Fight Aging!

Teaching the immune system to kill cancer is an ongoing concern in laboratories around the world, and the state of the art is pretty effective these days - though in the overregulated world of medicine, a decade or more can separate working methods in the laboratory from working therapies in the clinic, and most of that delay entirely unnecessary. Here is a good example of what is presently possible:

Researchers from UCLA's cancer and stem cell centers have demonstrated for the first time that blood stem cells can be engineered to create cancer-killing T-cells that seek out and attack a human melanoma. ... Researchers used a T-cell receptor from a cancer patient cloned by other scientists that seeks out an antigen expressed by this type of melanoma. They then genetically engineered the human blood stem cells by importing genes for the T-cell receptor into the stem cell nucleus using a viral vehicle. The genes integrate with the cell DNA and are permanently incorporated into the blood stem cells, theoretically enabling them to produce melanoma-fighting cells indefinitely and when needed.

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In the study, the engineered blood stem cells were placed into human thymus tissue that had been implanted in the mice, allowing Zack and his team to study the human immune system reaction to melanoma in a living organism. Over time, about six weeks, the engineered blood stem cells developed into a large population of mature, melanoma-specific T-cells that were able to target the right cancer cells. ... The study included nine mice. In four animals, the antigen-expressing melanomas were completely eliminated. In the other five mice, the antigen-expressing melanomas decreased in size.

I'm not overly worried about the cancers that my body is likely to start generating in two or three decades; they will be a risk, but a small risk, more of a financial inconvenience than a genuinely threatening medical condition. By the 2040s this sort of guided approach to eliminating cancer will have long been a mainstream staple in clinics, a mature technology that will benefit from years of refinement, experience, and incremental improvements - and bear in mind that this is just one of a number of different branches of next generation cancer therapy presently under development and achieving similar results.

The use of 3D printers is spreading in medical research and development: "researchers have used a 3D printer to create a bone-like material and structure that can be used in orthopedic procedures, dental work, and to deliver medicine for treating osteoporosis. Paired with actual bone, it acts as a scaffold for new bone to grow on and ultimately dissolves with no apparent ill effects. The authors [say] they're already seeing promising results with in vivo tests on rats and rabbits. It's possible that doctors will be able to custom order replacement bone tissue in a few years ... If a doctor has a CT scan of a defect, we can convert it to a CAD file and make the scaffold according to the defect ... The material grows out of a four-year interdisciplinary effort involving chemistry, materials science, biology and manufacturing. A main finding of the paper is that the addition of silicon and zinc more than doubled the strength of the main material, calcium phosphate. The researchers also spent a year optimizing a commercially available ProMetal 3D printer designed to make metal objects. The printer works by having an inkjet spray a plastic binder over a bed of powder in layers of 20 microns, about half the width of a human hair. Following a computer's directions, it creates a channeled cylinder the size of a pencil eraser. After just a week in a medium with immature human bone cells, the scaffold was supporting a network of new bone cells."

Link: http://medicalxpress.com/news/2011-11-3d-printer-bone-like-material.html

Via EurekAlert!: "One of the earliest known impairments caused by Alzheimer's disease - loss of sense of smell - can be restored by removing a plaque-forming protein in a mouse model of the disease. The study confirms that the protein, called amyloid beta, causes the loss. ... The evidence indicates we can use the sense of smell to determine if someone may get Alzheimer's disease, and use changes in sense of smell to begin treatments, instead of waiting until someone has issues learning and remembering. We can also use smell to see if therapies are working. ... just a tiny amount of amyloid beta - too little to be seen on today's brain scans - causes smell loss in mouse models. Amyloid beta plaque accumulated first in parts of the brain associated with smell, well before accumulating in areas associated with cognition and coordination. Early on, the olfactory bulb, where odor information from the nose is processed, became hyperactive. Over time, however, the level of amyloid beta increased in the olfactory bulb and the bulb became hypoactive. Despite spending more time sniffing, the mice failed to remember smells and became incapable of telling the difference between odors. The same pattern is seen in people with the disease. They become unresponsive to smells as they age. ... The team then sought to reverse the effects. Mice were given a synthetic liver x-receptor agonist, a drug that clears amyloid beta from the brain. After two weeks on the drug, the mice could process smells normally. After withdrawal of the drug for one week, impairments returned."

Link: http://www.eurekalert.org/pub_releases/2011-11/cwru-eso113011.php

Spurring regeneration of muscle is of interest as as a part of any future rejuvenation biotechnology package because humans and other mammals progressively lose muscle mass and strength with age - aside from the sedentary lifestyle that most older people adopt, there are underlying processes that sap muscle strength even in athletes. Stepping on the gas and telling the body to build new muscle - when it ordinarily would not do so - isn't as good an approach as preventing muscle loss from happening in the first place, or at least attenuating some of the mechanisms involved, but it certainly closer to realization at this point in time.

As a demonstration of that fact, here are researchers building new muscle in mice using one of the many specialist techniques for delivering stem cells that are presently evolving in the laboratory:

Researchers removed a portion of the tibialis anterior leg muscle in several mice (the muscle was chosen because injury to it affects the foot's range of motion but doesn't prevent the mice from walking). In some mice, the injuries were left to heal on their own. In others, the wound was filled with bundles of microthreads seeded with reprogrammed human muscle cells. The untreated mice developed significant scarring at the injury site, with no restoration of muscle function. In sharp contrast, the mice that received the reprogrammed cells grew new muscle fibers and developed very little scarring.

Tests done 10 weeks after implantation showed that the regenerated tibialis anterior muscle functioned with nearly as much strength as an uninjured muscle. The scientists expected that most of the regenerated muscle would be composed of human cells, since the implanted cells were from human muscle. Surprisingly, most of the new muscle fibers were made of mouse cells. The team theorized that the fibrin microthreads, which in their composition and shape are similar to muscle fibers, may encourage resident mouse progenitor cells to migrate into the wound and begin restoring the tissue (they may also forestall the natural inflammatory response that leads to scarring after a major injury).

This surprise finding suggests that fibrin microthreads alone could be used to treat major muscle trauma while research on enhancing regeneration with reprogrammed human cells continues.

Yet another line of research to keep an eye on: the ultimate destination of regenerative medicine is to move away from introducing new cells and towards using signals to tell existing cells to get to work. A lot of these potential signals are being discovered through accident and guided guesswork at the present time, but this will become a more purposeful process of discovery as understanding of the deepest and most complex levels of our biological processes increases.

Via ScienceDaily: "researchers studied hematopoietic stem cells, which create the cells that comprise the blood and immune system. Understanding when and how these stem cells begin to falter as the years pass may explain why some diseases, such as acute myeloid leukemia, increase in prevalence with age, and also why elderly people tend to be more vulnerable to infections such as colds and the flu. ... We know that immune system function seems to decline with increasing age. This is the first study comparing the function and gene expression profiles of young and old purified, human hematopoietic stem cells, and it tells us that these clinical changes can be traced back to stem cell function. ... Specifically, the researchers found that hematopoietic stem cells from healthy people over age 65 make fewer lymphocytes - cells responsible for mounting an immune response to viruses and bacteria - than stem cells from healthy people between ages 20 and 35. (The cells were isolated from bone marrow samples.) Instead, elderly hematopoietic stem cells, or HSCs, have a tendency to be biased in their production of another type of white blood cell called a myeloid cell. This bias may explain why older people are more likely than younger people to develop myeloid malignancies."

