Fight Aging! Newsletter, December 31st 2012

December 31st 2012

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!



- Longevity Research: Donate Now or Donate Later?
- Compression of Morbidity Versus Increasing Longevity
- From the Russian End of the Longevity Science Community
- An Interview With Stephen Valentine
- An Update on Organovo
- Discussion
- Latest Headlines from Fight Aging!
    - The Emergence of Biogerontology as a Discipline
    - Considering the Business of Regenerative Medicine
    - Reviewing Mitochondrial Activity and Longevity
    - Using Stem Cell Transplants to Boost Neurogenesis
    - Blocking miR-15 Boosts Regenerative Capacity in the Heart
    - Progress in Therapies for Retinitis Pigmentosa
    - Further Commentary on Hydra Longevity
    - Suppressing the Inflammasome in Alzheimer's
    - Repairing Blindness Due to Corneal Limbal Stem Cell Deficiency
    - Health Extension Salons, Bay Area and Expanding


Life is a sequence of decisions involving time and resources: how much, how long, now, or later? Everything from choosing a career to deciding whether to reach for the salt passes through the engine in your mind that weighs costs and time. In this, helping to further the advance of longevity science is the same as any other human endeavor. We choose when to support research, we try to pick the best research to support based on likely outcomes, and we choose how much support to give.

I've debated the money axis ad nauseam, so let us do something different and look at the time axis for a change. You could choose to donate resources today to an organization like the SENS Research Foundation, one that funds the most promising projects in the laboratory, or you could wait to donate in some future year. Some arguments to either side:

Donating Later

On balance, I am likely to have more resources to donate later. If I soundly invest what I would have donated now, it will most likely be worth more in later years. This is not a certainty, but a reasonable expectation.

The cost of life science research is falling dramatically. If I donate the same amount later, more can be accomplished, and more rapidly, than now.

Donating Now

Work that isn't accomplished today will have to be accomplished tomorrow. It may be faster and cheaper to complete that research project if we start twenty years from now, but what if we could be long done by then, even though today's progress is slow and expensive by comparison? Every year shaved from the time taken to develop new medicines means many lives saved.

If you don't use money when you have it, it has a way of vanishing amid life's slings and arrows. Not donating today easily turns into not donating at all. Just as "paying yourself first" is the way to enforce savings in spite of your worse nature, so maintaining a steady stream of donations today is the way to ensure that you actually make a difference.

Without providing support now, a range of researchers and organizations that can make best use of your resources will not emerge to accept later donations. Growth in the sciences is as much about establishing institutions that have authority and continuity as anything else. Funds here and now are needed for all of their functions: drawing new researchers into the field; bringing respect to the field; communicating to the public; educating students. No great research community, dedicated to a cause, arises spontaneously from nothing. Years or decades of steadily increasing funds and incremental progress are required.

Donating now encourages other people to donate very soon. It is a form of persuasion, granting legitimacy in other people's eyes to the project you favor. When you do not donate now, you miss the chance to persuade others now.

In Conclusion

Donate now. Unless you find yourself in the rare and envious position of knowing in certainty that a stupendous pile of money will fall upon your bank account in years to come. In which case, donate both now and after that fortunate event.

Over the years I have watched many people churning their way through the energetic startup community of the US West Coast, putting off many things in their lives because of the conviction that they would have time and much money to deal with them later. Among the ways to wealth, it is true that doing a good job of starting a company (and a good job of being networked while doing it) is the best shot at success - but best is a far way from a sure thing, or even a good chance. I can assure you that most of the people involved in that world do not end up wealthy enough to have justified putting off anything.

The same, at a more sedate pace, applies to the rest of us. Tomorrow is what we build today. If we set down no bricks, there will be no wall.


Back in the Fight Aging! archives, you'll find a post on breaking out historical data on increases in human longevity into two components: firstly an increase in the average years lived, and secondly a reduction in early mortality - that more people are reaching ever closer to the average. This second statistical behavior is often presented as compression of morbidity, with the goal being to reduce the time spent in ill health at the end of life.

