Fight Aging! Newsletter, June 13th 2011

June 13th 2011

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!



- Open Cures: a Protocol Outline for Protofection
- A Conversation with Aubrey de Grey on Aging and AI
- Pitching the Effects of Cancer as Accelerated Aging
- Subtle Twists in the Mitochondrial Free Radical Theory of Aging
- Discussion
- Latest Headlines from Fight Aging!


Open Cures is an initiative that aims to accelerate the development of existing longevity-enhancing biotechnologies demonstrated in the laboratory, but which are not being developed for commercial use in humans - largely due to regulatory barriers. One of the first projects is to produce a protocol document for mitochondrial protofection, a step by step guide that will allow anyone with a background in the life sciences to see exactly how to replicate this process. Protofection is important in longevity science because it is a potential way to replace damaged mitochondrial DNA, and thus remove dysfunctional mitochondria as a contributing cause of aging:

"Since the launch of Open Cures, [volunteers have] been looking into the published papers on mitochondrial protofection and writing up an outline for a protocol - the detailed step by step instructions that allow a technique in biotechnology to be replicated. The work to date can be found in the Open Cures wiki:"

The next step is to bring on life science writers and volunteers to fill this out into a full protocol document: if you know anyone who would be interested, send them over.


A recent h+ Magazine article is a conversational interview between Ben Goertzel and Aubrey de Grey, which touches on their shared areas of interest - both have been involved in artificial intelligence and the longevity science communities. Distinct from that conversation, it is my commentary on it that is quoted below:

"My take on it is that the researchers working on strong artificial intelligence are stretching the point when they discuss the relevance of their work to rejuvenation research - but this is based on my own particular estimate of how the near future of of artificial intelligence development will likely play out. Any and all systems that help biologists manage information will do their part in accelerating progress towards interventions in aging - but the next two decades don't look likely to see much more than incremental advances in expert systems. Better expert systems and knowledge management tools are a good thing, but they aren't strong AI.

"I think that the first strong AI will most likely emerge from emulation and simulation of the human brain, and the computing hardware powerful enough to enable that to happen will only just be emerging twenty years from today. Meanwhile, those twenty years between now and 2030 are a vitally important time for longevity science: either we get our act together and build (a) a meaningful, funded, supported research community and (b) the scientific basis for all the necessary biological repair technologies in that time frame, or rejuvenation biotechnology will not arrive in time for those of us heading into middle age today.

"So for us, I don't see that strong AI development has an enormous relevance to the future of human longevity - no more so than any line of development likely to spin off incrementally better knowledge management tools. For our descendants, strong AI will absolutely reshape the world. But we're in a far worse position than they will be when it comes to time to wait and the tools at hand - not a hopeless position, but one that requires a great deal more work right here and right now."


An interesting take on some of the mechanisms of cancer surfaced recently:


"In normal aging, DNA is damaged and the body begins to deteriorate because of oxidative stress. 'We are all slowly rusting, like the Tin-man in the Wizard of Oz,' Dr. Lisanti said. 'And there is a very similar process going on in the tumor's local environment.' Interestingly, cancer cells induce 'oxidative stress,' the rusting process, in normal connective tissue, in order to extract vital nutrients. Dr. Lisanti and his team previously discovered that cancer cells induce this type of stress response (autophagy) in nearby cells, to feed themselves and grow. However, the mechanism by which the cancer cells induce this stress and, more importantly, the relationship between the connective tissue and how this 'energy' is transferred was unclear.

"'Nobody fully understands the link between aging and cancer,' said Dr. Lisanti, who used pre-clinical models, as well as tumors from breast cancer patients, to study these mechanisms. 'What we see now is that as you age, your whole body becomes more sensitive to this parasitic cancer mechanism, and the cancer cells selectively accelerate the aging process via inflammation in the connective tissue.'"


A recent open access paper presents a very readable explanation of the implications in the last few years of research into mitochondria and their activities - which is of importance to aging and longevity science.