Link: http://www.sciencedaily.com/releases/2011/11/111128152414.htm

A commentary from the SENS Foundation: "Rejuvenation biotechnology encompasses a suite of advanced medical therapies, each of which removes, repairs, replaces, or renders harmless one of the forms of cellular or molecular damage that accumulates in an aging tissue over time and impairs its function. Through the comprehensive abatement of all such aging damage to levels approximating those of younger adults, tissue structure and function can be made more youthful, restoring the health and vigor of aging persons to that of persons years or decades younger. This approach is most prominently under pursuit in the development of cell therapy and tissue engineering, of which the most striking success to date has been the use of fetal and embryonic mesencephalic tissue grafts to replace dopaminergic (DA) neurons lost to the age-related neurodegenerative processes driving Parkinson's disease (PD). ... The promise of this approach has been foreshadowed in murine models of PD, in which DA neurons derived from mouse [embryonic stem cells] have been found highly effective in reversing motor symptoms. But the performance of ostensibly DA neurons derived from human pluripotent stem cells in the same systems has so far been poor, due to uncertain and unstable differentiation of the cells. In a new study, a team of researchers [have] used their novel DA neuron differentiation strategy to resolve these difficulties, leading to robust and stable engraftment of human pluripotent stem cell-derived DA neurons into the striatum and substantial evidence of efficacy in two rodent models of the disease, and provided preliminary data on the viability of their approach in nonhuman primates."

Link: http://sens.org/node/2506

Reversing progressive deafness is one of the many plausible goals for the field of regenerative medicine, and scientists have in recent years demonstrated a way to spur creation of hair cells in the ear through a form of gene therapy. Any method that can reliably generate new hair cells has the potential to reverse the common forms of deafness caused by loss of those cells, such as through damage or aging. Here's a popular science article on this latest advance:

Raphael's team first gave the guinea pigs antibiotics which destroyed their inner-ear hair cells. They then apparently repaired the damage by injecting them with genetically engineered adenoviruses. ... The therapy promotes the regrowth of crucial hair cells in the cochlea, the part of the inner ear which registers sound. After treatment, the researchers used sensory electrodes around the animals' heads to show that the auditory nerves of treated - but not untreated - animals were now registering sound. ... The experiment worked beyond expectation. "The recovery of hair cells brought the treated ears to between 50% and 80% of their original hearing thresholds," says Raphael. Even more surprising, the team found that the hair cells were created from cells lining the scala media which - according to biological orthodoxy - should not be able to turn into other cells.

And here is the paper:

To restore hearing, it is necessary to generate new functional hair cells. One potential way to regenerate hair cells is to induce a phenotypic transdifferentiation of nonsensory cells that remain in the deaf cochlea. Here we report that Atoh1, a gene also known as Math1 encoding a basic helix-loop-helix transcription factor and key regulator of hair cell development, induces regeneration of hair cells and substantially improves hearing thresholds in the mature deaf inner ear after delivery to nonsensory cells through adenovectors.

You'll notice that this is another application of transdifferentiation, an approach that changes a cell from one type directly to another type without going through the now standard process of first generating pluripotent cells, then differentiating them into the desired cell type. Thus transdifferentiation might prove to be a useful tool for in-situ biological repairs that require a small population of specific cells to be replaced or regenerated, such as the dopamine neurons lost in Parkinson's disease, for example, or beta cells in the pancreas.

Researchers continue to pick out specific biochemical differences that may contribute to the unusual longevity of the naked mole rat: "Naked mole-rats (Heterocephalus glaber), the longest-lived rodents, live 7-10 times longer than similarly-sized mice and exhibit normal activities for ∼75% of their lives. Little is known about the mechanisms that allow them to delay the aging process and live so long. Neuregulin-1 (NRG-1) signaling is critical for normal brain function during both development and adulthood. We hypothesized that long-lived species will maintain higher levels of NRG-1 and that this contributes to their sustained brain function and concomitant maintenance of normal activity. We monitored the levels of NRG-1 and its receptor ErbB4 in H. glaber at different ages ranging from 1 day to 26 years and found that levels for NRG-1 and ErbB4 were sustained throughout development and adulthood. In addition, we compared seven rodent species with widely divergent (4-32y) maximum lifespan potential (MLSP) and found that at a physiologically-equivalent age, the longer-lived rodents had higher levels of NRG-1 and ErbB4. Moreover, phylogenetic independent contrast analyses revealed that this significant strong correlation between MLSP and NRG-1 levels was independent of phylogeny. These results suggest that NRG-1 is an important factor contributing to divergent species MLSP through its role in maintaining neuronal integrity."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22103690

The mainstream of aging research is only interested in slowing aging through manipulation of metabolic processes, rather than trying to reverse aging through repair biotechnologies. Here is a look at the breadth of that potential research: "Aging is the major biomedical challenge of this century. The percentage of elderly people, and consequently the incidence of age-related diseases such as heart disease, cancer, and neurodegenerative diseases, is projected to increase considerably in the coming decades. Findings from model organisms have revealed that aging is a surprisingly plastic process that can be manipulated by both genetic and environmental factors. Here we review a broad range of findings in model organisms, from environmental to genetic manipulations of aging, with a focus on those with underlying gene-environment interactions with potential for drug discovery and development. One well-studied dietary manipulation of aging is caloric restriction, which consists of restricting the food intake of organisms without triggering malnutrition and has been shown to retard aging in model organisms. Caloric restriction is already being used as a paradigm for developing compounds that mimic its life-extension effects and might therefore have therapeutic value. The potential for further advances in this field is immense; hundreds of genes in several pathways have recently emerged as regulators of aging and caloric restriction in model organisms. Some of these genes, such as IGF1R and FOXO3, have also been associated with human longevity in genetic association studies. The parallel emergence of network approaches offers prospects to develop multitarget drugs and combinatorial therapies. Understanding how the environment modulates aging-related genes may lead to human applications and disease therapies through diet, lifestyle, or pharmacological interventions. Unlocking the capacity to manipulate human aging would result in unprecedented health benefits."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22090473

Progress in DNA sequencing is similar to that of computing power in general - which is to say that overall capacity is increasing and cost per unit processed is falling at a staggering pace. Five years from now, sequencing your entire genome will likely cost less than the chair you're sitting on while reading this. Thus DNA sequencing is a poster child for speed of development in modern biotechnology: advances in understanding that would have required an entire research group and years of work a decade ago are now projects suitable for a single post-graduate researcher to complete over a semester off in one corner of the lab.

But so what? Why is this relevant to those of us following the early stages of the development of rejuvenation biotechnology? DNA sequencing seems like it's off to the side and down in the depths, one tiny part of the technologies involved in, say, repair of mitochondria or removal of senescent cells. Fortunately, here is one of the Halcyon Molecular folk to explain how DNA sequencing dovetails with the research we are interested in:

We are improving DNA sequencing to achieve our goal of turning biology into an information science. Along the way, various SENS approaches will be accelerated by improved DNA sequencing, and we present here specific experimental paths for using the tool in service of SENS. As one example, sequencing offers extreme technical shortcuts in molecular directed evolution techniques, allowing larger populations to be interrogated with fewer rounds of evolution and increased stringency of selection. This will accelerate attempts to find, improve, or evolve enzymes and other catalysts targeting age-related molecular damage. As another example, sequencing will enable better quality control of stem cells in both clinical and laboratory settings. We will discuss these specific experimental strategies and others that leverage improved sequencing to hasten progress toward saving lives via SENS therapy approaches.

