Fight Aging! Newsletter, March 3rd 2014

March 3rd 2014

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

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  • David Gobel on Printing a Medical Revolution
  • Running the Numbers From Studies of Exercise and Mortality
  • Theorizing on the Origins of Human Longevity and Gender Differences in Life Span
  • The Immortalists
  • Reviewing the Development of Stem Cell Treatments for Muscle Wasting and Retinal Degeneration
  • Latest Headlines from Fight Aging!
    • Fundraiser to Distribute Copies of "Death is Wrong"
    • Human Skin Cells Transformed to Liver Cells, Used to Repopulate a Mouse Liver
    • Body Shape Index a Better Predictor of Mortality Than Body Mass Index
    • Video of SENS6 Conference Presentations
    • Arguing for Work on Telomerase Therapies in Humans
    • Applying Computing Power to the Search for Biomarkers of Aging and Drugs that Might Slow Aging
    • Old Neural Stem Cells Can Be Restored to Action
    • More on the Inverse Relationship Between Cancers and Neurodegenerative Conditions
    • Sirtuin Activator Modestly Extends Mean Life Span in Mice
    • Results From a Recent Rapamycin Life Span Study


We live in a time of accelerating change, the opening decades of a biotechnology revolution driven by rapid growth in communications and computing power. A single laboratory can achieve in months today what would have taken years and much of the research community twenty years ago. New capabilities in medicine are demonstrated in the laboratory with ever increasing frequency, and hidebound institutions that presently try to enforce extremely long development cycles for new treatments cannot survive for much longer - not when valuable potential applications of new medical technology pile up ever higher year after year. There is a broad world out there, and new therapies will be commercially developed in those regions that smooth the way rather than throwing up barriers to rapid innovation - and these new therapies will in due course include the first practical treatments to repair some of the causes of degenerative aging.

David Gobel is co-founder and CEO of the Methuselah Foundation, an organization that has influenced many of the most important changes in the culture and progress of longevity science over the past decade. He sees tissue engineering as an important engine in the years ahead, bioprinting especially, with the ultimate goal of generating patient-matched new organs from scratch as needed. This is a part of the acceleration of progress in biotechnology and its application to medicine, and Gobel made that point in this post to the Gerontology Research Group list:

Gentlemen, a single scribe would labor for 20 years to produce a single cathedral worthy Bible - his life's work - if he lived that long. We live in the scribal age of medicine where solutions take 20 years to achieve. The printing press reduced 20 years to 20 months, 20 days, hours, minutes, seconds, etc, etc. What we now actually have is a new printing press for micro and macro tissues such that profoundly confounding structures might be reduced and reproduced at will, in perfection and in such quantity as to make costs 17 years hence a mere trifle comparatively.

When we became first investor in Organovo, this was our vision. New parts for people. Simple, direct, engineering, we may not know in detail why it all works, but work it does (so far). In December we with the advice and support of our science advisors launched the $1,000,000 New Organ Liver Prize. This year we are investigating with our partners two additional prize challenges on bioengineering hearts and preserving whole organs. Methuselah also offers $500,000 to qualified fearless tissue engineering researchers to secure access to one of Organovo's printers as well as training, support, startup funds and supplies. We are as they say "all in" on this hand.

Till now, medical research reminds one of 16th century alchemy seeking the elixir of life by error and trials. It is time for a biological industrial revolution where the body and bodies of humanity itself are the direct beneficiary. We do indeed believe that 3D tissue printing will make major contributions to extending healthy lifespan by accelerating and improving toxicology models, pathology models, replacement tissues, and finally new organs. We expect that such advances will begin this very year with toxicology models, and that advances will accelerate and a new industry arise such that by 2018 (we hope) and 2021 (feel certain) that large and complex macro tissue systems will be available for experimental insertion and use in large mammals.

Shortly thereafter it is our hope that the SENS portfolio and similar efforts in rejuvenation will begin to come on stream to repair the molecular damage of our decaying selves. SENS is a firebreak for our futures.

You might recall that SENS research programs were first funded and organized under the Methuselah Foundation umbrella before the SENS Research Foundation launched as an independent organization back in 2009.


Animal data comprehensively demonstrates that regular exercise improves long-term health. The data on life extension is less conclusive, but in some studies more individuals lived into what is the late life period for their species, extending mean life span. Other studies show no such increase. Researchers can follow groups of animals for their entire life spans and crunch the numbers: the causality of results can be well demonstrated, and we can safely conclude that exercise is producing these benefits.

