Fight Aging! Newsletter, December 10th 2012

December 10th 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!



- Is Funding the Only Roadblock for Longevity Science?
- The Duty to Extend the "Biological Warranty Period"
- Nature Outlook: Ageing
- At Some Point Soon, Mouth Bacteria Will Be Defeated
- Discussion
- Latest Headlines from Fight Aging!
    - PGC-1 alpha-4 Spurs Muscle Growth
    - Being Older is Very Positive, Being Aged is Not
    - A Brief Look at Retinal Implants
    - Stem Cells and Scaffolds to Regrow the Cornea
    - Trialing Regenerative Medicine for Heart Failure
    - First Generation Stem Cell Therapies Moving Through Trials
    - Diastolic Dysfunction Correlates With AGE Levels
    - An Interview With a KrioRus Director
    - Considering NF-κB in Aging
    - Reviewing the Online Human Aging Genomics Resources


I was asked this question a few weeks back: is money the only real obstacle standing between us and good odds of greatly extending the healthy human life span within the next 20-30 years? The answer I gave was this: yes, yes it is is. A hundred times yes - a shortage of money is the central and only limiting factor to progress in slowing and reversing aging.

The world as a whole does not suffer from a shortage of money, of course. (If anything, the situation quite the opposite, sadly). When I say that money is a challenge, I mean that at present only a tiny faction of the optimal - or even somewhat adequate - research funds flow into the best projects in aging and longevity science. The field of aging research is as a whole underfunded in comparison to its importance, and a great deal of that funding is consistently misallocated - at least when seen from the perspective of someone who wants to produce concrete results in terms of years gained and lives saved. Very little of it goes to longevity science.

Nonetheless, clear research plans exist to address aging, such as the Strategies for Engineered Negligible Senescence (SENS) that aims to reverse its causes. The way ahead is known in great detail, the root causes of aging at the cellular and molecular level are so well specified at this point that proof or disproof by example lies within a handful of years, were suitable research programs funded. By that I mean go ahead and reverse or repair a root cause of aging in mice, then see what happens. That, however, takes money. Perhaps a billion dollars of it and ten years if a crash program was put together.

There are of course any number of other challenges I could point to - goals and line items that lie between the present and a possible future in which we will all live far longer in good health. For example, take the need to grow a longevity research community to rival the cancer research institution in energy and fundraising prowess. Or the need for SENS and related work on rejuvenation to win dominance over slowing aging by metabolic manipulation as the approach most favored by biogerontologists. Or the need to attract high net worth philanthropic donors and conservative funding institutions to the field. Or the need to make the public more aware of what progress could be achieved, and more demanding of that progress. I could go on. Yet these all boil down to money: sufficient funding will solve all of these challenges, as they will be flattened beneath a weight of money.

Consider this: if a few hundred million dollars fell upon the SENS Foundation today, and was spent aggressively, in five years the Foundation could be the leading US center for aging research. (For comparison, note that the Buck Institute draws an annual budget of a little less than $40 million, and the NIH itself budgets around $2.5 billion dollars a year, mostly spent on matters that have little to no impact on extending human life). That much money attracts more funding, opens doors, draws researchers, provides a megaphone for public speaking, and shifts the balance of interest and strategy in the way research is conducted in the field.

The bottom line: a section of the research community knows how to go about creating a good shot at reversing aging within a few decades. Only a trickle of money is flowing in their direction, and it is that level of funding that limits their progress. So the bootstrapping approach continues: get a little money, do the work, show positive results, leverage those results to gain more interest and more funding, repeat. This is a slow business, however, and will remain so until greater funding and interest in longevity science is achieved.

So money matters, is the limiting factor to progress, and will continue to be so until it is not.

Since we're talking about money, I should note that the year is coming to a close. This is traditionally a time to make charitable donations. If you want to have an impact on the future, then consider donating to help fund the active development of rejuvenation biotechnology or advocacy for longevity science. See the Take Action! page here at Fight Aging! for suggested charitable causes, such as the SENS Foundation, Methuselah Foundation, or New Organ initiative.


A couple of months back, I pointed out the first pair of posts in a series entitled "the Duty to Extend the Biological Warranty Period." In this Fight Aging! post, you'll find links to the full series. An except follows:

"For over the past decade now I have taught undergraduate and graduate students on ethical issues pertaining to life extension and aging and I am always struck by how easily and quickly intelligent people can convince themselves that it is better to accept the rate of aging selected for by the blind process of evolution through natural selection than by a rate humans consciously influence to expand the opportunities for health by reducing and delaying many of the afflictions of senescence.