There have been a number of research results in the past year or two that suggest the barriers posed by age to the production of patient-specific cells suitable for stem cell therapies are lower than first thought. Several research groups have obtained useful cells from old patients, showing that age-related damage to patient cells is no barrier to reprogramming them - indeed, the reprogramming appears to repair many types of damage. Here is another such result: "Somatic cells reprogrammed into induced pluripotent stem cells (iPSCs) acquire features of human embryonic stem cells (hESCs) and thus represent a promising source for cellular therapy of debilitating diseases, such as age-related disorders. ... Aged somatic cells might possess high susceptibility to nuclear and mitochondrial genome instability. Hence, concerns over the [potential of reprogrammed cells to spawn cancer] due to the lack of genomic integrity may hinder the applicability of iPSC-based therapies for age-associated conditions. ... Four iPSC lines were generated from dermal fibroblasts derived from an 84-year-old woman, representing the oldest human donor so far reprogrammed to pluripotency. ... all aged-iPSCs were able to differentiate into neurons, re-establish telomerase activity, and reconfigure mitochondrial ultra-structure and functionality to a hESC-like state. Importantly, aged-iPSCs exhibited high sensitivity to drug-induced apoptosis and low levels of oxidative stress and DNA damage, in a similar fashion as iPSCs derived from young donors and hESCs. Thus, the occurrence of chromosomal abnormalities within aged reprogrammed cells might not be sufficient to over-ride the cellular surveillance machinery and induce malignant transformation through the alteration of mitochondrial-associated cell death. Taken together, we unveiled that cellular reprogramming is capable of reversing aging-related features in somatic cells from a very old subject, despite the presence of genomic alterations."

Link: http://dx.doi.org/10.1371/journal.pone.0027352

We are our brains, and so there isn't much room for outright replacement with new tissue as a strategy for regeneration anywhere inside the skull. Thus it is very important that researchers develop ways to repair the brain in situ. Fortunately, it looks as though this goal will be achievable sooner rather than later, with comparatively early stage stem cell therapies: "Neuron transplants have repaired brain circuitry and substantially normalized function in mice with a brain disorder, an advance indicating that key areas of the mammalian brain are more reparable than was widely believed. ... [Researchers] transplanted normally functioning embryonic neurons at a carefully selected stage of their development into the hypothalamus of mice unable to respond to leptin, a hormone that regulates metabolism and controls body weight. These mutant mice usually become morbidly obese, but the neuron transplants repaired defective brain circuits, enabling them to respond to leptin and thus experience substantially less weight gain. Repair at the cellular-level of the hypothalamus - a critical and complex region of the brain that regulates phenomena such as hunger, metabolism, body temperature, and basic behaviors such as sex and aggression - indicates the possibility of new therapeutic approaches to even higher level conditions such as spinal cord injury, autism, epilepsy, ALS (Lou Gehrig's disease), Parkinson's disease, and Huntington's disease. ... There are only two areas of the brain that are known to normally undergo ongoing large-scale neuronal replacement during adulthood on a cellular level - so-called 'neurogenesis,' or the birth of new neurons - the olfactory bulb and the subregion of the hippocampus called the dentate gyrus, with emerging evidence of lower level ongoing neurogenesis in the hypothalamus. The neurons that are added during adulthood in both regions are generally smallish and are thought to act a bit like volume controls over specific signaling. Here we've rewired a high-level system of brain circuitry that does not naturally experience neurogenesis, and this restored substantially normal function."

Link: http://www.eurekalert.org/pub_releases/2011-11/hms-rtb112311.php

You may recall that an Italian group has been engineering and transplanting comparatively simple organ structures - such as tracheas - in recent years. The researchers have used a range of techniques to build these organs from the patient's own cells, such as decellularization and nanoscale polymer scaffolds. The former requires a donor organ to be stripped of cells in order to provide a scaffold formed of its extracellular matrix, while the latter results in a completely synthetic organ. In both cases, the raw materials that form that scaffold are populated with the patient's own cells, leading to a transplant without the risk of immune rejection.

This is all very promising groundwork for later and more extensive tissue engineering of replacement parts to order. The first synthetic trachea transplant occurred earlier this year, and an update is doing the rounds:

The Eritrean patient, 36-year-old Andemariam Teklesenbet Beyene, was the first person in the world to receive this type of transplant in June, 2011 at the Karolinska University Hospital, Stockholm, Sweden. ... Currently Beyene is living in Reykjavík, Iceland, where he is a geology student studying for his PhD. Beyene's wife and two children live in Eritrea. ... The patient has been doing great for the last 4 months and has been able to live a normal life. After arriving in Iceland at the start of July, he was 1 month in hospital and another month in the rehabilitation center. Already at the rehabilitation center he could start to work on his Master of Science Thesis in Geophysics, a scientific project that he has been working on for the last years at the University of Iceland here in Reyklavik. For the last two months he has been able to focus on his studies and the plan is the he will defend his thesis at the end of this year.

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A 30-year-old man from Maryland, USA, who also had primary cancer of the airway, is the second patient to receive a bioartificial scaffold transplantation from Prof. Macchiarini. The scaffold used in this case was created from nanofibres and therefore, according to Prof. Macchiarini, represents a further advance from the transplant Beyene received. Prof. Macchiarini's team is now hoping to use the same technique in order to treat a 13-month old South Korean infant.

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We will continue to improve the regenerative medicine approaches for transplanting the windpipe and extend it to the lungs, heart, and oesophagus. And investigate whether cell therapy could be applied to irreversible diseases of the major airways and lungs.

So good news all round so far - this is one of the more successful lines of work in tissue engineering, and with success so clearly demonstrated you can be certain that other clinics worldwide will adopt these techniques over the next few years.

Researchers are foraging for longevity-related genes that have nothing to do with the known processes of life extension through calorie restriction: "We believe that for the first time, we have a biochemical route to youth and aging that has nothing to do with diet. ... The chemical variation, known as acetylation because it adds an acetyl group to an existing molecule, is a kind of 'decoration' that goes on and off a protein - in this case, the protein Sip2 - much like an ornament can be put on and taken off a Christmas tree ... Acetylation can profoundly change protein function in order to help an organism or system adapt quickly to its environment. Until now, acetylation had not been directly implicated in the aging pathway, so this is an all-new role and potential target for prevention or treatment strategies, the researchers say. The team showed that acetylation of the protein Sip2 affected longevity defined in terms of how many times a yeast cell can divide, or 'replicative life span.' The normal replicative lifespan in natural yeast is 25. In the yeast genetically modified by researchers to restore the chemical modification, life span extended to 38, an increase of about 50 percent. The researchers were able to manipulate the yeast life span by mutating certain chemical residues to mimic the acetylated and deacetylated forms of the protein Sip2. They worked with live yeast in a dish, measuring and comparing the life spans of natural and genetically altered types. ... When we give back this protein acetylation, we rescued the life span shortening in old cells. Our next task is to prove that this phenomenon also happens in mammalian cells."

Link: http://www.hopkinsmedicine.org/news/media/releases/hopkins_scientists_turn_on_fountain_of_youth_in_yeast

A PDF document that I think you'll find interesting: "Reports on the latest research of what makes us unhealthy, or what could make us live longer, are common from magazines, newspapers and websites. Often, the messages get shortened so that it sounds like one risk factor dominates. The reality is that the way in which many relevant risk factors work together is still not yet fully understood, and there is an element of chance affecting the longevity prospects of each of us. ... the overarching context is consistent improvement in longevity worldwide. Life expectancy has only ever declined in a few countries subject to specific and significant negative mortality risk. While we need to examine the trees of individual risk factors, there is much to be said for pausing to look at the woods of the consistent achievement in longevity progress. Longevity Bulletin aims to provide a regular guide to the prospects for long lives. It presents and explains actuarial perspectives on population longevity and looks outside the profession for statistics, research and the latest thinking on related subjects. It is not intended as a comprehensive guide to everything new in longevity research but rather as a helpful companion for those interested in a most intriguing subject."

Link: http://www.actuaries.org.uk/research-and-resources/pages/longevity-bulletin

Connections make the world go round - networking and relationships, if you like: establishing and maintaining them. This is just as true of companies and their employees and customers as it is of any collection of people. A company that manages relationships well is a company that will prosper. This is actually surprisingly hard, however, even with resolve and the best of intentions from all parties, as anyone who has been on the inside of that part of business life will attest to.