In human studies statistics and population surveys have to substitute for following groups carefully segregated by amount of exercise, with scientific controls and consistent data gathering, for an entire life span. It is very hard to pull causality from this sort of data, but the data itself looks very similar to that generated in animal studies, in that regular exercise is a good thing for health and produces analogous short term changes in measures of metabolism. It isn't unreasonable to expect on the basis of all this evidence that regular exercise does indeed cause better health, on balance, across populations, in humans just as it does in animals.

All this has been said numerous times, and there are mountains of data to support it. You should be exercising, as your physician no doubt reminds you on every occasion that the two of you meet: it costs little and produces greater benefits for most people than any sort of presently available medical technology. There is so much epidemiological data on exercise available in this age of cheap computing that anyone with the time and skills can slice and dice it to come up with new measures - such as a guesstimate of the return on investment for exercise. What is the expected outcome in terms of time gained versus time invested? This will not be a simple linear relationship, but it is interesting to come up with simple speculative numbers - and bear in mind that it isn't just life gained, but also medical expenditures and pain and suffering reduced:

Every Minute Of Exercise Could Lengthen Your Life Seven Minutes

It's a daily struggle to make the time to exercise, and the current federal health guidelines call for at least 150 minutes a week of moderate exercise - a lot of time that somehow manages to seem like even more, magnified by the "should" it adds to so many days. There are hundreds of other reasons to exercise, and the one that works best for me is wanting to feel at my best on that very day. But it would be very comforting, I thought, if I knew that all of that time would come back to me.

Let me cut to the happy conclusion: It seems that it does. And then some. If you play with the data of a recent major paper on exercise and longevity, you can calculate that not only do you get the time back; it comes back to you multiplied - possibly by as much as seven or eight or nine.

Pooled data from six large studies that included more than 650,000 people followed over ten years [showed] that people who exercised at the recommended level gained 3.4 years of life after age 40. Say you start with someone 45 years old who begins to follow the 150-minute-a-week recommendation. Average American life expectancy is 78. So: "If you start exercising at 45 and you die at 78, that means that you exercise for 33 years, at 150 minutes a week. I calculated that over 33 years you would need to spend basically 4,290 hours in exercise, which is 179 days of exercise, which is less than half a year. So that's half a year, and you gain almost three and a half years, so it is worth exercising. That's an approximate scenario using reasonable assumptions, and you're getting a 1-to-7 return.

On the flip side of the coin, there is the now fairly established ballpark estimate that being sedentary is about as bad as smoking when it comes to the bottom line of whether you are going to be alive or dead or dying some number of years from now:

Lack of exercise kills roughly as many as smoking, study says

People across the world are falling so far short on exercise that the problem has become a global pandemic, causing nearly a tenth of deaths worldwide and killing roughly as many people as smoking, researchers warned this week. Eight out of 10 youngsters age 13 to 15 don't get enough exercise [and] nearly a third of adults fall short. The problem is even worse for girls and women, who are less active than boys and men, researchers found.

The results are fatal. Lack of exercise is tied to worldwide killers such as heart disease, diabetes and breast and colon cancer. If just a quarter of inactive adults got enough exercise, more than 1.3 million deaths could be prevented worldwide annually, researchers said. Half an hour of brisk walking five times a week would do the trick.


It is a given that women tend to live longer than men, a difference that becomes ever more apparent as demographic cohorts approach extreme old age. Four of every five centenarians are women, for example. This disparity has long been noted, and yet, as is the case for many apparently simple questions about the biochemistry of aging, there are as yet no definitive, final answers as to why this situation exists, how it came about though natural selection, and what exactly determines gender differences in longevity at the level of metabolic processes and epigenetic patterns of gene expression. There are a great many theories, however. If you want to see scientific undergrowth at its thickest, tangled and disputed, look no further than this topic.

Any proposed comprehensive theory on gender longevity differences in humans should probably also touch on two oddities in our species: firstly that women live long past menopause, and secondly that we are very long-lived in comparison to other mammals of a similar size, including our closest relatives among the primates. The grandmother hypothesis is often put forward in connection with these points, but is by no means universally accepted: it is the idea that our intelligence, tool-use, and culture allow older post-reproductive individuals to increase the reproductive success of their direct descendants in ways that simply don't happen in other species.

Here is a very readable open access paper that walks through one researcher's assembly of a theory of human aging and its unusual aspects, touching on a range of research from recent years, some of which you might recall being mentioned here. As for many similar topics this has very little bearing on the pressing issue of building effective treatments for degenerative aging, but it is a part of the very interesting backdrop to that work: there is great complexity to aging, and the genius of the repair based approach of SENS and similar initiatives is the recognition that most of that complexity can be bypassed and ignored. We simply don't need to fully comprehend degenerative aging in order to remove it from the human condition.