"The objections I have heard over the years range from a concern that reducing mortality could reduce our appreciation of life, to concerns that it would be boring to be married to the same person for longer and a concern that promoting the health of the elderly would make things worse for the employment of younger generations (a sentiment I find is more common among my undergraduate students who have anxieties about finding employment and paying off their student debts).

"Most of these objections can be dispensed with when one makes the benefits of age retardation more concrete. Adding 2 or 3 decades to the human lifespan, for example by a pill that mimics the effects of caloric restriction, would mean a delay of cancer, heart disease, stroke, AD, etc. When framed in that light the concerns typically raised against life extension begin to sound less compelling, even ridiculous. Would living with a lower risk of death from cancer, stroke or heart disease decrease our appreciation of living? If so, then is that a reason to promote smoking, obesity and an inactive lifestyle? Is it desirable that we increase the job prospects of today's younger adults by ensuring their parents' generation are afflicted with stroke or heart disease a decade or two earlier? Is increasing the risk of morbidity and mortality a fair and reasonable strategy for tackling societal problems like unemployment? No, of course not. But much work must be done to persuade people to think rationally about such issues rather than be governed by their knee jerk reactions to such cases."


Humans are the longest lived primates, with life expectancy in some developed nations surpassing 80 years. Of course, that doesn't stop us wanting more time. Research into the mechanisms of ageing is yielding insights, many of them diet-related, into how we might not only live longer but also stay healthier as we do.

While researchers wait for statistical proof of the diet's effects in primates, some people have elected to go on the diet anyway. CRONies - the label adopted by those on a diet of Caloric Restriction with Optimal Nutrition - voluntarily eat 30% fewer calories than recommended by the US Department of Agriculture. That can be as low as 1,400 calories a day for men, and 1,120 for women.

Fontana, who studies the CRONies, says most of the health benefits seen in animals on the caloric restriction diet also appear in humans. He says that people who started caloric restriction in middle age and stayed with the regimen for eight years have a "fantastic" cardiometabolic profile. He adds that he has seen subjects in their late 70s with the blood pressure of teenagers.


The modern age of antibiotics didn't do a great deal to combat the inexorable processes that contribute to tooth decay and gum disease, as it things turned out. One might have thought so at the outset: bacteria in the mouth are causing issues, we're developing all sorts of enormously improved methods of killing bacteria, ergo tooth decay and commonplace gum disease like gingivitis and should soon be a thing of the past. Alas not so, however - nothing is straightforward in the world of medicine. As one consideration, many of the hundreds of bacterial species in the mouth are actually beneficial.

In recent years, there has been some progress towards more sophisticated solutions. These include methods of sabotaging key mechanisms in problem bacterial species so as to leave other bacteria unharmed, or of targeting bacteria by their surface chemistry or other markers. I suspect that the next generation will very rarely visit dentists, as much of the need for regular dental services will be removed by products based on this and similar sorts of research. Here is one example of laboratory work in progress:

Porphyromonas gingivalis, the bacterium responsible for many cases of periodontitis, acts to "hijack" a receptor on white blood cells called C5aR. The receptor is part of the complement system, a component of the immune system that helps clear infection but can trigger damaging inflammation if improperly controlled. By hijacking C5aR, P. gingivalis subverts the complement system and handicaps immune cells, rendering them less able to clear infection from the gum tissue. As a result, numbers of P. gingivalis and other microbes rise and create severe inflammation. According to a study published [last year], mice bred to lack C5aR did not develop periodontitis.

[The] researchers synthesized and administered a molecule that blocks the activity of C5aR, to see if it could prevent periodontitis from developing. They gave this receptor "antagonist," known as C5aRA, to mice that were then infected with P. gingivalis. The C5aRA injections were able to stave off inflammation to a large extent, reducing inflammatory molecules by 80 percent compared to a control, and completely stopping bone loss. And when the mice were given the antagonist two weeks after being infected with P. gingivalis, the treatment was still effective, reducing signs of inflammation by 70 percent and inhibiting nearly 70 percent of periodontal bone loss.