On this topic, I see that cryonics provider Alcor, under the guidance of CEO Max More, is making an effort to make its operations far more transparent and in the process improve relationships with both its members and the broader community of people interested in cryonics - a source of future supporters and growth for the business. So, for example, you see regular sets of posts reporting on operations, intentions, research, and other progress such as these at the Alcor blog:

CEO Report

The never-ending quest for cost reductions continues. A review of Alcor's utility bills and an examination of the roof space made it clear that thousands of dollars per year have been avoidably incurred in the form of unnecessarily high air conditioning bills. We have asked for bids from three companies and will choose one in the coming week to improve insulation and install radiant barriers. Judging by the remarkable escalation in billing during the hotter months (in some units of the building more than others), the annual savings should make this investment pay off in a pleasingly short time.

...

On the communications front, Barry Aarons is helping us deploy the Alcor Speakers' Bureau to give talks to organizations in the area. A few weeks ago, we started this effort modestly with me giving a talk to the Midtown Lion's Club. The goal is to build a reputation and have a voice in the influential local business groups.

Readiness and Transport Report

An Alcor member in the New York area was placed on a ventilator following a recent serious medical event. Catherine Baldwin of Suspended Animation (SA) traveled to the area to establish a relationship with the medical facility and mortuary in the event stabilization was needed. Although the member's health has temporarily improved it was decided that a full standby was not warranted, she continues to struggle with her illness and may eventually need our services.

Research and Development

Based on our findings last month that the mylar cooldown blanket significantly reduced the LN2 usage of our automated perfusion and cooldown table with an empty patient pod, Steve Graber decided to conduct a more rigorous cooldown test utilizing four 20L water bladders in the pod cavity and a target cooling temperature of -80C.

If you look at the recent administrative report, you'll find a link to the membership and cryopreservation counts in graphical form for the last forty years - which is food for thought:

As of October 31, 2011, Alcor has 951 members and 108 patients.

In the grand scheme of things, cryonics has yet to climb into the big leagues. The potential is there, and much like the potential for rejuvenation biotechnology, there are great challenges inherent in trying to convince people to see it and believe it. "Why isn't cryonics a multi-billion dollar international industry?" is one of those questions like "Why don't more people wholeheartedly support research into reversing human aging?" - we can talk around the issue a great deal, but there are few firm answers at the end of the day. If we knew definitively where the point of failure was in persuasion and desire, why exactly the urge to spend money on the expectation of more life, so very much in evidence elsewhere, peters out for cryonics and longevity science, then we'd be working on fixing that problem as opposed to working on the various problems and challenges we only believe to be significant.

A reminder that progress in the production of nanoscale scaffolds and surfaces is just as important as progress in biology in the stem cell field: "It's easy to give a stem cell a goal in life, apparently. Simply placing a cell in contact with a surface can provide sufficient information (a cue) to dictate how the cell will develop, and incredibly, even simple length-scale changes are enough to affect the outcome of the cell development. Far-fetched as this may sound, if you think about the nature of stem cells for a moment, it becomes less surprising that they are so responsive to their environment: how else to explain the extraordinary variety of cell types that derive from a uniform base material? As stem cells continue to be the focus of much research into the concepts of regenerative medicine and tissue engineering, a corollary challenge for materials science is the design and build for artificial substrates that can mimic biological environments and thereby control the growth and specialization of the cells. For one thing, the subtleties make it easy to grow off in the wrong direction. Growing muscle tissue will need a different set of conditions from, say, a new liver, but the differences in the environment might turn out to be very slight. A small change in the period of a pattern on the substrate might result in completely the wrong kind of tissue. A challenge of a more mechanical nature is the actual fabrication of the substrates. Most cell-growth environments have cues that act over a number of different length scales, with multiple patterns and features of various sizes interacting to produce the end result. Current micro- and nanofabrication techniques don't mimic this complexity too well, or rather, don't mimic it too well without complex multi-step procedures, expensive instrumentation, and expertise on fabrication that is not readily available to medical researchers."

Link: http://www.materialsviews.com/details/news/1400141/Shrink-Wrap_Stem_Cell_Growth.html

The Genomics X Prize has been a while in the building, and has a focus on the genetics of human longevity. It has been in the news of late: "The contest to sequence 100 complete human genomes of people who are over 100 years old in one month for $1,000 or less per genome has started its recruitment process and has pulled in new several new partners to help it develop its sampling, protocols, informatics, and other scientific needs. ... The Archon Genomics X PRIZE [is] an incentivized prize competition that will award $10 million to the first team to rapidly, accurately and economically sequence 100 whole human genomes to a level of accuracy never before achieved. The 100 human genomes to be sequenced in this competition will be donated by 100 centenarians (ages 100 or older) from all over the world, known as the Medco 100 Over 100. Sequencing the genomes of the Medco 100 Over 100 presents an unprecedented opportunity to identify those 'rare genes' that protect against diseases, while giving researchers valuable clues to health and longevity. These centenarians' genes are providing us with a window to the past that will significantly impact the future of healthcare. The result will be the world's first 'medical grade' genome, a critically-needed clinical standard that will transform genomic research into usable medical information to improve patient diagnosis and treatment. This global competition will inspire breakthrough genome sequencing innovations and technologies that will usher in a new era of personalized medicine."

Link: http://genomics.xprize.org/

Long after the time in which anyone can easily recall who was US president in 2011, or what party was in power, or which wars of declining empire were fought, and then long after anyone even cares about that ancient history, and later, long after the whole downward slope of the history of the US is but a footnote of interest to scholars of the transition from second to third millennium, and later still, long after anyone can even find out with any great reliability who was US president in 2011 ... long after all these things are forgotten, the first half of the 21st century will still be clearly recalled as the dawn of the era in which aging was conquered.

Progress in science and technology is really the only thing that matters in the long term. In that area of human endeavor, the truly transformative advances stand out like beacons across millennia of time - even long after the details of that period are hard to reconstruct, archaeologists can show clearly both when and how the use and understanding of technology changed. So we see the impact of agriculture and we know when it began, for example: it looms large in our considerations of deep human history at the present time, because it utterly transformed the course of our species. Similarly for iron working, and other important advances.

The advent of ways to reverse the effects of aging, largely through biotechnologies in the early stages of development that will repair the low-level biochemical damage that causes aging, will transform the shape and course of human society no less than the great advances of prehistory and early history - but undoubtedly much faster, as we're far better at talking to one another and coordinating our efforts in these years.

So in the final analysis, how much of what we do in our day to day lives actually matters? That's a meaning of life sort of a question, so everyone gets to write their own answer into the box and it's still right, but it's intended to provoke thought. Do you care about end results, or do you care about the journey? Billions of lives in the future hang in the balance of a few dollars or a convincing argument for the development of rejuvenation biotechnology: it's early enough still that we're talking butterfly wings and hurricanes when it comes to how our efforts today will affect the next four decades of progress in ways to slow and reverse aging. I suppose, for someone like myself who isn't in it so much for the journey, it's the case that you can choose to live a life in which you made a difference, or you can choose to live a life in which it doesn't much matter whether you ever existed.

The future can be made a golden place within our lifetimes, and billions of people who are presently destined to suffer and age to death could instead by saved through biotechnology to live full, healthy, and vigorous lives thousands of years long. That all depends on how well and rapidly the present research community works on the first generation of rejuvenation therapies, which in turn depends on acts of fundraising and persuasion carried out by otherwise ordinary folk like you and I. There's an avalanche to be started here, a few pebbles that will bring the whole slope rushing down with it, profoundly transform humanity in the process by banishing aging and the decrepitude, disease, and death it brings.

