Fight Aging! Newsletter, June 18th 2012

FIGHT AGING! NEWSLETTER
June 18th 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!

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CONTENT

- Discussions of Mind Uploading
- More on DNA Methylation and Aging
- A Good Article on Naked Mole-Rats
- On Sarcopenia and Therapies Under Investigation
- Discussion
- Latest Headlines from Fight Aging!
    - Xenobiotic Metabolizing Enzymes as Biomarker of Longevity
    - C1q and Reversing the Decline in Muscle Regeneration With Age
    - Testing a Cell Therapy to Regenerate the Cornea
    - A Successful Decellularized Vein Transplant
    - Considering the Business Economics of Alcor
    - Senescent Cells Create More Senescent Cells
    - Telomeres and Late Fatherhood
    - Working on Better Ways to Grow Bone
    - The State of Gene Therapy
    - Shaped Nanoparticles Target Narrowed Blood Vessels

DISCUSSIONS OF MIND UPLOADING

At some point it will be possible to completely and accurately replicate the structure and operations of a brain, either in software or using some form of dedicated machinery. Given the extremely rapid expansion of computing power, that point will arrive within a few decades - and then things start to get interesting on a number of fronts:

https://www.fightaging.org/archives/2012/06/mind-uploading-at-the-international-journal-of-machine-consciousness.php

"Whole brain emulation is the topic for today: being able to run all of the processes of a brain on some form of computing machinery other than the evolved biological structures we presently possess. Considered in the long term this is an important line of research, as radical life extension will ultimately require moving away from flesh and into some more robust form of machinery in order to better manage the risk of fatal accidents. 'Ultimately' here is a long way into the future, centuries or more, long after we have solved the basic problems of repairing our aging biology so as to attain continual youth. Some people will be satisfied with copying themselves from their biological substrate into a machine substrate and letting that machine copy continue on, but that seems to me little more than an expensive form of procreation - continuation of the self requires a slow transformation of the original, not a quick cut and paste of data to a new computing device. But this is an old and often rehashed argument between identity as pattern and identity as continuity.

"Regardless of how people decide to use the ability to host a conscious individual somewhere other than a human brain, the technologies of whole brain emulation will have to be built. They are a precursor to any program of replacing the brain's present biological machinery with something better. From where I stand, brain emulation is also the most plausible path to true artificial intelligence, which at this time looks far more likely to arise from attempts to duplicate and then improve on the operation of human brains than from efforts to improve expert systems of varying sorts.

"Reasonable people differ on this, of course, as even a brief survey of publications on artificial intelligence will tell you. If you find this topic interesting, you might look at the latest issue of the International Journal of Machine Consciousness, featuring many of the usual suspects from the transhumanist community - folk who have been putting in time on AI and molecular nanotechnology research for some years."

MORE ON DNA METHYLATION AND AGING

Our genes are decorated with appended chemical structures that determine the pace at which proteins are produced from their blueprints. DNA methylation is one such form of decoration, and it changes in response to circumstances and over the course of life:

https://www.fightaging.org/archives/2012/06/more-on-dna-methylation-and-aging.php

"DNA methylation changes with age, location within the body, and type of cell, a fuzzy and very complicated pattern of decorated genes. Some of the myriad changes are sufficiently similar from person to person to be a possible method to determine age quite accurately. Others are known to reflect the degree to which a person becomes frail with age. Many more are not understood at all, or may be largely random.

"A great many debates within aging science revolve around the difference between cause and consequence - and so too with DNA methylation. Is it a part of the expected attempts by the body to adapt to increasing levels of cellular damage caused by aging, or is at least some alteration in DNA methylation a form of damage in and of itself? Good arguments can be made either way, but for my money I'd be surprised to see significant levels of epigenetic changes that were anything other than the results of underlying damage and evolutionary adaptations that try (and ultimately fail) to cope with that damage.

"This debate is significant, of course, because of how it directs research and development funding. Will scientists try to patch over the root causes of aging by altering its secondary effects - inevitably doomed to be expensive and comparatively ineffective - or will they work to repair the true causes, and thereby remove the secondary effects for free? There's been a great deal too much work on patching over the cracks in the medicine of past decades, and in this age of biotechnology it seems a sin to continue that way when we don't have to."