There is some debate over whether compression of morbidity is in any way a realistic or even useful goal for medical science, as opposed to aiming for increased human longevity through repair and reduction in the ongoing damage that causes aging. If you consider aging in terms of reliability theory, for example, it seems dubious that one could engineer the machineries of human life to last a set time and then fall apart very rapidly at the end - at least not without deliberately making it fall apart at the end. If all you are doing is consistently removing damage, then you extend the length of life, but don't do much about the time taken to fall apart when you stop repairing damage.

In any case, here is a recent paper that revisits this structural decomposition of increased longevity. The researchers here suggest that it is longevity, not compression of morbidity, that is the important factor:

In low-mortality countries, life expectancy is increasing steadily. This increase can be disentangled into two separate components: the delayed incidence of death (i.e. the rectangularization of the survival curve) and the shift of maximal age at death to the right (i.e. the extension of longevity).

We studied the secular increase of life expectancy at age 50 in nine European countries between 1922 and 2006. The respective contributions of rectangularization and longevity to increasing life expectancy are quantified with a specific tool.

For men, an acceleration of rectangularization was observed in the 1980s in all nine countries, whereas a deceleration occurred among women in six countries in the 1960s. These diverging trends are likely to reflect the gender-specific trends in smoking. As for longevity, the extension was steady from 1922 in both genders in almost all countries. The gain of years due to longevity extension exceeded the gain due to rectangularization. This predominance over rectangularization was still observed during the most recent decades.


Right now one can't come to the hospital and say, "doctor, I've got a problem, I am aging." People would laugh at such a patient, however this is the best kind of patient, the smartest one, one who cares about his future and wants to prevent the upcoming illnesses and frailty.

Let's say you touched the light of truth and decide to convince people of the need to spend their resources on radical life extension. First, please accept my admiration - what you think - is the most important task for you, for me and for all the people on the planet. Now your goal is to convey a simple message to your buddies to live - good and bad die. Here you will find a shock, most people do not agree with this rather obvious postulate. The overwhelming majority stand against their own immediate death, but insist on the fact that the after-life is beautiful and that man should not argue with nature in the matter of aging.

There is another school in transhumanism, which states that people need to talk about a more moderate view of prevention of age-related diseases and healthy aging, and then most people will agree to help. In my view, this agreement is not worth anything, because for one it has not yet gained any great success, but more importantly it does not lead to scientific experiments aimed at radical life extension. I believe that you first need to attract people who want to live a long time, who want to live come what may. Then you deliver the motivation, a way to wake up such a man. You have the most wonderful news for him that ever he heard: "You have a chance not to die!"


No one's claiming that human reanimation is within our grasp yet, although the Cryonics Institute claims that insects, vinegar eels and human brain tissue (not to mention human embryos, as shown by the growing success of IVF treatment) have been stored at liquid nitrogen temperature, at which point all decay ceases, and then revived fully.

"No one's saying, 'Hey, we cryopreserved a dog and brought it back,'" says Stephen. "The breakthroughs come at a slow, slow pace, but the advantage with being cryopreserved is that you have time. If they can work it out in 100 or 200 years, you're not going anywhere. You're on ice for a while..."

The early part of the procedure is now certainly feasible, thanks to a process called vitrification. Before, one of the main stumbling blocks to freezing bodies was the damage caused to tissue by ice crystals (think about how inferior a steak that's been in the freezer tastes: that's because of molecular damage caused by crystallisation).

Not surprisingly, Stephen is optimistic. "Many scientists are saying that this is going to be considered the century of immortality," he says. [Meanwhile], he insists that life-preservation is not just for the elite few. "This is no exclusive club," he says. "It's affordable to anybody, because it can be paid for through life insurance. Most people around the world can do it if they want."

Irritated that doubters still see life extension as a crackpot notion, Stephen points out that every major scientific breakthrough in history was once deemed unthinkable. "When Christiaan Barnard did the first heart transplant in 1967 in South Africa, they thought the guy was an unethical monster," he says. "Today, thousands of heart transplants take place every year and - rightly - no one questions the moral or ethical issues of it."