"Mitochondria are organelles of eukaryotic cells that contain their own genetic material and evolved from prokaryotic ancestors some 2 billion years ago. They are the main source of the cell's energy supply and are involved in such important processes as apoptosis, mitochondrial diseases, and aging. During recent years it also became apparent that mitochondria display a complex dynamical behavior of fission and fusion, the function of which is as yet unknown. In this paper we develop a concise theory that explains why fusion and fission have evolved, how these processes are related to the accumulation of mitochondrial mutants during aging.

"If you look back in the Fight Aging! archives, you'll find a layman's explanation of how degenerative aging is caused in part by accumulating mitochondrial mutations. Mitochondria go bad as a natural consequence of their operation, and if enough go bad in the right way, and manage to escape the natural recycling mechanisms of the cell, then they take over that cell - causing it to malfunction, damage its surroundings, and release harmful reactive molecules that are carried throughout the body. Given enough cells doing this, you will become frail and eventually die as vital systems in your body become too damaged to operate correctly.

"In this, we're all in the same boat. The interesting part of this process is that mitochondria swarm around a cell in bacteria-like herds, but the real damage only starts after a cell is completely taken over by clones of one particular mutant form of mitochondrion - a different dysfunctional clone army for each dysfunctional cell, each based on a particular random set of mutations. The question all along has been how that clonal takeover happens, and here the researchers propose that fusion is the culprit.

"Another important finding of recent years is that individual mitochondria do not exist as permanently distinct entities, as has long been believed, but instead form a dynamic network within which the mitochondria regularly exchange proteins, [mitochondrial] DNA, and lipids by rapid fusion and fission processes ... The fact that mitochondrial fusions do occur revives an earlier idea that the selection advantage of deletion mutants is their reduced size, which allows them to replicate faster ... we propose that mitochondrial fusion is the underlying mechanism that opens the door for the clonal expansion of mitochondrial deletion mutants."


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, June 10, 2011
Another example of simultaneously boosting life span and reducing cancer in mice in the laboratory - not maximum lifespan, however, or the paper would be much more triumphant. This is the first I've seen of this particular mechanism, so your guess is as good as mine as to what is going on under the hood. Once thing I'm pleased to note is that the researchers controlled for calorie restriction, and considered it important enough to state as much in the abstract. That's progress: "Sulfate (SO(4)(2-)) plays an important role in mammalian growth and development. In this study, hyposulfatemic NaS1 null (Nas1-/-) mice were used to investigate the consequences of perturbed SO(4)(2-) homeostasis on longevity. Median life spans were increased (by ≈25%) in male and female Nas1-/- mice when compared with Nas1+/+ mice on identical food intakes. At 1yr of age, serum SO(4)(2-) levels remained low in Nas1-/- mice (≈0.16mM) when compared to Nas1+/+ mice (≈0.96mM). RT-PCR revealed increased hepatic mRNA levels of Sirt1 (by ≈60%), Cat (by ≈48%), Hdac3 (by ≈22%), Trp53 and Cd55 (by ≈36%) in Nas1-/- mice, genes linked to ageing. Histological analyses of livers from 2yr old mice revealed neoplasms in >50% of Nas1+/+ mice but not in Nas1-/- mice. This is the first study to report increased lifespan, decreased hepatic tumours and increased hepatic expression of genes linked to ageing in hyposulfatemic Nas1-/- mice, implicating a potential role of SO(4)(2-) in mammalian longevity and cancer."

Friday, June 10, 2011
Here another study of the long-lived confirms the common wisdom: "Objectives: To identify predictors of extraordinary survival. Design: Longitudinal study of a cohort of elderly people followed up until almost all have died. Setting: Two counties in Iowa; a part of the Established Populations for Epidemiologic Study of the Elderly. Participants: Two thousand eight hundred ninety community-dwelling citizens aged 65 to 85 at baseline and surviving at least 3 years. Measurements: Data relating to age, sex, birth order, parental longevity, marital status, education, family income, social support, self-reported health, chronic diseases, blood pressure, body mass index, physical ability, exercise, life attitude and mental health were obtained. Extraordinary survivors (ESs) were defined to include approximately 10% of the longest survivors in their sex group. Results: The 253 ESs were far more likely never to have smoked. In models adjusted for age, sex, and smoking, the earlier-life factors such as parental longevity, being earlier in the birth order (in women only), and body mass index at age 50 were associated with extraordinary survival. In similar models for predictors at age 65 to 85, extraordinary survival was associated with excellent self-reported health, fewer chronic diseases, better physical mobility and memory, and positive attitude toward life, but it was not associated with depression, anxiety, or sleep quality. In multivariable models, attitude toward life was not an independent predictor. Women in the top third of a cumulative score of independent predictors were 9.3 times as likely to reach extraordinary survival as those in the bottom third. Conclusion: ESs had fewer 'classical' risk factors and were in better health than their contemporaneous controls. Possibly genetic factors such as parental longevity and birth order appear to be less predictive in men than in women."