Evolution of sexually dimorphic longevity in humans

The pattern of human aging exhibits a number of salient features that have long engaged evolutionary biologists. For one, among the higher primates, human being are unusually long lived. The maximum lifespans of orang-utans and gorillas are 58.7 and 54 years, respectively, and those of our closest relatives, bonobos and chimpanzees are 50 and 53.4 years, respectively. By contrast, maximum human lifespan varies from 85 in foraging groups such as the Aché in Paraguay and Kung bushmen, to 122 in the developed world. This implies that an evolutionary spurt of increased longevity must have occurred since the last common ancestor of humans and chimpanzees/bonobos walked the earth some 5-7 million years ago.

Another striking feature of human aging is its sexual inequality. As life expectancy has increased with improvements in living conditions during the last century, there has consistently emerged a survival difference between the sexes, with women living longer. For example, in the UK estimated life expectancies for women and men from birth (2012) are 82.4 and 78.0 years, respectively, a difference of 4.4 years. Some other examples of gender gaps are the USA 5.0 years (81.0F - 76.0M), France 6.4 years (84.7F - 78.3M) and Russia 13.0 years (73.1F - 60.1M). The gender gap reflects a greater susceptibility of men to a wide range of aging related pathologies, including cardiovascular disease, type II diabetes, infection and sarcopenia (aging-related loss of muscle mass). The basis of male frailty remains unclear, either in terms of its evolutionary origins or somatic causes.

The other gender gap in aging affects reproductive lifespan. Women's capacity reproduce is lost in their late 40s, as they undergo the menopause, while men can remain fertile at least into their early 80s. The significance of the early cessation of reproduction in women is a topic of much discussion, in particular, whether or not it is an adaptation and contributes to evolutionary fitness.

Why do humans live longer than other higher primates? Why do women live longer than men? What is the significance of the menopause? Answers to these questions may be sought by reference to the mechanisms by which human aging might have evolved. Here, an evolutionary hypothesis is presented that could answer all three questions.


The Immortalists is a human interest film focused on Aubrey de Grey of the SENS Research Foundation and Bill Andrews of Sierra Sciences, and will premier at this year's SXSW.

Two extraordinary scientists struggle to create eternal youth with medical breakthroughs in a world they call "blind to the tragedy of old age." Bill Andrews is a lab biologist and famed long-distance runner racing against the ultimate clock. Aubrey de Grey is a genius theoretical biologist who conducts his research with a beer in hand. They differ in style and substance, but are united in their common crusade: cure aging or die trying. They publicly brawl with the old guard of biology who argue that curing aging is neither possible nor desirable. As they battle their own aging and suffer the losses of loved ones, their journeys toward life without end ultimately become personal.

As you might guess this isn't really a popular science effort, but rather an entry into the time-honored documentary genre of giving screen time to strong characters in an industry largely unfamiliar to the public, people who are forging their way against the flow, working to achieve great and unusual things. There's a blog and PDF press kit if you want to look further.

You can also get a sense of the thing from the trailer, but I'll use this as a springboard to note the existence of a very real challenge when it comes to advocacy and fundraising for efforts to develop the means to treat and reverse degenerative aging. The public at large, and even people who take a little time to investigate the work of the research community, largely cannot tell the difference between serious efforts that might actually work, such as the work of the SENS Research Foundation and its allies, and scientific-sounding efforts that are in fact just ways to sell supplements that cannot possibly do anything meaningful to the course of aging, which is what has become of Sierra Sciences.

Sierra Sciences was at one point a serious effort to investigate manipulation of telomeres and telomerase as a means to treat aging, but at some point venture capital demands profits. Hence the slide of this company, like others before it, from legitimate research venture to just another group selling packaged herb extracts. Somewhere back in the day someone figured out that if you sound like a scientist people will buy what you sell regardless of how dubious your pitch is. It works even better if you actually used to be a scientist - so that's what we tend to see in this sort of situation. It's a damn shame, but it is what it is.

So you have a film equating de Grey, who coordinates a well-supported disruption of the status quo in aging research, complete with ongoing research projects aimed at the creation of actual, real rejuvenation over the next few decades, with Andrews, who is a scientist turned supplement seller - yet another in the long series of people to leave the rails of doing meaningful research in favor of hawking marginal and frankly dubious products here and now. These two people and the broader efforts they represent couldn't be more different. One is a shot at rejuvenation, and the other has made himself irrelevant to that goal.