The international cryonics community certainly has no shortage of widely celebrated scientists on its side. Marvin Minsky, the pioneer of artificial intelligence, is a supporter; Ray Kurzweil, the author and inventor, has signed up with for preservation with Alcor; molecular nanotechnologist K Eric Drexler is an advocate; as are prominent stem-cell researcher Michael West and Aubrey de Grey, a prominent gerontologist (the scientific study of ageing).


Organovo is the organ printing company that was partially funded in the early days with an investment from the Methuselah Foundation - an investment that the Foundation has done well by so far. In turn, the Organovo founders are noteworthy supporters of the crowdfunded New Organ Prize that the Foundation is working on these days.

Organovo has engineered a good position for itself even though the technologies it works on will take another decade or two to arrive at maturity. The research community won't be printing organs next year, but between here and the arrival of printed organs somewhere in the 2020s there are many commercially viable products that build upon one another: tissue for research, machinery for laboratories, and so forth.


The highlights and headlines from the past week follow below. Remember - if you like this newsletter, the chances are that your friends will find it useful too. Forward it on, or post a copy to your favorite online communities. Encourage the people you know to pitch in and make a difference to the future of health and longevity!



Friday, December 28, 2012
Here is a review paper that looks back at the recent history of biogerontology as a field of study, noting the struggle with long-held perceptions of fraud associated with the intersection of aging and medicine: "Through archival analysis this article traces the emergence, maintenance, and enhancement of biogerontology as a scientific discipline in the United States. At first, biogerontologists' attempts to control human aging were regarded as a questionable pursuit due to: perceptions that their efforts were associated with the long history of charlatanic, anti-aging medical practices; the idea that anti-aging is a "forbidden science" ethically and scientifically; and the perception that the field was scientifically bereft of rigor and scientific innovation. The hard-fought establishment of the National Institute on Aging, scientific advancements in genetics and biotechnology, and consistent "boundary work" by scientists, have allowed biogerontology to flourish and gain substantial legitimacy with other scientists and funding agencies, and in the public imagination. In particular, research on genetics and aging has enhanced the stature and promise of the discipline by setting it on a research trajectory in which explanations of the aging process, rather than mere descriptions, have become a central focus. Moreover, if biogerontologists' efforts to control the processes of human aging are successful, this trajectory has profound implications for how we conceive of aging, and for the future of many of our social institutions."

Friday, December 28, 2012
Looking back at past commercial development in medicine is a fair way to manage expectations for present efforts to bring therapies to the clinic. The short version of the story is that there are certainly cycles in which expectations outpace results, but those results arrive in the end: "Like many advanced technologies, the field of regenerative medicine has gone from boom to nearly bust to boom again in the span of just 30 years. Today, there are over 55 regenerative medicine products on the market focused on diverse therapeutic areas, including repair of skin/soft tissue, wound care, cardiology, oncology, and diabetes. Thirty years in, regenerative medicine has truly "come of age," the result of a tenacious pursuit to translate groundbreaking research into therapeutic products and overcome initial setbacks that almost derailed this critical new medical approach. Yet while the past decade's focus on scientific advances and business fundamentals has propelled regenerative medicine forward, I believe this is just the start. By reflecting on the successes and lessons learned over the past three decades, we can begin to chart a roadmap for the future that will help to ensure that regenerative medicine continues to deliver important new treatments for patients, while creating sustainable value for shareholders. From its origins in the mid-1980s, regenerative medicine was greeted with the kind of extreme excitement that has accompanied other potential breakthroughs, including monoclonal antibodies and RNA interference. By the year 2000, more than a decade after the first companies were formed, regenerative medicine companies were valued at over $2.6 billion, TIME named tissue engineering one of the hottest jobs for the 21st century, and Barron's predicted it would become a $100 billion industry. A few years later, the bubble had burst, and company valuations plummeted to a tenth of their year 2000-high. Several factors contributed to these setbacks. First, like many new medical advances, expectations far exceeded reality. Investors and the media saw incredible promise in early research, and unrealistic timelines were set for when a product could be on the market. Second, the initial regenerative medicine products to reach the market had limited commercial success, as the few companies in the space had not yet understood all that was required to achieve both clinical and commercial success. From a scientific perspective, the field was poised to deliver, but it had not yet developed the regulatory, business, and commercial expertise required for long-term success. In the wake of these setbacks, there came a clear understanding of what was needed to propel regenerative medicine forward and strike the appropriate balance between promise and reality. When I joined Organogenesis in 2003, the company was emerging from bankruptcy and a dissolved commercial partnership with big pharma. In the decade since, I have experienced firsthand the rebirth of our company, and on a larger scale, of the regenerative medicine field itself. Our path over the past decade has taught us several lessons about what it will take to succeed in this space going forward."