Thursday, June 9, 2011
Transhumanism is in many ways the urge to self-improvement taken to its logical conclusion - that in addition to improving in ways that are presently possible, we should carry out the foundational work in technology that creates new ways for us to improve ourselves. So it all starts with simple, available tools to improve health, per this post at Sentient Developments: "there are a number of things we can do to extend our capacities and optimize our health in a way that's consistent with transhumanist ideals - even if it doesn't appear to be technologically sophisticated. While the effects of these interventions are admittedly low impact from a future-relativistic perspective, the quest for bodily and cognitive enhancement is part of the broader transhumanist aesthetic which places an emphasis on maximal performance, high quality of life, and longevity. ... Sure, part of being a transhumanist involves the bringing about of a radical future, including scientific research and cheerleading. But it's also a lifestyle choice; transhumanists actively strive to exceed their body's nascent capacities, or, at the very least, work to bring about its full potential. In addition to building a radical future, a transhumanist is someone who will, at any time in history, use the tools and techniques around them to maximize their biological well-being." Which is a slightly different take on the utilitarian considerations of keeping in shape so as to have the best chance of living into the era of rejuvenation biotechnology - with the pace of technology, a few years may matter. The decade or more of change you can exert on your life expectancy via lifestyle choices may make the difference between missing the boat or living a life of centuries. Or longer.

Thursday, June 9, 2011
A review paper notes a number of lines of research aimed at introducing new DNA into mitochondria or new mitochondria into cells. Although discussed in the context of introducing specific types of damage to study, the much more important prospect is for repairing mitochondria - and thus the possibility of removing the significant contribution to aging caused by damaged mitochondria: "Maintenance of the mitochondrial genome is a major challenge for cells, particularly as they begin to age. Although it is established that organelles possess regular DNA repair pathways, many aspects of these complex processes and of their regulation remain to be investigated. Mitochondrial transfection of isolated organelles and in whole cells with customized DNA synthesized to contain defined lesions has wide prospects for deciphering repair mechanisms in a physiological context. We document here the strategies currently developed to transfer DNA of interest into mitochondria. Methodologies with isolated mitochondria claim to exploit the protein import pathway or the natural competence of the organelles, to permeate the membranes or to use conjugal transfer from bacteria. Besides biolistics, which remains restricted to yeast and Chlamydomonas reinhardtii, nanocarriers or fusion proteins have been explored as methods to target custom DNA into mitochondria in intact cells. In further approaches, whole mitochondria have been transferred into recipient cells. Repair failure or error-prone repair leads to mutations which potentially could be rescued by allotopic expression of proteins. The relevance of the different approaches for the analysis of mitochondrial DNA repair mechanisms and of aging is discussed."