This is a microcosm of the reasons why much of the mainstream scientific community are exceedingly unhappy with the "anti-aging" marketplace. When folk in the street - and journalists who know better, but who live and die by page view counts - don't take the time to distinguish between fraudulent "anti-aging" products and legitimate laboratory research, and the largest megaphones are wielded by supplement sellers, then the fundraising environment for aging research becomes challenging.

The future of longevity is not herbal supplements, never was herbal supplements, and never will be herbal supplements. Anyone trying to sell you a supposedly longevity-enhancing ingested product here and now, today, has left the real road to human rejuvenation far behind. All they have to sell are wishes, dreams, and lies. The only valid, viable way forward is to fund the right sort of research: the development of targeted therapies capable of repairing or reversing the known root causes of aging, and stop-gap treatments such as stem cell therapies that can temporarily reverse some of the consequences of aging to a degree that merits the high cost of development. Nothing exists today that can accomplish that first goal, and it will be at least two decades before early rejuvenation therapies emerge, even assuming great progress in fundraising over that time.

So to meander to a conclusion: there is probably no such thing as bad publicity. The more that the public hears about the prospects for treating aging, more likely it is that some people will come to favor that goal, and the easier it becomes for scientists to raise funds for new ventures or to expand existing SENS programs. But I, not in the target audience of course, would much prefer to see that done in a more discriminating way than the example herein.


Below you'll find links to open access reviews on the current state of two different areas of applied stem cell science: reversing muscle loss in aging and degenerative conditions, and repairing forms of blindness caused by retinal degeneration. Consider these representative of many other similar efforts, as for near every part of the body there are teams out there somewhere working on how to apply stem cells to reverse damage and restore function. It is a very broad, active, and well-funded field of research, all told.

Retinal Stem Cells and Regeneration of Vision System

Eye formation requires the coordination of complex interactions from multiple cellular sources to create the cell behaviors that progressively shape the developing eye. The mechanisms of development and differentiation of eye are remarkably similar in all vertebrates. During retinogenesis, proliferating retinal pigment cells (RPCs) and newly generated cells are confined at the peripheral margin of the retina. In fish and amphibians, this region is maintained after embryonic development and this specialized region referred to as the CMZ. The retina of many fish and amphibians continue to grow throughout their life. The increase in retinal size is due to in part to the addition of new neurons, at the CMZ. In birds, neurogenesis at the CMZ decreases dramatically than that observed in fish and amphibians. Furthermore, in rodents the retinal margin does not exhibit mitotic activities after the first week of postnatal life. It is interesting to note that there might be a direct correlation of the evolutionary importance of the ability of retina to regenerate with the presence of RPCs and their potential to generate retinal neurons.

Adult mammalian retina has long been known to be devoid of stem cells and has lost the ability to regenerate after damage. Nevertheless, several groups have reported that pigmented cells isolated from the adult human ciliary epithelium can transdifferentiate to retinal progenitor-like cells and Müller glia cells can display characteristics of neural progenitor cells, thus identified both cell populations as potential candidate for stem-cell based therapies to regenerate visual function.

It seems logical that it is preferable to mobilize endogenous RPCs to drive the repair process in the retina. However, the challenge of using endogenous RPCs for self repair will be to identify appropriate cellular sources and molecules, including pharmacological agents, that can expand the endogenous cell pool and reactivate the regenerative processes similar to those described for the lower vertebrates in the mammalian retina.

Recent advances in stem cell research have raised the possibility to use human embryonic stem cells and induced pluripotent stem cells to repair or regenerate damaged mammalian retina. Cell transplantation is the most direct approach towards replacing damaged retinal cells and restoration of lost visual function. To achieve a breakthrough in cell replacement therapies in retinal degenerative diseases would require isolation and molecular characterization of human RPCs for specific neuronal replacement in the actively degenerating adult retina and that these new cells survive without immune suppression as well as displaying evidence of integration into host circuitry.

Advancements in stem cells treatment of skeletal muscle wasting

Muscular dystrophies (MDs) are a heterogeneous group of inherited disorders, in which progressive muscle wasting and weakness is often associated with exhaustion of muscle regeneration potential. Although physiological properties of skeletal muscle tissue are now well known, no treatments are effective for these diseases. Muscle regeneration was attempted by means of transplantation of myogenic cells (from myoblast to embryonic stem cells) and also by interfering with the malignant processes that originate in pathological tissues, such as uncontrolled fibrosis and inflammation. Taking into account the advances in the isolation of new subpopulation of stem cells and in the creation of artificial stem cell niches, we discuss how these emerging technologies offer great promises for therapeutic approaches to muscle diseases and muscle wasting associated with aging.