One of the benefits of pregnancy is increased regenerative ability in the mother, a fact observed in a number of studies. The underlying mechanisms are illustrated in recent research, and is one of a number of related effects that might inform future research directions in regenerative medicine: "Scientists are devoting countless research hours to treatments based on embryonic stem cells, differentiating these blank-slate cells from embryos into brain cells, light-sensing retinal cells, blood cells, and more to replace damaged or destroyed tissues in the body. Now, a new study in mice shows such that nature has arrived at just such a solution, too: When a pregnant mouse has a heart attack, her fetus donates some of its stem cells to help rebuild the damaged heart tissue. ... The researchers started with two lines of mice: normal mice and mice genetically engineered to express green fluorescent protein (GFP), which glows a distinctive green when exposed to blue light, in their cells. They mated normal female mice with GFP-producing male mice. This meant that half the resulting fetuses had the GFP gene, too, making their cells glow, too. Twelve days later - a little less than two-thirds of the way through a normal mouse pregnancy - the researchers gave half the pregnant mice heart attacks. When the scientists examined the female mice's heart tissue two weeks after the heart attacks, they found lots of glowing green tissue - cells that came from the fetus - in the mom's heart. Mice who had heart attacks had eight times as many cells from the fetus in their hearts as mice who hadn't had a heart attack did, meaning the high volume of fetal cells was a response to the heart attack. ... Doctors have observed that women who experience weakness of the heart during pregnancy or shortly after giving birth have better recovery rates than any other group of heart failure patients. This study suggests that fetal stem cells may help human mothers, as well as mice, recover from heart damage."

Link: http://blogs.discovermagazine.com/80beats/2011/11/21/helpful-mouse-fetuses-naturally-send-stem-cells-to-mom-to-fix-her-damaged-heart/

A New York Times piece from earlier in the month: "Is physical frailty inevitable as we grow older? That question preoccupies scientists and the middle-aged, particularly when they become the same people. Until recently, the evidence was disheartening. A large number of studies in the past few years showed that after age 40, people typically lose 8 percent or more of their muscle mass each decade, a process that accelerates significantly after age 70. Less muscle mass generally means less strength, mobility and among the elderly, independence. It also has been linked with premature mortality. But a growing body of newer science suggests that such decline may not be inexorable. Exercise, the thinking goes, and you might be able to rewrite the future for your muscles. ... [researchers] recruited 40 competitive runners, cyclists and swimmers. They ranged in age from 40 to 81. ... There was little evidence of deterioration in the older athletes' musculature, however. The athletes in their 70s and 80s had almost as much thigh muscle mass as the athletes in their 40s, with minor if any fat infiltration. The athletes also remained strong. There was, as scientists noted, a drop-off in leg muscle strength around age 60 in both men and women. They weren't as strong as the 50-year-olds, but the differential was not huge, and little additional decline followed. The 70- and 80-year-old athletes were about as strong as those in their 60s. ... We think these are very encouraging results. They suggest strongly that people don't have to lose muscle mass and function as they grow older. The changes that we've assumed were due to aging and therefore were unstoppable seem actually to be caused by inactivity. And that can be changed."

Link: http://well.blogs.nytimes.com/2011/11/09/aging-well-through-exercise/

Amongst the better known genetic longevity enhancements in mice is GHRKO, or growth hormone receptor knockout. The gene that encodes the growth hormone receptor protein is deleted, and as a consequence these mice live a lot longer than their peers - but only if well cared for, as they have trouble maintaining their body temperature. Unexpectedly, they are also obese, while at the same time exhibiting a biochemistry that is very uncharacteristic for obese mice. GHRKO mice are not in the slightest bit insulin resistant, for example, which is the otherwise normal end result of obesity in mammals, leading to metabolic syndrome and type 2 diabetes.

If you're a regular reader, you'll know that excess visceral fat is bad for you, and the more of it you have and the longer you keep it, the worse the end result. It significantly raises your risk of suffering all of the common age-related conditions, and shortens your life expectancy to boot. So don't get fat and don't stay fat is good advice for nearly everyone.

research showed that for those who had a medium number of years lived with obesity (between five years and 14.9 years), the risk of mortality more than doubled than for those who had never been obese. The risk of mortality almost tripled for those with the longest duration of obesity (more than 15 years). Furthermore, the research showed for every additional two years lived with obesity, the risk of mortality increased by between six and seven per cent.

Interestingly enough, surgical removal of visceral fat extends life in ordinary mice. But if you do the same to GHRKO mice, it actually harms their health. As a recent paper shows, the removal of that growth hormone receptor dramatically changes the biochemistry of visceral fat, switching it from being a net harm to a net benefit.

Metabolic effects of intra-abdominal fat in GHRKO mice

Mice with targeted deletion of the growth hormone receptor (GHRKO mice) are GH resistant, small, obese, hypoinsulinemic, highly insulin sensitive and remarkably long-lived. To elucidate the unexpected coexistence of adiposity with improved insulin sensitivity and extended longevity, we examined effects of surgical removal of visceral (epididymal and perinephric) fat on metabolic traits related to insulin signaling and longevity.

Comparison of results obtained in GHRKO mice and in normal animals from the same strain revealed disparate effects of visceral fat removal (VFR) on insulin and glucose tolerance, adiponectin levels, accumulation of ectopic fat, phosphorylation of insulin signaling intermediates, body temperature and respiratory quotient (RQ). Overall, VFR produced the expected improvements in insulin sensitivity and reduced body temperature and RQ in normal mice and had opposite effects in GHRKO mice.

...

We conclude that in the absence of GH signaling the secretory activity of visceral fat is profoundly altered and unexpectedly promotes enhanced insulin sensitivity. The apparent beneficial effects of visceral fat in GHRKO mice may also explain why reducing adiposity by calorie restriction fails to improve insulin signaling or further extend longevity in these animals.

As the researchers note, this sheds light on a few previously puzzling observations.

Why aren't more wealthy people funding aging research? My answer is that wealth does not grant vision, but here is Aubrey de Grey on this topic: "Biogerontology is not your average scientific discipline. It is the study of a phenomenon that currently accounts for two-thirds of all deaths worldwide, and 90% of all deaths within the industrialized world. If measured in terms of suffering or of health care costs, the numbers are equally staggering. As several of my colleagues have noted over many decades, and with increasing energy since the turn of the millennium, the impact of even a modest degree of progress in postponing age-related diseases, as a result of intervening in their common cause (aging), would be immense. ... So why is everyone still oblivious to this disaster? Ultimately, I believe that the answer comes down to just one thing: a failure to appreciate who can potentially benefit from progress. The massive Achilles' heel of biomedical gerontology in terms of appeal to the wider world has always been its focus on lifelong interventions. Those in a position to influence the level of financial support for such work, therefore, are required to start from a position of disenfranchised altruism (since they are already too old to benefit from therapies that need to be begun in youth or earlier). That is a noble position, to be sure, but realistically it is not one that enjoys prolific favor from the public. In particular, it is not a promising target for philanthropy. But the regenerative approach changes all that - indeed, it abolishes it. The whole point of all regenerative medicine is to start with people who are already carrying a significant quantity of damage, which the intervention will then repair. As such, if it can be made to work, rejuvenation biotechnology has the capacity to deliver the substantial (exactly how substantial remains to be seen, but we won't know until we try) postponement of all the debilities that we most fear as we progress toward the age at which we expect our health to fail. And it can deliver it to people who are already in middle age or older by the time the therapies materialize."