Wednesday, June 8, 2011
In a self-repairing system, a little damage is actually a good thing - it wakes up the repair mechanisms and sets them to work, producing an overall net benefit. Thus a given form of damage may be good or bad for system longevity, depending on its degree, where it happens, and whether it is noticed by the repair mechanisms. This is why you'll see superficially contradictory research papers on reactive oxygen species, the damaging oxidant molecules emitted by mitochondria, and their impact on aging. See this, for example: "researchers have identified a pathway by which reactive oxygen species (ROS) molecules, which are usually implicated in the aging process due to their damage to DNA, can also act as cellular signaling molecules that extend lifespan. ... Increased ROS, and their effects at the cellular level, can lead to oxidative stress, which is involved in many diseases and aging. But ROS are also necessary for the proper functioning of the immune system and other biological functions. ... Inhibiting a signaling pathway called Target of Rapamycin (TOR), which is involved in sensing nutrients and cell growth, increases lifespan in yeast, as it does in mice. ... a key way this occurs is by altering the function of cellular powerhouses called mitochondria so that they produce more signaling ROS. ... The concept that ROS are important cellular signaling molecules, and not just agents of damage and stress, has grown to be widely accepted. Remarkably, in this study, we show that their purposeful production by mitochondria can even provide an adaptive signal that can delay aging. ... Trials targeting the TOR pathway as an anti-cancer strategy in humans are already underway. Our study suggests that carefully augmenting mitochondria and ROS production in humans may also be beneficial in combating aging and associated diseases." Note that "carefully augmenting mitochondria and ROS production" is a fair description of the results of exercise, and is one of the ways in which exercise works to improve long-term health. You may recall that researchers demonstrated that antioxidants applied generally tend to block this effect by mopping up the ROS that act as signals to the body's repair systems.

Wednesday, June 8, 2011
It is known that centenarians - and their immediate families - tend to have better immune systems, a capability that is increasingly important in old age as people become more vulnerable to infections. Here is more research to illustrate this fact: "Aging is characterized by a progressive alteration of homeostatic mechanisms modulated by environmental and genetic factors. It is associated with a pro-inflammatory status. In centenarians, an increase of pro-inflammatory cytokine production balanced by anti-inflammatory immune response that would promote longevity is observed. Cytokine dysregulation is believed to play a key role in the proposed remodeling of the immune-inflammatory responses accompanying old age. IL-22 is a pro-inflammatory cytokine belonging to the IL-10 family and represents an important effector molecule of activated [T cells]. We recruited 17 healthy centenarians (4 males, 13 females, range 100-105 years). All ultralongeval subjects were living at home or in a nursing home. Sixteen healthy, sex-matched individuals (4 males, 12 females, range 60-95 years) were also recruited as controls. Centenarians displayed significantly higher circulating IL-22 levels compared to control population. It's well known that IL-22 is a pro-inflammatory cytokine produced by activated T lymphocytes and NK cells. IL-22 stimulates the production of acute phase reactants and promotes the antimicrobial defense. The results of the present study show, for the first time, that there is an increase of IL-22 in healthy centenarians. This pro-inflammatory condition probably is protective against infection, promoting the longevity of these subjects."

Tuesday, June 7, 2011
The nature of medical research is that it is an uncertain business - sometimes the practical applications just don't work: "GDNF first showed promise as a treatment for Parkinson's patients when scientists discovered that it could boost the survival of dopamine-producing neurons - cells that degenerate in the disease - back in 1993. But so far, the results in humans have not borne out those hopes. Early trials involving injecting the protein directly into the brain showed some promise, but a second, more comprehensive trial subsequently showed no benefit. Another recent trial that used a gene therapy approach to deliver a similar compound, neurturin, showed some signs of benefit but failed in its primary goal of improving symptoms after one year. [Researchers] believe that other attempts failed because they didn't target the right tissue precisely enough. The first attempts, he said, injected the GDNF protein into the spaces near the brain regions of interest, where it failed to diffuse far enough into the brain. Infusing the treatment directly into the relevant brain tissue, he says, caused leakage into the surrounding fluid. ... They all turned out to be negative, because the delivery was never controlled ... The new trial will introduce the gene encoding GDNF into the putamen, a brain area involved in Parkinson's disease. The gene will be carried by a virus, and will be injected directly into the brain using a technique called convection-enhanced delivery, which uses positive pressure to drive fluid deep into targeted regions. The injection will include an MRI contrast agent, and the researchers will use an MRI-based imaging system to track the distribution of the treatment during delivery. ... the imaging system will allow the team to make sure the gene gets to where it's needed. ... It still remains to be seen whether GDNF really is something that helps people with Parkinson's disease."