New approaches using organisms genetically modified and transgenic mouse models proposed the importance of the microenvironment - like the niche and the extrinsic factors - to be a key component in stem cell regulation. Particularly, significant progress has been made in understanding how satellite cells can act as tissue-specific adult stem cells in skeletal muscle. In the same time, many studies investigated the satellite cell properties in term of efficacy after in vivo transplantation using novel approaches such as non-invasive bioluminescence imaging. These tools provided information for assessing not only satellite cell function but, in general, stem cell function. Investigations on the molecular nature of stem cell niche signals on in vivo models and short-term cultures of isolated myofibers, are now on-going.

Bioengineering offers significant tools for the development of strategies to mimic biochemical and biophysical features of the in vivo niche microenvironment. We hope that the synthesis of biomaterials, micro-fabrication technology and stem cell biology will provide systems potentially innovative to better understand how stem cell fate is controlled. Development of biomaterials able to re-create an in vitro stem cell niche could give rise to novel insights into understanding the molecular cues, critical for the in vitro maintenance and expansion of muscle stem cells. Above all, these in vitro systems can well lead to the generation of adequate numbers of stem cells and the ability to control their differentiation in order to maximize their utility, not only as cell-based therapeutics for tissue regeneration and replacement, but also as the control of inflammation after muscle damage.


Monday, February 24, 2014

Death is Wrong is a child's primer on efforts to develop treatments for degenerative aging, so as to prevent the enormous toll of suffering and death it causes. Here the author is raising funds to distribute copies to activists for longevity science. The ongoing process of persuading the world to take an interest in and provide sufficient support for building a cure for aging is made of many such modest steps:

Death is Wrong fills an important void and can inspire a new generation to join the struggle for greatly increased longevity. Virtually everyone learns about death as a child, and the initial reaction is the correct one: bewilderment, horror, and outrage. Yet there has been no resource to validate these completely correct first impressions. Almost immediately, the young ones are met with excuses and rationalizations, so that they might be consoled and return to a semblance of normalcy. Over millennia of facing indeed inevitable demises, humans have constructed elaborate edifices of rationalization, designed to keep thoughts of death from intruding upon their day-to-day lives.

While transhumanists and life-extension advocates have made headway with conveying their aspirations for the future to some of the most technically educated and philosophically inclined adults, the mainstream of society remains pervaded by the old death-acceptance arguments - religious and secular: from the fear of "playing God" to the specter of overpopulation. Every mind held captive by these traditional and Malthusian pro-death prejudices is a mind that will at best not help life-extension progress and at worst hinder it greatly - a higher likelihood for the most intelligent purveyors of the death-acceptance mindset. People who embrace these notions and find them credible (despite the relative ease of debunking them using logic and evidence) largely do so because the fallacies were ingrained into them since childhood, with no counterarguments being presented or even posited as conceivable. So, if the antidote to these fallacies is to be most effective, it must be administered in childhood.

Death is Wrong will be easily understood by most eight-year-olds, though my aim is to encompass as young an audience as possible. The beautiful and detailed illustrations will help keep young minds engaged as they read about long-lived organisms found in nature, as well as the great advocates of life extension from the past and the present. The book discusses successes in animal life extension, along with providing a concise introduction to Dr. de Grey's SENS program and the seven principal types of damage that must be addressed in order to reverse senescence. The book also focuses of refuting the common pro-death rationalizations and presenting young readers with all of the amazing opportunities and possibilities that can only exist if humans live much, much longer than is presently the case. At the end is a call to action and a list of further resources for young readers to find out more and to become involved with the life-extension movement.

Monday, February 24, 2014

In recent years some progress has been made towards the distinct goals of complete regeneration of a damaged liver in situ and the creation of new livers on demand for transplantation. Here, researchers demonstrate the ability to generate a patient-matched source of liver cells for repair purposes:

In previous studies on liver-cell reprogramming, scientists had difficulty getting stem cell-derived liver cells to survive once being transplanted into existing liver tissue. Writing in the latest issue of the journal Nature, researchers reveal a new cellular reprogramming method that transforms human skin cells into liver cells that are virtually indistinguishable from the cells that make up native liver tissue.

"Earlier studies tried to reprogram skin cells back into a pluripotent, stem cell-like state in order to then grow liver cells. However, generating these so-called induced pluripotent stem cells, or iPS cells, and then transforming them into liver cells wasn't always resulting in complete transformation. So we thought that, rather than taking these skin cells all the way back to a pluripotent, stem cell-like state, perhaps we could take them to an intermediate phase."