Link: http://hplusmagazine.com/2011/11/21/why-arent-more-wealthy-people-funding-aging-research/

You might recall Peter Thiel's advocacy for radical philanthropy, akin to venture investing, wherein high risk high reward projects are funded rather than just the same old staid and conservative institutional funding strategies. This sort of visionary philanthropy seems to be the only way we'll see the groundwork for rejuvenation biotechnology funded to the level at which staid conservative funding sources will agree that it was wonderful all along - and then fund it themselves. Here's a different perspective on the same issue of risk, funding, and institutional biases: "The discovery that aging can be delayed in mice is just the kind of experiment one might suppose would be supported by the National Institutes of Health, the government agency that spends $30 billion a year on financing biomedical research. So after Mayo Clinic researchers discovered they could delay degeneration of the tissues in a fast-aging strain of mice by purging senescent cells, they applied to the agency's National Institute on Aging for financing for the next essential step, that of repeating the test in mice with a normal life span. Under the agency's peer review system, panels of fellow experts judge each proposal and assign it a score. On paper, it's hard to think of a better system. But in practice, experts often differ, even on the best proposals, and a single dissenting vote can reduce a proposal's overall score too low to get financed. The Mayo proposal got a less than perfect score, and was denied money. ... Their peer review process is not promoting innovative, high-risk research. ... They were able to get their research started only because private funds were available from the Ellison Medical Foundation, supported by Larry Ellison of the Oracle software company, and from Robert P. Kogod, a philanthropist in Washington. After publication of the Mayo Clinic team's paper in Nature this month, they were approached by the Glenn Foundation, set up by the commodities trader Paul F. Glenn, who has a longstanding interest in aging research. The foundation gave them an unsolicited $60,000 and said it would be around to talk later." You'll recognize a number of those names as supporters of the SENS Foundation.

Link: http://www.nytimes.com/2011/11/22/science/research-on-senescent-cells-is-denied-nih-grant.html

So very much of the research we watch is conducted in mice, rats, and - increasingly - in naked mole rats and other more esoteric members of the rodent order of mammals. Some of this work is fairly directly applicable to we humans, and some of it is not. For example, the types and proportions of advanced glycation end-product (AGE) that accumulate to damage our cells in later life are very different between rodents and humans, and so early promising work in rats aimed at developing AGE-breaker drugs to wash out these unwanted compounds translated poorly to humans.

So how much attention should we give to promising results in mice? That can only be answered for any specific case by knowing more about the use of mice in the laboratory; it is very helpful for the layperson to have a better grasp as to the benefits, limitations, and expectations held by scientists when it comes to research in rodent species that is expected to be applicable to humans. On this note, let me draw your attention to a trio of long articles from Slate that examine the humble laboratory mouse:

The Mouse Trap

Just how ubiquitous is the experimental rodent? In the hierarchy of lab animal species, the rat and mouse rule as queen and king. A recent report from the European Union counted up the vertebrates used for experiments in 2008 - that's every fish, bird, reptile, amphibian, and mammal that perished in a research setting, pretty much any animal more elaborate than a worm or fly - and found that fish and birds made up 15 percent; guinea pigs, rabbits, and hamsters contributed 5 percent; and horses, monkeys, pigs, and dogs added less than 1 percent. Taken together, lab rats and lab mice accounted for nearly all the rest - four-fifths of the 12 million animals used in total,

The Trouble With Black-6

According to one estimate, distributors like Charles River and the scientists who buy from them have created at least 400 standard, inbred strains of mouse, and 200 inbred strains of rat. Yet one stands out from the rest as the model among models in biomedicine. If you want to set up a trading post for biology, a place where researchers from around the world can exchange and compare their data, then it helps to have a common coin - a stable currency that undergirds the system. In the global marketplace of discovery, the Black-6 mouse (more formally known as the "C57BL/6") serves as the U.S. dollar.

The Anti-Mouse

As a matter of taxonomy, the naked mole rat is closer to a guinea pig or porcupine than a mouse or a rat, but really it's neither one nor the other. Buffenstein knows that she's working with an oddball; she did a lot of the work that proves it. "[The naked mole rat] does have very unique mechanisms that are not seen in other animals," she says, referring both to its superficial quirks and to whatever private biochemistry helps it to shrug off cancer, deflect toxic chemicals, ignore painful stimuli, and otherwise live five times longer than one might expect.

...

Ten years ago, Buffenstein was one of just a handful of biologists studying naked mole rats in captivity; now her field comprises some three dozen labs around the world. Her colleagues have looked at why naked mole rats are immune to the pain caused by spicy foods, or how they avoid getting itchy when doused with histamine, or what allows their brains to get by without much oxygen and a shriveled pineal gland. In Rochester, N.Y., a pair of Russian-born biologists, Andrei Seluanov and Vera Gorbunova, are devoted to finding out exactly how naked mole rats keep from getting cancer.

If you read around the warnings of doom by laboratory rodent monoculture - good news sells no papers, and the story of mice as research tools is one of great success when considered at the high level - you'll find a great deal of fascinating information. It pays to understand more about how the sausage is made when it comes to longevity research, and mice are an important part of the process. Knowing more about the limitations helps to better place the steady flow of newly announced results into context.

An open access commentary: "Aging is now viewed as a plastic phenotype that can be altered by nutritional, pharmacological and genetic manipulations. However, most pro-longevity mutations are discovered by systematic gene deletion or RNA interference screens, which mainly reveal abolished or diminished gene functions. In our recent publications, we used global acetylation proteome screens to study aging in yeast, and showed that enhancing the function of certain genes through specific acetylation can promote longevity. ... It is well known that acetylation of histone proteins in cultured human fibroblasts decreases during aging, which is believed to be directly related to decreased metabolic rate and reproductive capacity associated with aging. However, histone deacetylation is not likely to be a universal driving force of aging because histone acetylation and deacetylation mimetics similarly shortened life span, which could simply reflect nonspecific fitness decreases in both instances. Extension of lifespan promoted by certain genetic and/or pharmacological perturbations will more likely lead to identification of bona fide regulatory factors of aging. ... Aging is conventionally thought to be characterized by accumulation of molecular, cellular, and organ damage, leading to increased vulnerability to disease and death. Our data, on the contrary, support the idea that the gradual loss of a crucial component promoting 'healthy young status' might underlie an intrinsic aging process. Many of the mutations that extend life span decrease the activity of external nutrient signaling, such as the IGF (insulin-like growth factor)/insulin and the TOR (target of rapamycin) pathways, suggesting that they may induce a metabolic state similar to that resulting from periods of food shortage."

Link: http://impactaging.com/papers/v3/n10/full/100398.html

If you can build new living tissue to be implanted in patients, then why not also give it the capacity to perform additional useful tasks? This is a technology platform with some potential: "combining gene therapy with tissue engineering could avoid the need for frequent injections of recombinant drugs. Patients who rely on recombinant, protein-based drugs must often endure frequent injections, often several times a week, or intravenous therapy. Researchers [have demonstrated] the possibility that blood vessels, made from genetically engineered cells, could secrete the drug on demand directly into the bloodstream. ... Such drugs are currently made in bioreactors by engineered cells, and are very expensive to make in large amounts. ... The paradigm shift here is, 'why don't we instruct your own cells to be the factory?' ... [Researchers] provide proof-of-concept, reversing anemia in mice with engineered vessels secreting erythropoietin (EPO). ... The researchers created the drug-secreting vessels by isolating endothelial colony-forming cells from human blood and inserting a gene instructing the cells to produce EPO. They then added mesenchymal stem cells, suspended the cells in a gel, and injected this mixture into the mice, just under the skin. The cells spontaneously formed networks of blood vessels, lined with the engineered endothelial cells. Within a week, the vessels hooked up with the animals' own vessels, releasing EPO into the bloodstream. Tests showed that the drug circulated throughout the body and reversed anemia in the mice."

Link: http://www.marketwatch.com/story/engineered-drug-secreting-blood-vessels-reverse-anemia-in-mice-2011-11-15

We might look on aging as damage that happens as a stochastic, inevitable consequence of the operation of a biochemical system. So the buildup of chemical gunk between your cells is a part of aging, while those times you managed to break bones in your enthusiasm for life are not aging, despite the fact that what's left in the wake of those unfortunate accidents is definitely damage.

There are always special cases and grey areas worth thinking about, however. Such as teeth, for example, as I was reminded earlier today. Teeth have a pretty hard time of it, actually, when you stop to think about it. Even in this modern age our teeth maintenance technologies remain woefully inadequate in the face of bacterial species that break down enamel, and so our teeth are one of the most failure-prone and damage-prone parts of the body - and they get to the point of painful dysfunction far earlier than the rest of our organs if left to their own devices.