Thursday, December 27, 2012
Mitochondria are the power plants of your cells, responsible for creating the energy stores that are used to power cellular operations. Mitochondrial composition is an important determinant of longevity, and accumulating mitochondrial damage - self-inflicted in the course of the operation of metabolism - is one of the root causes of aging. Here researchers review what is know of mitochondrial decline in aging, and the ways in which mitochondrial function can be altered to extend life in laboratory animals: "For decades, aging was considered the inevitable result of the accumulation of damaged macromolecules due to environmental factors and intrinsic processes. Our current knowledge clearly supports that aging is a complex biological process influenced by multiple evolutionary conserved molecular pathways. With the advanced age, loss of cellular homeostasis severely affects the structure and function of various tissues, especially those highly sensitive to stressful conditions like the central nervous system. In this regard, the age-related regression of neural circuits and the consequent poor neuronal plasticity have been associated with metabolic dysfunctions, in which the decline of mitochondrial activity significantly contributes. Interestingly, while mitochondrial lesions promote the onset of degenerative disorders, mild mitochondrial manipulations delay some of the age-related phenotypes and, more importantly, increase the lifespan of organisms ranging from invertebrates to mammals. Here, we survey the insulin/IGF-1 and the TOR signaling pathways and review how these two important longevity determinants regulate mitochondrial activity. Furthermore, we discuss the contribution of slight mitochondrial dysfunction in the engagement of pro-longevity processes and the opposite role of strong mitochondrial dysfunction in neurodegeneration."

Thursday, December 27, 2012
Failing neural plasticity, the ability of the brain to adapt and continue creating new neurons, seems to be important in aging. Here researchers investigate the ability of some forms of stem cell transplant to boost the pace of>neurogenesis, the creation of neurons: "Neurogenesis occurs throughout life but significantly decreases with age. Human umbilical cord blood mononuclear cells (HUCB MNCs) have been shown to increase the proliferation of neural stem cells (NSCs) in the dentate gyrus (DG) of the hippocampus and the subgranular zone of aging rats, but it is unclear which fraction or combination of the HUCB MNCs are responsible for neurogenesis. To address this issue, we examined the ability of HUCB MNCs [to] increase proliferation of NSCs. [We] injected HUCB cells intravenously in young and aged [rats] and examined proliferation in the DG at 1 week and 2 weeks postinjection. HUCB-derived [cells] increased NSC proliferation at both 1 and 2 weeks while also enhancing the density of dendritic spines at 1 week and decreasing inflammation at 2 weeks postinjection. Collectively, these data indicate that a single injection of HUCB-derived T cells induces long-lasting effects and may therefore have tremendous potential to improve aging neurogenesis."

Wednesday, December 26, 2012
One important outgrowth of stem cell research is the search for ways to manipulate existing cell populations into greater feats of regeneration. Eventually, it would be hoped, the research community can gain sufficient control over cells in the body so as not to need stem cell transplants at all. Meanwhile scientists are uncovering advances such as this one: "Researchers have pinpointed a molecular mechanism needed to unleash the heart's ability to regenerate, a critical step toward developing eventual therapies for damage suffered following a heart attack. Researchers found that hearts of young rodents mounted a robust regenerative response following myocardial infarction, but this restorative activity only occurs during the first week of life. They then discovered that a microRNA called miR-15 disables the regenerative capacity after one week, but when miR-15 is blocked, the regenerative process can be sustained much longer. Further research will be needed to optimize the ways in which medical scientists, and eventually clinicians, may be able to control this regenerative process. "This may well be the beginning of a new era in heart regeneration biology. Our research provides hope that reawakening the regenerative capacity of adult mammalian hearts is within reach.""