A GOOD ARTICLE ON NAKED MOLE-RATS

Research into the longevity and cancer immunity of naked mole-rats has been underway for some years, but has reached the public eye only comparatively recently:

https://www.fightaging.org/archives/2012/06/a-good-article-on-naked-mole-rats.php

"Pitch dark, dank, and seething with saber-toothed, sausage-shaped creatures, the world of the African naked mole-rat is a hostile habitat. In the 1980s, scientists made the remarkable discovery that naked mole-rats live like termites with a single, dominant breeding queen and scores of nonbreeding adult helpers that never leave their natal colony. But the bizarreness doesn't stop there. Naked mole-rats, unlike other mammals, tolerate variable body temperatures, attributed to their lack of an insulatory layer of fur. Their pink skin is hairless except for sparse, whisker-like strands that crisscross the body to form a sensitive sensory array that helps them navigate in the dark. Both the naked mole-rat's skin and its upper respiratory tract are completely insensitive to chemical irritants such as acids and capsaicin, the spicy ingredient in chili peppers. Most surprisingly, they can survive periods of oxygen deprivation that would cause irreversible brain damage in other mammals, and they are also resistant to a broad spectrum of other stressors, such as the plant toxins and heavy metals found in the soils in which they live. Unlike other mammals, they never get cancer, and this maintenance of genomic integrity, even as elderly mole-rats, most likely contributes to their extraordinarily long life span. In contrast to similar-size mice that only live 2-4 years, naked mole-rats can survive and thrive, maintaining normal function and reproduction, into their 30s.

"Naked mole rats are in the press ever more often of late - their longevity and cancer resistance makes them an ideal subject of study for researchers who aim to tinker human metabolism into a better state. We're all mammals in this end of the biosphere, so perhaps some of the mechanisms used by exceptional species can be ported over to humans in the form of medicine - gene therapies or carefully designed protein treatments that replicate the effects of having a particular gene."

ON SARCOPENIA AND THERAPIES UNDER INVESTIGATION

Here I point out a good review paper that discusses present progress in finding ways to slow or reverse sarcopenia, the progressive loss of muscle mass and strength with aging:

https://www.fightaging.org/archives/2012/06/on-sarcopenia-and-various-therapies-under-investigation.php

"Sarcopenia, the age-related loss of skeletal muscle, is characterized by a deterioration of muscle quantity and quality leading to a gradual slowing of movement, a decline in strength and power, and an increased risk of fall-related injuries. Since sarcopenia is largely attributed to various molecular mediators affecting fiber size, mitochondrial homeostasis, and apoptosis, numerous targets exist for drug discovery. In this paper, we summarize the current understanding of the endocrine contribution to sarcopenia and provide an update on hormonal intervention to try to improve endocrine defects. Myostatin inhibition seems to be the most interesting strategy for attenuating sarcopenia other than resistance training with amino acid supplementation.

"Several researchers have investigated the effect of inhibiting myostatin to counteract sarcopenia using animals. Lebrasseur et al. found that treatment with a mouse chimera of antihuman myostatin antibody (24 mg/Kg, 4 weeks), a drug for inhibiting myostatin, elicited a significant increase in muscle mass and in running performance ... More recently, Murphy et al. showed, by way of once weekly injections, that a lower dose of this anti-human myostatin antibody (10 mg/Kg) significantly increased the fiber cross-sectional area (by 12%) and in situ muscle force (by 35%) of aged mice (21 mo old). These findings highlight the therapeutic potential of antibody-directed myostatin inhibition for sarcopenia by inhibiting protein degradation."

Work on myostatin therapies is one of the topics worthy of greater attention here, as this seems like it would be a generally beneficial gene therapy for everyone - something that, given a good safety profile, most people would want to undergo earlier in life.

DISCUSSION

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!

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LATEST HEADLINES FROM FIGHT AGING!

XENOBIOTIC METABOLIZING ENZYMES AS BIOMARKER OF LONGEVITY
Friday, June 15, 2012
https://www.fightaging.org/archives/2012/06/xenobiotic-metabolizing-enzymes-as-biomarker-of-longevity.php
The continued search for ways to more quickly determine differences in expected longevity between members of the same species finds a potential marker: "Xenobiotic metabolism has been proposed to play a role in modulating the rate of aging. Xenobiotic-metabolizing enzymes (XME) are expressed at higher levels in calorically restricted mice (CR) and in GH/IGF-I-deficient long-lived mutant mice. In this study, we show that many phase I XME genes are similarly upregulated in additional long-lived mouse models, including "crowded litter" (CL) mice, whose lifespan has been increased by food restriction limited to the first 3 weeks of life, and in mice treated with rapamycin. Induction in the CL mice lasts at least through 22 months of age, but induction by rapamycin is transient for many of the mRNAs. Cytochrome P450s, flavin monooxygenases, hydroxyacid oxidase, and metallothioneins were found to be significantly elevated in similar proportions in each of the models of delayed aging tested, whether these are based on mutation, diet, drug treatment, or transient early intervention. The same pattern of mRNA elevation can be induced by 2 weeks of treatment with tert-butylhydroquinone, an oxidative toxin known to active Nrf2-dependent target genes. These results suggest that elevation of phase I XMEs is a hallmark of long-lived mice and may facilitate screens for agents worth testing in intervention-based lifespan studies."