But that isn't aging - it's parasitism, no more aging than the consequences of contracting malaria. It's still something we need to fix, of course, and I post on this and related topics because it is of general interest to anyone who follows research into rejuvenation and regeneration. If most or all of us suffer a particular form of bacterial malfeasance that manages to be as damaging as that which chews upon our teeth, than dealing with that problem has to be included in any general toolkit for enhanced human longevity.

As an aside, I should note that the hard components of teeth do age:

enamel thickness related to age showed a steady decrease, beginning at approximately age 50.

There are apparently chemical composition changes, increased brittleness, and so forth - none of which seems to have much to do with the bacteria that cause cavities.

Another completely unrelated grey area is something I touch on frequently: the structural changes that take place in the due to exposure to infectious agents. The adaptive component of the immune system performs throughout life just as it evolved to do - which means it devotes space and cells to remembering the pathogens it has encountered so that it can effectively destroy them in the future. But by continuing to function in this way, it becomes less and less effective over time: in later life too much of its capacity is taken up with memory cells and too little with killer cells. So quite aside from what we might think of as biological aging, the adaptive immune system succeeds itself into an increasingly broken state just by doing its job. Whether or not we call this process aging, it still has to be fixed, auch as by using targeted cell destruction therapies to eliminate memory cells and free up space.

There are other examples. But you get the point: not all of the degenerations that we suffer with advancing age are in fact aging per se, or at least they will not fit into the usefully narrow definitions of aging that I find helpful. They will still need to be addressed, prevented, and their consequences repaired.

From h+ Magazine: "As serious life extension appears on an ever nearer horizon simultaneous with a period of social and economic rebellion and an increasing sense of global chaos, this may be a good time to entertain these anxieties while thinking beyond the two extant competing simplistic arguments. The current conflicting views seem to be these: A: Hyperlongevity will be for rich people only and we can't afford to add to the population vs. B: Technologies get distributed to more and more people at an increasing rate of speed through the auspices of the free market. Demand increases. Production increases. The price gets lower. Demand increases. Production increases. The price gets lower... ad infinitum. In fact, the wealthy who are the early adopters of a new technology get to spend a lot of money on crappy versions of new technologies that are not ready for prime time. At the risk of being obvious, it seems like there's a lot of room in the middle for more nuanced, less certain views. ... Very few people would say that we shouldn't cure cancer or heart disease because only the wealthy will be able to afford it - and those who did would be seen by most as anti-human and/or insufferably whiny. Seen in this light, it becomes obvious that this whole 'only the rich will get hyperlongevity' mentality is pathetic in the extreme - a concession of defeat before the outset. If you think optimal health and longevity should be distributed, you won't say, 'Well, it won't be distributed so I'm against it.' You will try to make sure it gets distributed. Whether you believe in medical care for all through government or pushing these solutions towards a very large mass market or creating an open source culture that takes production and distribution into its own decentralized hands, you'll work or fight for one or several (or all) of these solutions."

Link: http://hplusmagazine.com/2011/11/15/live-long-and-prosper-umm-well-get-back-to-you-on-that-prosper-bit/

Teeth are one of the first parts of our body to become seriously damaged as the years go by, thanks to bacterial agents, but that will soon enough be a thing of the past. On the one hand enamel regeneration is close to realization, and on the other hand so are ways of eliminating the agents of tooth decay: "A new mouthwash developed by a microbiologist at the UCLA School of Dentistry is highly successful in targeting the harmful Streptococcus mutans bacteria that is the principal cause tooth decay and cavities. In a recent clinical study, 12 subjects who rinsed just one time with the experimental mouthwash experienced a nearly complete elimination of the S. mutans bacteria over the entire four-day testing period. ... This new mouthwash is the product of nearly a decade of research conducted by Wenyuan Shi ... Shi developed a new antimicrobial technology called STAMP (specifically targeted anti-microbial peptides) [which] acts as a sort of 'smart bomb,' eliminating only the harmful bacteria and remaining effective for an extended period. ... With this new antimicrobial technology, we have the prospect of actually wiping out tooth decay in our lifetime."

Link: http://www.sciencedaily.com/releases/2011/11/111116045657.htm

Loss of the p66(Shc) gene is a canonical example of the rampant complexity of metabolism when it comes to determinants of longevity. If you look back in the Fight Aging! archives, you'll see what I mean: years of work on p66(Shc) mutant mice that piles higher with each new paper, an accumulation of mechanisms, alterations, chains of cause and effect, altered feedback loops, and so forth - all spawned from knocking out this one gene.

It is the height of optimistic hubris to suppose that we'll be safely tinkering with human metabolism in the same way any time soon - which is one of the reasons why efforts to merely slow aging are the slow boat to China. The fast path is to work on ways to repair our existing metabolism; don't change it, just find methods to put it back the way it was when we were young. A great deal more is known about how to go about reversing aging than is known about how to slow aging.

But I digress, as I really did want to talk about p66(Shc). In addition to being a poster child for the complexities of metabolism and genetic determinants of longevity, this gene also turns out to be a good example to draw upon when explaining why it is that there are so many small genetic tweaks capable of extending life in mice. Why didn't evolution select for these small modifications in the first place? See this paper for a starting point:

Deletion of the p66(Shc) gene results in lean and healthy mice, retards aging and protects from aging-associated diseases, raising the question of why p66(Shc) has been selected, and what is its physiological role. We have investigated survival and reproduction of p66(Shc) -/- mice in a population living in a large outdoor enclosure for a year, subjected to food competition and exposed to winter temperatures. Under these conditions deletion of p66(Shc) was strongly counterselected. Laboratory studies revealed that p66(Shc) -/- mice have defects in fat accumulation, thermoregulation and reproduction, suggesting that p66(Shc) has been evolutionarily selected because of its role in energy metabolism. These findings imply that the health impact of targeting aging genes might depend on the specific energetic niche and caution should be exercised against premature conclusions regarding gene functions that have only been observed in protected laboratory conditions.

So in other words, lack of p66(Shc) only extends life and causes the mutants to prosper as individuals if they have the benefits of civilization and technology: secure food supplies, secure heating, protection from the elements, and so forth. If shoved out into the uncaring world, they fare poorly - and would soon enough vanish as a genetic line, out-competed by animals with shorter life spans but a better adapted metabolism. We might expect to see similar results for the range of other longevity genes discovered in small mammals: if there was an evolutionary benefit to their selection for animals in the wild, then we should expect that these longevity mutations would already have been selected.

Is this result anything other than just interesting for those of us following along at home? Well, it might help to further inform out thinking as to the odds of significant human longevity mutations - which I suspect are low, by the way, though I do think there will be many minor longevity genes found in humans, with very limited effects. We are already unusually long-lived for primates, and primates are long-lived in comparison to other similarly sized mammals, and that seems to have squeezed down the range of life span differences that can be created through metabolic tinkering - or at least this is currently the consensus based on what is known of the effects of calorie restriction on metabolism and health in humans.