Tuesday, June 7, 2011
A long piece from Chronosphere covers a fair amount of ground, and holds up the AIDS patient advocacy of the 80s and 90s as a model of success that could be and should be emulated for longevity science advocacy: "[It is plausible that] maturation of the technologies required to extend lifespan indefinitely for most people now living who are aged 30 or older will not be developed with sufficient rapidity to prevent their being cryopreserved. ... [For example], mature, clinically available, and FDA-approved therapies to slow or halt brain cell loss are a decade, and likely closer to two decades, away. And when clinical application does come, it will likely be only for the most serious disease states, such as [Alzheimer's disease], Huntington's Disease (HD), and Amyotrophic Lateral Sclerosis (ALS). Even in these conditions, access to treatment may be limited by many factors, including high cost and government regulation. Thus, for many of us, even another decade of waiting will be too long. ... One of the hardest things for people to understand is that it is possible to do good, without doing good enough; and nowhere is this more the case than in medical research. ... [Looking at the history of AIDS], by 1983 demonstrations, peaceful and otherwise, had begun, and those men who found themselves or loved ones dying of AIDS decided to take both research and treatment into their own hands. Broadly, this effort took two forms: intense lobbying and application of pressure within the system to obtain government money at every level to support research and provide care for the dying, and the creation of the 'AIDS Underground': a guerrilla effort to find or to develop treatments that would do anything to improve the situation for those ill with or dying of the disease. Those efforts ranged from finding more effective ways to manage symptoms, to a full blown effort to find a definitive cure. Importantly, any advance in treating the illness and extending the lives of patients suffering from it, was the subject of underground research efforts. ... If you want graphic proof of just how miraculously effective their efforts were, all you need to do is look at [the present mortality data, and the fact that AIDS is now a largely controllable condition]. We cryonicists are in exactly the same position today [with respect to aging]. The question is, are we smart enough to realize it, and courageous enough to take the necessary action?"

Monday, June 6, 2011
From EurekAlert!: "transplantation of adult stem cells enriched with a bone-regenerating hormone can help mend bone fractures that are not healing properly. ... stem cells manufactured with the regenerative hormone insulin-like growth factor (IGF-I) become bone cells and also help the cells within broken bones repair the fracture, thereby speeding the healing. ... A deficiency of fracture healing is a common problem affecting an estimated 600,000 people annually in North America. ... This problem is even more serious in children with osteogenesis imperfecta, or brittle bone disease, and in elderly adults with osteoporosis, because their fragile bones can easily and repeatedly break, and bone graft surgical treatment is often not successful or feasible. ... Fractures that do not mend within the normal timeframe are called non-union fractures. Using an animal model of a non-union fracture, a 'knockout' mouse that lacks the ability to heal broken bones, Spagnoli and her colleagues studied the effects of transplanting adult stem cells enriched with IGF-I. They took mesenchymal stem cells (adult stem cells from bone marrow) of mice and engineered the cells to express IGF-I. Then they transplanted the treated cells into knockout mice with a fracture of the tibia, the long bone of the leg. Using computed tomography (CT) scanning, the researchers showed that the treated mice had better fracture healing than did mice either left untreated or treated only with stem cells. Compared with controls left to heal on their own or recipients of stem cells only, treated mice had more bone bridging the fracture gap, and the new bone was three to four times stronger."

Monday, June 6, 2011
Via EurekAlert!: "The world's first clinical trial for the treatment of patients with torn meniscal cartilage has received approval from the UK regulatory agency, the MHRA, to commence. The current treatment for the majority of tears is the removal of the meniscus, a procedure that often results in the early onset of osteoarthritis. The Phase I trial, one of the first in the UK to be approved using stem cells, will treat meniscal tear patients with a cell bandage product, seeded with the patient's own, expanded, stem cells. The cell bandage, produced by Azellon Ltd, a University of Bristol spin-out company, is focused on the research, development and commercialisation of an adult autologous (patient's own) stem cell technology which in vitro (tissue culture) has shown great promise for the healing of meniscal tears. The trial is designed primarily to test the safety profile of Azellon's cell bandage in ten meniscal tear patients, but some information on whether or not it works will also be obtained. The bandage, containing the patient's own stem cells will be implanted in a simple surgical procedure using a specially designed instrument that helps to deliver the cells into the injured site as a first-line treatment in place of removal of the meniscus. Patients will be closely monitored for safety over a five-year follow-up period."


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