C1Q AND REVERSING THE DECLINE IN MUSCLE REGENERATION WITH AGE
Friday, June 15, 2012
https://www.fightaging.org/archives/2012/06/c1q-and-reversing-the-decline-in-muscle-regeneration-with-age.php
Researchers here report on another way to tell old stem cells to get back to work on maintaining muscle tissue - though not one that has immediate application, as it requires removal of an important component of immune system function. Thus this is only promising if researchers can pick apart the different functions of this component and interfere only where it suppresses stem cell activity in muscle regeneration: "Wnt signaling plays critical roles in development of various organs and pathogenesis of many diseases, and augmented Wnt signaling has recently been implicated in mammalian aging and aging-related phenotypes. We here report that complement C1q activates canonical Wnt signaling and promotes aging-associated decline in tissue regeneration. Serum C1q concentration is increased with aging, and Wnt signaling activity is augmented during aging in the serum and in multiple tissues of wild-type mice, but not in those of C1qa-deficient mice. ... Skeletal muscle regeneration in young mice is inhibited by exogenous C1q treatment, whereas aging-associated impairment of muscle regeneration is restored by C1s inhibition or C1qa gene disruption. Our findings therefore suggest the unexpected role of complement C1q in Wnt signal transduction and modulation of mammalian aging."

TESTING A CELL THERAPY TO REGENERATE THE CORNEA
Thursday, June 14, 2012
https://www.fightaging.org/archives/2012/06/testing-a-cell-therapy-to-regenerate-the-cornea.php
Via EurekAlert!: "Regenerative medicine, or the use of specially grown tissues and cells to treat injuries and diseases, has been successful in treating disorders of a number of organs, including heart, pancreas, and cartilage. However, efforts to treat disorders of the corneal endothelium, a single cell layer on the inner surface of the cornea, with regenerative techniques have been less effective. Now, a group of scientists has developed a method that enhances the adhesion of injected corneal endothelial cells (CECs), allowing for successful corneal transplantation to repair pathological dysfunctions. ... Previous studies demonstrated that Rho-associated kinase (ROCK) signaling interferes with adhesion. We found that transplanting cultivated CECs in combination with a low-molecular weight compound that inhibits ROCK (ROCK inhibitor Y-27632), successfully achieved the recovery of corneal transparency. ... Using rabbit cells, researchers cultivated CECs in the lab and injected them into the anterior chamber of rabbit eyes with damaged corneal endothelia. Based on the recovery of the corneal endothelial function, they found that when the cultivated cells were injected along with Y-27632, the rabbit corneas regained complete transparency 48 hours after injection. ... Since rabbit CECs are highly prolific in vivo, the scientists performed another round of experiments with monkey CECs, which are more similar to those in humans. The transplantation of CECs in these primates also achieved the recovery of long-term corneal transparency with a monolayer of hexagonal cells, suggesting that cell adhesion modified by ROCK inhibitor may be an effective treatment for human corneal endothelial disorders."

A SUCCESSFUL DECELLULARIZED VEIN TRANSPLANT
Thursday, June 14, 2012
https://www.fightaging.org/archives/2012/06/a-successful-decellularized-vein-transplant.php
From the BBC: "A 10-year-old girl has had a major blood vessel in her body replaced with one grown with her own stem cells. ... A vein was taken from a dead man, stripped of its own cells and then bathed in stem cells from the girl, according to a study published in the Lancet. Surgeons said there was a "striking" improvement in her quality of life. This is the latest is a series of body parts grown, or engineered, to match the tissue of the patient. Last year, scientists created a synthetic windpipe and then coated it with a patient's stem cells. ... In this case, other options such as using artificial grafts to bypass the blockage, had failed. ... It used a process known as "decellularisation". It starts with a donor vein which is then effectively put through a washing machine in which repeated cycles of enzymes and detergents break down and wash away the person's cells. It leaves behind a scaffold. This is then bathed in stem cells from the 10-year-old's bone marrow. The end product is a vein made from the girl's own cells. ... The young girl was spared the trauma of having veins harvested from the deep neck or leg with the associated risk of lower limb disorders."