Wednesday, December 26, 2012
Therapies for several forms of degenerative blindness have been under development for some years. Here is news of progress towards trials for two of them: "Two recent experimental treatments - one involving skin-derived induced pluripotent stem (iPS) cell grafts, the other gene therapy - have been shown to produce long-term improvement in visual function in mouse models of retinitis pigmentosa (RP). Researchers tested the long-term safety and efficacy of using iPS cell grafts to restore visual function in a mouse model of RP. [The] cells were administered, via injection directly underneath the retina, when the mice were five days old. The iPS cells assimilated into the host retina without disruption, and none of the mice receiving transplants developed tumors over their lifetimes, the researchers reported. The iPS cells were found to express markers specific to retinal pigmented epithelium (the cell layer adjacent to the photoreceptor layer), showing that they had the potential to develop into functional retinal cells. Using electroretinography, a standard method for measuring retinal function, the researchers found that the visual function of the mice improved after treatment and the effect was long lasting. In the [other] study, the [researchers] tested whether gene therapy could be used to improve photoreceptor survival and neuronal function in mice with RP caused by a mutation to a gene called phosphodiesterase-alpha (Pde6α) - a common form of the disease in humans. To treat the mice, the researchers used adeno-associated viruses (AAV) to ferry correct copies of the gene into the retina. The AAV were administered by a single injection in one eye, with the other eye serving as a control. When the mice were examined at six months of age (over one-third of the mouse lifespan), photoreceptor cells were found in the treated eyes but not in the untreated eyes, the researchers reported. More important, the treated eyes showed functional visual responses, while the untreated eyes had lost all vision."

Tuesday, December 25, 2012
Last month the popular press was doing its normal breathless job of failing to adequately understand and present the facts in relation to research into aging and longevity. In this case it related to recent research into hydra. These small water creatures may be ageless, or at least age very slowly, and are certainly very competent when it comes to regeneration from injury, but that's about as far as it goes - it seems unlikely that profound advances immediately applicable to humans lurk in hydra biology. Instead this is the standard slow gathering of new knowledge, adding to the grand picture of the evolution of aging, longevity, and the plethora of individual mechanisms that contribute to these traits. Here is a short open access commentary on the recent hydra research: "Clues to the role of FOXO3A in controlling longevity may be available through the comparative study of organisms which show no sign of aging. One of the very few examples of animals which appear to be truly immortal is the freshwater polyp Hydra. Much of Hydra's remarkable immortality can be traced back to the asexual mode of reproduction by budding which requires a tissue consisting of stem cells with continuous self-renewal capacity. [Hydra's] stem cells indeed continuously proliferate and generate eternal lineages. How? This question has been plaguing some of us since the late 1980s. In the new study, a literally immortal model organism was induced to both stem cell senescence and immune senescence by altering the expression level of a single gene, the longevity factor FoxO. The data suggest that FoxO has ancient roles in controlling stem cell behavior that may underlie longevity. The findings have captured the imagination of the popular press, and raised the skeptic's eyebrows. What lessons can actually be learned from the Hydra study? What does this mean for understanding human longevity? First, the Hydra results have moved the longevity-enabling FOXO3A gene from reported association to possible functions, corroborating and extending beyond previous observations in C. elegans and Drosophila. Second, the link between FoxO and components of the innate immune system is of particular interest since aging processes in humans are known to result in impairment of both innate and adaptive immunity ("immunosenescence") as well as in a pro-inflammatory status ("inflammaging"). Third, the Hydra study strengthens the earlier described role of FOXO3A in human stem cell maintenance and regulation. This hypothesis warrants further investigation and indicates another plausible mechanism through which FOXO3A variation may exert its effect on longevity. Attempts to extend the lessons learnt from Hydra to more complex organisms including humans will be challenging. However, the recent study is a proof of principle that investigations in Hydra stem cells hold promise. The more we learn about the role of FoxO in Hydra, the better we will understand how the gene and its variants contribute to longevity in humans."