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 7, 2012
Researchers have found a number of potential ways to spur growth of muscle tissue, and some of these might be used in attempts to fend off the loss of muscle mass and strength that occurs with aging - not by fixing the root causes, but by trying to compensate through another mechanism. Here is a recent example: "The protein is an isoform, or slight variant, of PGC-1 alpha, an important regulatory of body metabolism that is turned on by forms of exercise, such as running, that increase muscular endurance rather than size. [A rise in] PGC-1 alpha-4 with exercise increases activity of a protein called IGF1 (insulin-like growth factor 1), which facilitates muscle growth. At the same time, PGC-1 alpha-4 also represses another protein, myostatin, which normally restricts muscle growth. In effect, PGC-1 alpha-4 presses the accelerator and removes the brake to enable exercised muscles to gain mass and strength. Several experiments demonstrated the muscle-enhancing effects of the novel protein. The investigators used virus carriers to insert PGC-1 alpha-4 into the leg muscle of mice and found that within several days their muscle fibers were 60 percent bigger compared to untreated mice. They also engineered mice to have more PGC-1 alpha-4 in their muscles than normal mice who were not exercising. Tests showed that the treated mice were 20 percent stronger and more resistant to fatigue than the controls; in addition, they were leaner than their normal counterparts."

Friday, December 7, 2012
It should be noted that, on balance, everything except physical health becomes better with age. Outside of degenerative aging, becoming older is so good that people are driven to apologism for the fact that aging cripples and kills them - they conflate being old and being aged, seeing two very different things as one, and a certain confusion arises after that point. Consider how much better it will be to be older once we start being able to treat the root causes of the degenerative medical condition called aging. If you're not there yet, consider just how good being older must be in order for people to be able to say they are well off even while their health is crumbling: "The SAGE study included adults between the ages of 50 and 99 years, with a mean age of just over 77 years. In addition to measures which assessed rates of chronic disease and disability, the survey looked at more subjective criteria such as social engagement and participants' self-assessment of their overall health. Participants were asked to rate the extent to which they thought they had "successfully aged," using a 10-point scale and using their own concept of the term. The study found that people with low physical functioning but high resilience, had self-ratings of successful aging similar to those of physical healthy people with low resilience. Likewise, the self-ratings of individuals with low physical functioning but no or minimal depression had scores comparable to those of physically healthy people with moderate to severe depression. "It was clear to us that, even in the midst of physical or cognitive decline, individuals in our study reported feeling that their well-being had improved with age.""

Thursday, December 6, 2012
Retinal implants are currently in their earliest stage of development: comparatively crude electrode arrays that provide an alternative to vision rather than restoring it. From here the path to ever more sophisticated systems seems assured, however: "A coming generation of retinal implants that fit entirely inside the eye will use nanoscale electronic components to dramatically improve vision quality for the wearer, according to two research teams developing such devices. Current retinal prostheses, such as Second Sight's Argus II, restore only limited and fuzzy vision to individuals blinded by degenerative eye disease. Wearers can typically distinguish light from dark and make out shapes and outlines of objects, but not much more. The Argus II, the first "bionic eye" to reach commercial markets, contains an array of 60 electrodes, akin to 60 pixels, that are implanted behind the retina to stimulate the remaining healthy cells. The implant is connected to a camera, worn on the side of the head, that relays a video feed. A similar implant, made by Bionic Vision Australia, incorporates just 24 electrodes. With so few electrodes, the amount of visual information transmitted to the brain is limited: text, for example, is difficult to read. Second Sight recently announced a method by which Argus II wearers are able to visualize Braille instead of traditional text. Recognizing this limitation, both Second Sight and Bionic Vision Australia have announced that they are developing next-generation devices with 200-plus electrodes. But arrays of nanoscale electrodes, which are currently being incorporated into new retina devices, could someday give blind people 20/20 vision."

Thursday, December 6, 2012
One of a number of methods under development to regenerate or rebuild the cornea is outlined here: "Using a combination of techniques known as microstereolithography and electrospinning, the researchers are able to make a disc of biodegradable material which can be fixed over the cornea. The disc is loaded with stem cells which then multiply, allowing the body to heal the eye naturally. "The disc has an outer ring containing pockets into which stem cells taken from the patient's healthy eye can be placed. The material across the centre of the disc is thinner than the ring, so it will biodegrade more quickly allowing the stem cells to proliferate across the surface of the eye to repair the cornea." A key feature of the disc is that it contains niches or pockets to house and protect the stem cells, mirroring niches found around the rim of a healthy cornea. Standard treatments for corneal blindness are corneal transplants or grafting stem cells onto the eye using donor human amniotic membrane as a temporary carrier to deliver these cells to the eye. For some patients, the treatment can fail after a few years as the repaired eyes do not retain these stem cells, which are required to carry out on-going repair of the cornea. Without this constant repair, thick white scar tissue forms across the cornea causing partial or complete sight loss. The researchers have designed the small pockets they have built into the membrane to help cells to group together and act as a useful reservoir of daughter cells so that a healthy population of stem cells can be retained in the eye. "Laboratory tests have shown that the membranes will support cell growth, so the next stage is to trial this in patients in India. One advantage of our design is that we have made the disc from materials already in use as biodegradable sutures in the eye so we know they won't cause a problem in the body. This means that, subject to the necessary safety studies and approval from Indian Regulatory Authorities, we should be able to move to early stage clinical trials fairly quickly.""

