "D" half of "R&D". But the reason that we need NSF (and NIH and NIA) as public funding institutions is that the rewards of science are difficult to predict.

I venture to propose that the more unpredictable the result, the more important the experiment. The best prospects for future scientific breakthroughs lie in the direction of things that we already know but don't understand - things that don't make sense. Most of these will turn out to be mistakes in experimental technique or interpretation; but there are some that have such broad corroboration from diverse laboratories that this is unlikely. I could say that "professional scientist" is already a oxymoron. Scientists work best when they are driven by curiosity and a passion to find out, when they are doing what they love. How can that be consistent with centralized decision-making and bureaucratic control of research priorities? If we pay a scientist to do science, we should not make the payment contingent on studying anything in particular. No one in a government bureaucracy has the wisdom to predict next year's breakthroughs, or to single out the scientists most likely to achieve them.

In the late 1970s, when I was a low-level researcher at a government contract research house, we always worked one year ahead of our funding. By the time a proposal was written, we had worked out the science in sufficient detail that we knew the results. If the proposal was funded, we would use the proceeds to support us while we worked on next year's proposal. We may be outraged at 70% overhead rates for administration, and think of this as "slush money" that is ripe for abuse. I agree that bureaucrats receive too big a share of the pie, and scientists too little. But there is some portion of the overhead money that finds its way back through departments to the researchers themselves, and offers them some slack between contracts, their only real freedom to think and to innovate. I asked my collaborator at Prominent Midwestern U whether he had funding for the exploratory, groundbreaking work on population dynamics that he was doing with me, but I already knew the answer. He was doing it with soft funding for a follow-on to previously successful research. He had prudently kept the funders in the dark about this specific project. There's plenty of time to tell them about it if we succeed.

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