Tuesday, December 25, 2012
Inflammation is an important process in the progression of Alzheimer's disease, and researchers have been turning their attention to ways to manipulate inflammation as a form of treatment: "The complex named "NLRP3 inflammasome" is composed of several proteins and plays a key role in the immune system. It resembles a fire alarm sensor that triggers a chain reaction when activated. As a result, immune cells are mobilized and substances that foster inflammation are released. This process can be triggered by infections, which are subsequently suppressed by the immune response. However, in the case of Alzheimer's disease, the activation of the molecular alarm may have negative consequences: nerve cells are damaged and die. Ultimately, this leads to the loss of brain function and mental capabilities in humans. The researchers collected a comprehensive chain of evidences: they examined both the brains of deceased Alzheimer patients and of mice who exhibited behavioural disorders that are typically associated with Alzheimer's disease. The researchers found an activated form of the NLRP3 inflammasome in both cases. Looking at another group of mice, the scientists examined possibilities for suppressing inflammatory reactions. To achieve this, they removed the genes that trigger production of the NLRP3 inflammasome. Therefore, these mice were no longer able to synthesize the protein complex. As a result, the animals developed only relatively mild symptoms of the disease. Moreover, their brains showed only reduced amounts of the damaging plaques."

Monday, December 24, 2012
Here is an example of a stem cell therapy that is just a little advanced over established medical techniques - in effect just a more sophisticated and cost-effective version of a tissue transplant: "A variety of things can cause [corneal limbal stem cell deficiency], including chemical and thermal burns to the corneas, which are the glass "domes" over the coloured part of our eyes. But it's also thought that microbial infections and wearing daily wear contact lenses for too long without properly disinfecting them can lead to the disease, too. Since a corneal transplant was not an option for Binns, his doctors at Toronto Western Hospital proposed something new: a limbal stem cell transplant. The limbus is the border area between the cornea and the whites of the eye where the eye normally creates new epithelial cells. Since Binns' limbus was damaged, doctors hoped that giving him healthy limbal cells from a donor would cause healthy new cells to grow over the surface. While the treatment is available in certain centres around the U.S., Binns became the first patient to try the treatment at a new program at Toronto Western Hospital. Though Binns knew he'd need to take anti-rejection drugs, he decided the procedure was worth a try. Just like with an organ transplant, Binns' doctors had to find a healthy match. It turned out his younger sister, Victoria, was the ideal candidate for the job. In the operating room, doctors removed the scar tissue on Taylor's eyes, then took some healthy stem cells from Victoria's eyes and stitched them to the surface of Binns' eyes. "Within a month he could see 20/40. His last visit he was 20/20 and 20/40." Researchers are also working on using stem cells from deceased donors and even using limbal stem cells from a patient's own eyes. While that would require growing the cells in a lab to force them to multiply, it would also mean that patients might be able to skip anti-rejection drugs."

Monday, December 24, 2012
The Health Extension salons are an ongoing series of meetups in the Bay Area for people interested in supporting and advancing longevity science, associated with the energetic technology entrepreneur community there. This sort of initiative is important, as grassroots efforts associated with this community have a way of growing and getting things done. There are a number of presentation videos at the meetup site from previous events, and you might consider helping out if you are in the area: "The Health Extension community is committed to information sharing and collaborative action to extend healthy and happy human lifespans to 123 years and beyond. Our members are scientists, entrepreneurs and social influencers dedicated to fixing the degenerative cellular processes that cause deadly human diseases. This community began in early 2012 as informal meet-ups in the home of Joe and Lisa Betts-La Croix. Our 100+ members now meet monthly at Y Combinator HQ in Mountain View, California with plans to launch salons and other projects in Los Angeles and New York in 2013."



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