This research [involved] using a 'cocktail' of reprogramming genes and chemical compounds to transform human skin cells into cells that resembled the endoderm. Endoderm cells are cells that eventually mature into many of the body's major organs - including the liver. Next, the researchers discovered a set of genes and compounds that can transform these cells into functioning liver cells. And after just a few weeks, the team began to notice a transformation. Now that the team was encouraged by these initial results in a dish, they wanted to see what would happen in an actual liver. So, they transplanted these early-stage liver cells into the livers of mice. Over a period of nine months, the team monitored cell function and growth by measuring levels of liver-specific proteins and genes.

Two months post-transplantation, the team noticed a boost in human liver protein levels in the mice, an indication that the transplanted cells were becoming mature, functional liver cells. Nine months later, cell growth had shown no signs of slowing down. These results indicate that the researchers have found the factors required to successfully regenerate liver tissue.

Tuesday, February 25, 2014

This research is worth noting as a measure of the relative importance of visceral fat to long-term health. The more of it you have the worse off you are:

[Researchers] developed a new method to quantify the risk specifically associated with abdominal obesity. A follow-up study [supports] their contention that the technique, known as A Body Shape Index (ABSI), is a more effective predictor of mortality than Body Mass Index (BMI), the most common measure used to define obesity.

The team analyzed data for 7,011 adults, 18+, who participated in the first Health and Lifestyle Survey (HALS1), conducted in Great Britain in the mid 1980s, and a follow-up survey seven years later (HALS2). The sample was broadly representative of the British population in terms of region, employment status, national origin, and age. They used National Health Service records through 2009 to identify deaths and cancer cases: 2,203 deaths were recorded among the sample population.

The analysis found ABSI to be a strong indicator of mortality hazard among the HALS population. Death rates increased by a factor of 1.13 for each standard deviation increase in ABSI. Persons with ABSI in the top 20 percent were found to have death rates 61 percent higher than those with ABSI in the bottom 20 percent.

Tuesday, February 25, 2014

SENS, the Strategies for Engineered Negligible Senescence, provides an overview of the causes of aging and detailed research plans aimed at the production of repair therapies that can reverse those causes. This is all drawn from and built atop past decades of work in many life science fields relevant to medicine.

Every other year for the past decade a SENS conference has been held: a way to look at progress, make connections, and draw new scientists into the field. You'll find an array of presentation videos from last year's SENS6 conference on rejuvenation biotechnology at the SENS Research Foundation. If you have a few hours to spare then take some time to browse, as this is a very good way to gain an impression of the state of this comparatively young field of medical research as it stands today:

The SENS6: Reimage Aging Conference in September of 2013 marked the sixth conference held at historic Queens' College at the University of Cambridge. World-renowned scientists and other visionaries in the field of regenerative medicine presented the latest cutting-edge advances in regenerative medicine and biotechnology. Here you can view an overview of the conference as well as selected presentations and interviews. See why many remarked that it was the best SENS Conference to date.

Wednesday, February 26, 2014

The best understood activity of the enzyme telomerase is that it lengthens telomeres, the repeating DNA sequences at the end of chromosomes that form a part of the mechanism to limit the number of times a cell can divide. Average telomere length in tissues is very dynamic, a reflection of the interplay of numerous processes that lengthen and shorten telomeres or change the number of cells with long versus short telomeres. The average tends to fall with ill health and age, which is how work on telomerase-enhancing treatments started, with the aim of reversing this signature in the hope that it will improve matters.

My take on reduced telomere length is that it is a consequence of damage and dysfunction, not a primary cause of aging - though it might have further detrimental effects once it exists. The principle counterpoint to that position is that telomerase enhancement in mice lengthens life. So either I'm wrong or one of the other activities of telomerase is significant, such as interactions between telomerase and mitochondria.

This open access review is a fair summary of the arguments to try increasing the activity of telomerase in humans. Note that many of the groups most vocal on this topic at the moment are selling supplements or herbal extracts backed by sketchy or irrelevant data, the usual modus operandi in the "anti-aging" industry, and an annoyance for anyone looking for serious scientific work on targeting telomerase - so take everything that contingent has to say with a grain of salt:

The elderly population is increasing progressively. Along with this increase the number of age related diseases, such as cardiovascular, neurodegenerative diseases, metabolic impairment and cancer, is also on the rise thereby negatively impacting the burden on health care systems. Telomere shortening and dysfunction results in cellular senescence, an irreversible proliferative arrest that has been suggested to promote organismal aging and disabling age-related diseases.