Wednesday, December 5, 2012
Since clinical trials for comparatively simple forms of stem cell therapy seem to be today's topic, here is another example: "Cardio3 BioSciences (C3BS) announced it has received authorization from the Belgian Federal Agency for Medicines and Health Products (FAMHP) to begin its Congestive Heart failure Cardiopoietic Regenerative Therapy (CHART-1) European Phase III trial. [The] therapy, called C3BS-CQR-1, involves taking stem cells from a patient's own bone marrow and [re-programming] those cells so that they go onto becoming heart cells. The cells, known as cardiopoietic cells, are then injected back into the patient's heart through a minimally invasive procedure using a catheter, [with] the aim of repairing damaged tissue and improving heart function and patient clinical outcomes. The trial will recruit a minimum of 240 patients with chronic advanced symptomatic heart failure. The primary endpoint of the trial is a composite endpoint including mortality, morbidity, quality of life, Six Minute Walk Test and left ventricular structure and function at 9 months post-procedure. Studies in additional countries will commence once national regulatory approvals have been received."

Wednesday, December 5, 2012
Stem cell therapies based on comparatively uncomplicated transplants of cells - either grown from the patient's own tissue or from donors - are still working their way through trials in the more regulated parts of the world, and will be for years yet. For wider access to these therapies, one has to look to medical tourism and reputable clinics overseas. So far these therapies usually result in modest or better improvements over presently available treatment options. Here is an example: "Critical limb ischemia (CLI) is a vascular disease affecting lower limbs, which is going to become a demanding challenge because of the aging of the population. Despite advances in endovascular therapies, CLI is associated with high morbidity and mortality. Patients without direct revascularization options have the worst outcomes. To date, 25%-40% of CLI patients are not candidates for surgical or endovascular approaches, ultimately facing the possibility of a major amputation. This study aimed to assess the safety and efficacy of autologous bone marrow (BM) [stem cell] transplantation performed in "no-option" patients, in terms of restoring blood perfusion by collateral flow and limb salvage. A multicenter, prospective, not-controlled phase II study for no-option CLI patients was performed. Patients were subjected to intra-arterial infusion of autologous bone marrow and followed for 12 months after the treatment. Sixty patients were enrolled and treated with BM transplantation, showing improvement in objective and subjective measures of perfusion. Furthermore, survival analysis demonstrated improved amputation-free survival rates at 12 months after the treatment."

Tuesday, December 4, 2012
Advanced glycation end-products (AGEs) are a form of metabolic byproduct that build up with age, causing increasing damage through their effects on cellular machinery, which ultimately manifest in harmful conditions such as reduced elasticity in blood vessels and skin. Ways to safely break down the most important forms of AGE would be greatly beneficial - but research aimed at achieving that goal is unfortunately very sparse and poorly funded. Here researchers show that some of the mechanisms of heart failure and decline in heart function correlate with the level of AGEs in the body: "Aging is accompanied by increased vascular and ventricular stiffness, diastolic dysfunction and an increased risk of heart failure. Heart failure, with either reduced or preserved ejection fraction, is associated with abnormalities of myocardial structure and microvasculature including increased fibrosis, cardiomyocyte hypertrophy and reduced microvascular density, and animal models suggest that these abnormalities precede the development of heart failure in older age. In addition, advanced glycation end-products (AGEs) are proposed to contribute to the increased myocardial stiffening of aging by cross-linking collagen and elastin and promoting collagen accumulation, and by promoting inflammation and oxidative stress mediated by the receptor for AGEs (RAGE). Moreover, plasma AGE levels correlate with the severity and prognosis of heart failure and predict all-cause and cardiovascular disease mortality in older adults. We investigated the hypothesis that diastolic dysfunction of aging humans is associated with altered myocardial structure and plasma AGE levels. [We found that] diastolic dysfunction of aging was independent of myocardial structure but was associated with plasma AGE levels."