CONSIDERING THE BUSINESS ECONOMICS OF ALCOR
Wednesday, June 13, 2012
https://www.fightaging.org/archives/2012/06/considering-the-business-economics-of-alcor.php
An article from Cryonics Magazine: "Cryopreserved patients must be cared for for at least decades and some anticipate centuries. During this time, some caretaker organization must look after the patients. This involves paying the rent and utilities, replacing liquid nitrogen, maintaining and replacing dewars, hiring and paying staff, and a host of other activities that must be done reliably and economically. The usual arrangement is for the patient to make a lump sum payment into a common fund, the interest from which will then pay the expenses of maintaining a group of patients in cryopreservation for whatever period of time might be required. At Alcor, the lump sum payment is made into the PCT (Patient Care Trust), and the payment made by each patient is the 'PCT allocation,' taken from the total payment made by the patient at the time of cryopreservation. Determining the appropriate amount of the PCT allocation can raise questions whose answers are not always obvious and can sometimes be quite dilemmatic. ... Contractual and financial arrangements must usually be in place before a patient can be cryopreserved. The financial arrangements involve payment for both the up-front procedures and long term care. These payments are usually bundled, and at Alcor the total amount of money that is required is called the 'funding minimum'. The funding minimum is usually paid with life insurance. ... The focus of this article is on the lump sum payment made into the common fund from the funding minimum by the patient at the time of the patient's cryopreservation."

SENESCENT CELLS CREATE MORE SENESCENT CELLS
Wednesday, June 13, 2012
https://www.fightaging.org/archives/2012/06/senescent-cells-create-more-senescent-cells.php
The build up of senescent cells is one of the contributing causes of aging, and is partially due to the progressive failure of the immune system to destroy these cells as they crop up. Many of the changes that come with aging accelerate as they progress, and this piece provides one example as to why this is the case; for senescent cells, the more you have the faster they accumulate: "Cells may become senescent in an effort to protect the body such as when tumor suppressor genes shut down division to prevent cancer. However other sorts of damage may lead cells to stop dividing as well. A pivotal study last year showed elegantly using a trangenic approach that if senescent cells were regularly cleared from the body of mice, signs of aging in many tissues were dramatically reduced. The explanation for this result was that somehow senescent cells were damaging nearby cells, perhaps by excreting toxic materials. ... A newly published study [proves] or the first time that senescent cells do indeed damage nearby cells causing them to become senescent too. It also shows this occurs through direct cell to cell contact and resultant spread of reactive oxygen species. Furthermore it shows evidence this process occurs in the living organism as clusters of cells bearing senescent makers are found in mice livers. Clearly the next and important step for helping to reduce aging in humans is developing a safe and effective method presumably using a pharmacological agent in which senescent cells can be removed from the body."

TELOMERES AND LATE FATHERHOOD
Tuesday, June 12, 2012
https://www.fightaging.org/archives/2012/06/telomeres-and-late-fatherhood.php
A finding here ties into research suggesting that life can be lengthened through selective breeding at later ages - this, like the response to calorie restriction, is a form of metabolic variability that may have evolved to make a species better able to adapt to changing environmental circumstances: "Children and even grandchildren of older fathers may live longer than children of younger men. ... Scientists found that children born to fathers between the ages of late 30s to early 50s inherit longer 'telomeres' or tiny protective caps on the ends of chromosomes that protect against aging degeneration and disease. ... Researchers measured the telomere length of DNA by using blood samples collected from 1,779 young Filipino adults and their mothers and determined the ages of the children's fathers and grandfathers. Study results show that a person's telomeres became longer not only with their father's age at birth, but also with their paternal grandfather's age at their father's birth, meaning that the longevity effect is amplified over the generations. ... The findings suggest that delayed paternal reproduction can lead to cumulative, multi-generational increases in telomere length in offspring which may promote longer life. Researchers also believe that longer telomeres may delay sexual development, and instead invest energy into the extra resources necessary to maintain healthy functioning at more advanced ages. ... late fatherhood may serve as a sigh that mortality rates are low. ... If your father and grandfather were able to live and reproduce at a later age, this might predict that you yourself live in an environment that is somewhat similar - an environment with less accidental deaths or in which men are only able to find a partner at later ages. In such an environment, investing more in a body capable of reaching these late ages could be an adaptive strategy from an evolutionary perspective."