Given that telomerase, the enzyme responsible for maintaining telomere lengths, is not expressed at levels sufficient to prevent telomere shortening in most of our cells, telomeres progressively erode with advancing age. Telomerase activation, therefore, might serve as a viable therapeutic strategy to delay the onset of cellular senescence, tissue dysfunction and organismal decline. Here we analyze the more recent findings in telomerase activation as a potential key modulator for human healthspan and longevity.

Wednesday, February 26, 2014

It might be argued that the ability to generate data in the life sciences is presently somewhat ahead of innovation in ways to make that data useful. There is the sense, looking at just how much can be measured and the power of modern computing and analysis methodologies, that there must be more ways to extract useful predictions of the life-extending potential of various treatments.

The direction of much of modern medicine is to focus on the development of treatments that work by altering gene expression or otherwise manipulating levels of specific proteins. The process of finding targets is made more effective via analysis of the vast amounts of gene expression data that can be cheaply obtained from patients and healthy individuals nowadays. Relationships between proteins can be established and differences between healthy and unhealthy biology identified.

My objection to this approach taken as a whole is that it is essentially only a more efficient continuation of the same old take on applied medicine: to patch over the problem rather than address the underlying cause. It is adjusting the engine's fuel feed to force your way past the fact that critical components are worn and faulty. Some forms of adjustment in biology can produce overall benefits on the level of damage in the system: think of approaches that boost the operation of cellular housekeeping, for example. But that isn't the case for most of what comes out of this school of research and development.

Here is an example of applying this approach to aging - the paper is open access, but not yet available in plain text format, so note the provisional PDF link on the page if you want to dive in. I'd say that this is a great path ahead if you favor programmed aging theories, as in that worldview aging is caused by evolved changes in gene expression over time: reverse the changes and you reverse aging. If you hold of the majority view of aging as accumulated cellular and molecular damage, however, then all of what I said above applies.

The major challenges of aging research include absence of the comprehensive set of aging biomarkers, the time it takes to evaluate the effects of various interventions on longevity in humans and the difficulty extrapolating the results from model organisms to humans. To address these challenges we propose the in silico method for screening and ranking the possible geroprotectors followed by the high-throughput in vivo and in vitro validation.

The proposed method evaluates the changes in the signaling pathway cloud constructed using the gene expression data and epigenetic profiles of young and old patients' tissues. The possible interventions are selected and rated according to their ability to regulate age-related changes and minimize differences in the signaling pathway cloud. This flexible and scalable approach may be used to predict the efficacy of the many drugs that may extend human longevity before conducting pre-clinical work and expensive clinical trials.

Thursday, February 27, 2014

Numerous studies now show that stem cell populations in old tissues remain large, and have explored a few of the mechanisms that explain why these stem cells are no longer as active in tissue maintenance as they were in youth. In a number of cases researchers have been able to demonstrate partial reversal of this decline by altering the signaling environment, overriding the age-related changes that seem to be responsible without addressing the underling causes of these changes, which are no doubt reactions to rising levels of cellular damage.

It is likely that researchers will find naive applications of this sort of restoration of stem cell activity will greatly raise cancer risk, as cancer suppression is probably the reason why stem cells have evolved this diminished action response to the damage of aging - our longevity is thought by many researchers to be a balancing act between risk of cancer and levels of tissue maintenance in an environment of steadily rising damage. The ability to detect and selectively and safely treat cancer is improving rapidly, however, so a blunt restoration of stem cell activity may well turn out to be an acceptable stop-gap approach to improve health in old age:

Previous studies have demonstrated an age related decline in the size of the neural stem cell (NSC) pool and a decrease in neural progenitor cell proliferation, however, the mechanisms underlying these changes are unclear. In contrast to previous reports, we report that the numbers of NSCs is unchanged in the old age subependyma and the apparent loss is because of reduced proliferative potential in the aged stem cell niche.

Transplantation studies reveal that the proliferation kinetics and migratory behavior of neural precursor cells are dependent on the age of the host animal and independent of the age of the donor cells suggesting that young and old age neural precursors are not intrinsically different. Factors from the young stem cell niche rescue the numbers of NSC colonies derived from old age subependyma and enhance progenitor cell proliferation in vivo in old age mice. Finally, we report a loss of Wnt signaling in the old age stem cell niche that underlies the lack of expansion of the NSC pool after stroke.

Thursday, February 27, 2014

Cancer and Alzheimer's disease appear to be inversely related. If you have cancer your odds of Alzheimer's are lower, and vice versa. Since the lifestyle risk factors for both are essentially the same, this is an interesting finding, to say the least. Researchers are digging into the biochemical mechanisms that might explain this state of affairs:

There is epidemiological evidence that patients with certain Central Nervous System (CNS) disorders have a lower than expected probability of developing some types of Cancer. We tested here the hypothesis that this inverse comorbidity is driven by molecular processes common to CNS disorders and Cancers, and that are deregulated in opposite directions.