Tuesday, December 4, 2012
Igor Artyukhov of the Institute of Biology of Aging is director of research for Russian cryonics provider KrioRus, and here is interviewed by Pravda: "Pravda: If you live forever, then you stop rushing somewhere. You can always take time because it would seem that you will always have time for everything, that you can do everything later. Igor Artyukhov: If you know you'll die anyway, you do not rush either. And most of us, by the way, live by this principle. Few people can write a book, trying to finish it before the end of life. Most of us just live. You can not bring the meaning of life from the outside. People set all goals themselves. If life is long, they will be able to set a lot of goals and reach them. If life is short, people just die. Imagine how much Galois could do, who at age 20 proved an important mathematical theorem. Let us understand one simple thing - there is nothing good either about aging or death. This is something that we have imposed on us by nature, events, our lifestyle. We do not know any laws of nature that could make aging and death inevitable. If we can cope with aging, then we should do it. Many say that it is not like this, they say that it is contrary to the laws of nature. This is incorrect. They mention the second law of thermodynamics, which has nothing to do with aging. Moreover, it turns out that there are ageless creatures in the world. The naked mole rat revealed no signs of aging. This is a tiny animal, the size of a mouse. Maybe we will be able to make man ageless too. Pravda: Old age - this is still weakness. Imagine how young people will suffer, when they are forced to endure endless moods. Igor Artyukhov: Depression is one of the manifestations of senile debility, when a person wants to die soon. It happens that people commit suicide at this age. But this is a manifestation of aging, and we want to fight with it. If we can push aging away, elderly people would stay longer in sober mind, they would feel useful to society. Pravda: How can we make old age not feeble and horrible, but joyful and fulfilling? Igor Artyukhov: Well, you first need to make it come as late as possible. In the words of biologist Ashley Montague, "I want to die young as late as possible." From my point of view, if it were possible not to die, it would be better to do without it. If this is impossible, then we must find a way to postpone death. My mission is to extend the active period of life in perpetuity."

Monday, December 3, 2012
Researcher have been examining the role of NF-κB in accelerated aging conditions such as Hutchinson-Gilford Progeria Syndrome, and believe that the findings may also be relevant as a basis for therapies to slow the ordinary progression of degenerative aging: "NF-κB transcription factors respond to a large variety of external and internal stress signals, having essential roles in development and tissue>homeostasis maintenance. The in vivo monitoring of NF-κB activity by using a reporter-based assay revealed that this pathway was constitutively hyperactivated in progeroid mice. Further experiments allowed us to unveil the molecular pathway involved in this aberrant activation. [Our] results indicate that these findings can be extended to normal aging, suggesting that a common accumulation of genetic damage and nuclear envelope alterations with age could be responsible, at least in part, of the abnormal NF-κB activity reported in tissues from advanced aged donors. The accumulation of senescent cells together with the decline in adult stem cell function is a primary cause of the compromise of tissue homeostasis during aging. The primary function of NF-κB activation in this context could be related to the prevention of apoptosis of damaged cells, so that chronic activation of this pathway with the subsequent immunological decline could preclude a proper clearance of senescent and damaged cells. [Experimental data] confirm that NF-κB signaling is active during normal aging, its hyperactivation is associated with the development of accelerated aging and its amelioration retards the aging process. These characteristics support the use of strategies aimed at controlling NF-κB related inflammation as putative rejuvenation strategies during both normal and pathological aging."

Monday, December 3, 2012
Since online databases on aging research have been a recent topic, here is an open access paper that discusses a set of such databases: "The Human Ageing Genomic Resources (HAGR) is a freely available online collection of research databases and tools for the biology and genetics of ageing. HAGR features now several databases with high-quality manually curated data: (i) GenAge, a database of genes associated with ageing in humans and model organisms; (ii) AnAge, an extensive collection of longevity records and complementary traits for more than 4000 vertebrate species; and (iii) GenDR, a newly incorporated database, containing both gene mutations that interfere with dietary restriction-mediated lifespan extension and consistent gene expression changes induced by dietary restriction. Since its creation about 10 years ago, major efforts have been undertaken to maintain the quality of data in HAGR, while further continuing to develop, improve and extend it. This article briefly describes the content of HAGR and details the major updates since its previous publications, in terms of both structure and content. ... Altogether, we hope that through its improvements, the current version of HAGR will continue to provide users with the most comprehensive and accessible resources available today in the field of biogerontology."



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