WORKING ON BETTER WAYS TO GROW BONE
Tuesday, June 12, 2012
https://www.fightaging.org/archives/2012/06/working-on-better-ways-to-grow-bone.php
An example of the sort of work presently taking place in the stem cell field: "scientists purified a subset of stem cells found in fat tissue and made from them bone that was formed faster and was of higher quality than bone grown using traditional methods, a finding that may one day eliminate the need for painful bone grafts that use material taken from the patient during invasive procedures. ... Traditionally, cells taken from fat had to be cultured for weeks to isolate the stem cells which could become bone, and their expansion increases risk of infection and genetic instability. ... [Researchers] used a cell sorting machine to isolate and purify human perivascular stem cells (hPSC) from adipose tissue and showed that those cells worked far better. They also showed that a growth factor called NELL-1 [enhanced] the bone formation in their animal model. ... People have shown that culture-derived cells could grow bone, but these are a fresh cell population and we didn't have to go through the culture process, which can take weeks. The best bone graft is still your own bone, but that is in limited supply and sometimes not of good quality. What we show here is a faster and better way to create bone that could have clinical applications. ... The purified human hPSCs formed significantly more bone [and] these cells are plentiful enough that patients with not much excess body fat can donate their own fat tissue. ... if everything goes well, patients may one day have rapid access to high quality bone graft material by which doctors get their fat tissue, purify that into hPSCs and replace their own stem cells with NELL-1 back into the area where bone is required. The hPSC with NELL-1 could grow into bone inside the patient, eliminating the need for painful bone graft harvestings. The goal is for the process to isolate the hPSCs and add the NELL-1 with a matrix or scaffold to aid cell adhesion to take less than an hour."

THE STATE OF GENE THERAPY
Monday, June 11, 2012
https://www.fightaging.org/archives/2012/06/the-state-of-gene-therapy.php
From The Scientist: "After 20 years of high-profile failure, gene therapy is finally well on its way to clinical approval. The concept is simple: if a mutated gene is causing a problem, replace or supplement it with a new, accurate copy. In theory, such a strategy could not just treat, but cure countless human genetic diseases. In practice, however, developing safe and effective gene therapies has not been easy. Even when identifying a disorder's genetic basis is fairly straightforward, finding the appropriate delivery vector to target the diseased tissues in the body, while avoiding unintended consequences, has challenged would-be gene therapists for more than 20 years. But more and more researchers are convinced that the technique is on the brink of becoming a common medical practice. ... In the last year alone, he says, major breakthroughs have been published for the use of gene therapy in patients with hemophilia, solid tumors, and leukemia, not to mention the dozens of trials yielding positive results for gene therapies to treat various types of blindness. ... It's just remarkable. These decades of work are suddenly really paying off. ... The history of medicine says every new technology starts with a great idea and then requires hard work and optimization. And I think that's exactly what's happened with gene therapy. Hurdles were identified - and there's always hurdles once you get into a complex human disease situation - and they've been addressed. ... The concepts aren't that much different than they were early on, but the tools are much better. Now [gene therapy] is actually fulfilling the promise that people said it would have."

SHAPED NANOPARTICLES TARGET NARROWED BLOOD VESSELS
Monday, June 11, 2012
https://www.fightaging.org/archives/2012/06/shaped-nanoparticles-target-narrowed-blood-vessels.php
A clever way to target an infused therapy to particular regions in the body by using their physical properties: "Treatment options [for atherosclerosis] are currently available to people who suffer from the disease but no drug can target solely the diseased areas, often leading to generalized side effects. Intravenous injection of a vasodilator (a substance that dilates blood vessels), such as nitroglycerin, dilates both the diseased vessels and the rest of our arteries. Blood pressure can thus drop, which would limit the desired increased blood flow generated by vasodilatation of diseased vessels and needed for example during a heart attack. In order to increase the effectiveness of treatments against atherosclerosis and to reduce side effects, a team of researchers [have] developed nanocontainers having the ability to release their vasodilator content exclusively to diseased areas. ... Though no biomarker specific to atherosclerosis has been identified, there is a physical phenomenon inherent to stenosis (the narrowing of blood vessels) known as shear stress. This force results from fluctuations in blood flow induced by the narrowing of the artery and runs parallel to the flow of blood. It is by making use of this phenomenon that the team of researchers has developed a veritable 'time bomb', a nanocontainer which, under pressure from the shear stress in stenosed arteries, will release its vasodilator contents. By rearranging the structure of certain molecules (phospholipids) in classic nanocontainers such as liposome, scientists were able to give them a lenticular shape as opposed to the normal spherical shape. In the form of a lens, the nanocontainer then moves through the healthy arteries without breaking. This new nanocontainer is perfectly stable, except when subjected to the shear stress of stenosed arteries."

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