We conducted transcriptomic meta-analyses of three CNS disorders (Alzheimer's disease, Parkinson's disease and Schizophrenia) and three Cancer types (Lung, Prostate, Colorectal) previously described with inverse comorbidities. A significant overlap was observed between the genes upregulated in CNS disorders and downregulated in Cancers, as well as between the genes downregulated in CNS disorders and upregulated in Cancers. We also observed expression deregulations in opposite directions at the level of pathways.

Our analysis points to specific genes and pathways, the upregulation of which could increase the incidence of CNS disorders and simultaneously lower the risk of developing Cancer, while the downregulation of another set of genes and pathways could contribute to a decrease in the incidence of CNS disorders while increasing the Cancer risk. These results reinforce the previously proposed involvement of the PIN1 gene, Wnt and P53 pathways, and reveal potential new candidates, in particular related with protein degradation processes.

Friday, February 28, 2014

The history of results achieved while trying to extend mouse life span via manipulation of sirtuins with drugs is not particularly impressive, all told, characterized by an inability to replicate early results, a lack of effectiveness, and challenges from the rest of the scientific community. Nonetheless sirtuins play a role in numerous cellular mechanisms of general interest, so research continues in that sense.

Here one of the later drug candidates for sirtuin manipulation is claimed to modestly extend mean mouse life span - but based on the history you should probably not be terribly excited by this news, even if you consider the development of drugs to slow aging by metabolic manipulation to be a useful activity rather than a distraction from better forms of longevity science:

The prevention or delay of the onset of age-related diseases prolongs survival and improves quality of life while reducing the burden on the health care system. Activation of sirtuin 1 (SIRT1), an NAD+-dependent deacetylase, improves metabolism and confers protection against physiological and cognitive disturbances in old age. SRT1720 is a specific SIRT1 activator that has health and lifespan benefits in adult mice fed a high-fat diet.

We found extension in lifespan, delayed onset of age-related metabolic diseases, and improved general health in mice fed a standard diet after SRT1720 supplementation. Inhibition of proinflammatory gene expression in both liver and muscle of SRT1720-treated animals was noted. SRT1720 lowered the phosphorylation of NF-κB pathway regulators in vitro only when SIRT1 was functionally present. Combined with our previous work, the current study further supports the beneficial effects of SRT1720 on health across the lifespan in mice.

Friday, February 28, 2014

There is some debate over whether rapamycin administration actually slows aging or only reduces cancer risk in mice: both sides argue the point from rigorous studies, but unlike many other compounds and methodologies the evidence for life extension in mice is strong and reproducible. These are debates over the cause of that life extension.

The recent paper quoted below comes from researchers who favor manipulation of mTOR as a way forward to treat aging, and who argue that rapamycin does slow aging. But again, from my point of view all such efforts to develop drugs to alter metabolism to modestly extend life are the slow, expensive road to a poor end result. We should be focused on building therapies to repair the damage that causes aging, an end result that is both of greater utility and can meaningfully help old people. There is not much use in a way to slow aging when you are already old.

Target of Rapamycin (TOR) is involved in cellular and organismal aging. Rapamycin extends lifespan and delays cancer in mice. It is important to determine the minimum effective dose and frequency of its administration that still extends lifespan and prevents cancer. Previously we tested 1.5 mg/kg of rapamycin given subcutaneously 6 times per two weeks followed by a two-week break. This intermittent treatment prolonged lifespan and delayed cancer in cancer-prone female FVB/N HER-2/neu mice.

Here, the dose was decreased from 1.5 mg/kg to 0.45 mg/kg per injection. This treatment was started at the age of 2 months (group Rap-2), 4 months (Rap-4), and 5 months (Rap-5). Three control groups received the solvent from the same ages. Rapamycin significantly delayed cancer and decreased tumor burden in Rap-2 and Rap-5 groups, increased mean lifespan in Rap-4 and Rap-5 groups, and increased maximal lifespan in Rap-2 and Rap-5 groups. In Rap-4 group, mean lifespan extension was achieved without significant cancer prevention.

The complex relationship between life-extension and cancer-prevention depends on both the direct effect of rapamycin on cancer cells and its anti-aging effect on the organism, which in turn prevents cancer indirectly. We conclude that total doses of rapamycin that are an order of magnitude lower than standard total doses can detectably extend life span in cancer-prone mice.


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