As knowledge of cellular programming and signaling systems increases, the future of cell therapies will most likely move away from transplants and towards controlling existing populations of cells in the body: "In order to regenerate damaged heart muscle as caused by a heart attack [simpler] vertebrates like the salamander adopt a strategy whereby surviving healthy heart muscle cells regress into an embryonic state. This process, which is known as dedifferentiation, produces cells which contain a series of stem cell markers and re-attain their cell division activity. Thus, new cells are produced which convert, in turn, into heart muscle cells. The cardiac function is then restored through the remodelling of the muscle tissue. An optimised repair mechanism of this kind does not exist in humans. Although heart stem cells were discovered some time ago, exactly how and to what extent they play a role in cardiac repair is a matter of dispute. It has only been known for a few years that processes comparable to those found in the salamander even exist in mammals. ... [Researchers have] now discovered the molecule responsible for controlling this dedifferentiation of heart muscle cells in mammals. The scientists initially noticed the high concentration of oncostatin M in tissue samples from the hearts of patients suffering from myocardial infarction. It was already known that this protein is responsible for the dedifferentiation of different cell types, among other things. ... Using a mouse infarct model, the [researchers] succeeded in demonstrating that oncostatin M actually does stimulate the repair of damaged heart muscle tissue as presumed. One of the two test groups had been modified genetically in advance to ensure that the oncostatin M could not have any effect in these animals. ... The difference between the two groups was astonishing. Whereas in the group in which oncostatin M could take effect almost all animals were still alive after four weeks, 40 percent of the genetically modified mice had died from the effects of the infarction."

Link: http://www.sciencedaily.com/releases/2011/11/111111095220.htm

Here is an interesting application of cell therapy, which demonstrates the point that an artificial replacement for an organ doesn't necessarily have to replicate the form and structure of that organ: "Eight-month-old Iyaad Syed now looks the picture of health - but six months ago he was close to death. A virus had damaged his liver causing it to fail. Instead of going on a waiting list for a transplant, doctors injected donor liver cells into his abdomen. These processed toxins and produced vital proteins - acting rather like a temporary liver. The cells were coated with a chemical found in algae which prevented them from being attacked by the immune system. After two weeks his own liver had begun to recover. ... The question now is whether the technique could be used to benefit other patients with acute liver failure. The team [is] urging caution - a large clinical trial is needed to test the effectiveness of the technique. ... The principle of this new technique is certainly ground-breaking and we would welcome the results of further clinical trials to see if it could become a standard treatment for both adults and children."

Link: http://www.bbc.co.uk/news/health-15744176

The US Food and Drug Administration is a ball and chain holding back progress; its policies form a straitjacket of regulation that is heavy and stifling even by modern Western standards of governance, in which bureaucratic bodies intervene aggressively in near every aspect of life and economic activity. Interventions in clinical development, scientific research, and application of medical products impose staggering costs, and so what little can get through the onerous FDA process is made very expensive. But costs come in more forms than just the financial - there are the many beneficial forms of medicine that are simply not developed, or that exist but are not available in the US because FDA regulations make it impossible to offer them profitably. There is the research that is not funded because the end results cannot be brought to the clinic under present FDA rules.

That last point is particularly important for longevity science and the future of rejuvenation biotechnology. It is illegal in the US to bring therapies for aging to the clinic, because the FDA doesn't recognize aging as a legitimate use for medicine. Medical research moves fast these days, but it can still take five to ten years and millions of dollars in lining lobbyists' and politicians' pockets to get the FDA to recognize a new medical condition - which is only the start of spending hundreds of millions more to jump through the largely unnecessary hurdles of clinical trials as they are presently structured.

The FDA, like all bureaucratic organizations, long ago came to serve its own continuance above and beyond all other goals. Its own continuance as a political organization depends on releasing as few new medical advances as possible. Approval of medicine that never causes problems gains the bureaucrats no reward, while approval of medicine that does at some point cause problems results in punishment - there is no such thing as an absolutely safe medicine, of course, and the popular media will pillory the FDA for events that are well within the expected range of risk and reward in medicine. A low rate of approval of new technologies causes little harm to the bureaucrats, in comparison, and thus is acceptable for their needs, which is to say a job and a career. Thus the self-interest of those in charge of the FDA at all levels leads to an organization structured to actively sabotage its original goals; this is more or less the place in which all government organizations wind up.

In any case, here is an example of the cost of the FDA, with some numbers, and a line of research abandoned as being too expensive under the present regulations:

Biotechnology firm Geron said last night that it would discontinue its stem-cell research program and halt a pioneering clinical study in people with spinal-cord injury. The decision brings to a halt the world's largest and longest-running program to develop medical treatments from embryonic stem cells, versatile cells able to form many other types of human tissue.

...

The company denied it had given up on stem cells for scientific reasons. "We're not doing this because we were souring on the field, or as a result of any problems - we have not had any safety issues at all," Scarlett told Bloomberg news.

...

The attempt to study stem cells in humans had proved stupendously expensive and slow-moving for Geron. The company estimated that it spent $45 million just to win FDA approval for the initial safety trial of its treatment, known as GRNOPC1. As of October, however, only four patients had been treated, and the company would have had to spend tens of millions more in order to finish the study.

We can be fairly certain that, because embryonic stem cells were a political topic for some years, career-minded heads at the FDA found all sorts of ways to make it more costly for Geron to satisfy their requirements, and at greater cost. If a bureaucrat sees a raised likelihood of review, blame, and greater attention, then he will require far more effort from those he is regulating. More data, more cast iron assurances, more studies, and so forth. Though of course if you read much of the mainstream press on the topic, you'll see no commentary on the role of the FDA and the related costs in this end result. A cynic would not be surprised.

Autophagy is a collection of similar processes for cellular housekeeping: recycling broken components so that they can't cause harm. More autophagy means a better running biological machine, and that in turn brings enhanced longevity. Aging, after all, is really nothing more than the accumulation of unrepaired biological damage. Here is another example of this principle in action: "Evidence for a regulatory role of the miR-34 family in senescence is growing. However, the exact role of miR-34 in aging in vivo remains unclear. Here, we report that a mir-34 loss-of-function mutation in Caenorhabditis elegans markedly delays the age-related physiological decline, extends lifespan, and increases resistance to heat and oxidative stress. We also found that RNAi against [autophagy-related genes] significantly reversed the lifespan-extending effect of the mir-34 mutants. Furthermore, miR-34a inhibits [gene expression of an autophagy-related gene] at the post-transcriptional level in vitro ... Our results demonstrate that the C. elegans mir-34 [loss of function] mutation extends lifespan by enhancing autophagic flux in C. elegans, and that miR-34 represses autophagy by directly inhibiting the [expression of autophagy-related genes] in mammalian cells."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22081425

More evidence for the utility of early stage stem cell therapies of the sort that have been available overseas through medical tourism for a number of years, and which would also be available in the US if not for the FDA: "16 patients with severe heart failure received a purified batch of cardiac stem cells. Within a year, their heart function markedly improved. The heart's pumping ability can be quantified through the "Left Ventricle Ejection Fraction," a measure of how much blood the heart pumps with each contraction. A patient with an LVEF of less than 40% is considered to suffer severe heart failure. When the study began, Bolli's patients had an average LVEF of 30.3%. Four months after receiving stem cells, it was 38.5%. Among seven patients who were followed for a full year, it improved to an astounding 42.5%. A control group of seven patients, given nothing but standard maintenance medications, showed no improvement at all. ... We were surprised by the magnitude of improvement. ... [Elsewhere] 17 patients [were] given stem cells approximately six weeks after suffering a moderate to major heart attack. All had lost enough tissue to put them 'at big risk' of future heart failure ... The results were striking. Not only did scar tissue retreat - shrinking [between] 30% and 47% - [but] the patients actually generated new heart tissue. On average, the stem cell recipients grew the equivalent of 600 million new heart cells .... By way of perspective, a major heart attack might kill off a billion cells. ... the heart contains a type of stem cell that can develop into either heart muscle or blood vessel components - in essence, whatever the heart requires at a particular point in time. The problem for patients [is] that there simply aren't enough of these repair cells waiting around. The experimental treatments involve removing stem cells through a biopsy, and making millions of copies in a laboratory."

Link: http://www.cnn.com/2011/11/14/health/stem-cells-heart-damage-reverse/

A while back I mentioned the Methuselah Generation, a documentary film on progress on longevity science and the future of the human life span. The more of this sort of media project underway the better, I think - the state of the science really just sells itself once you kick people into waking up and thinking about the topic of aging and rejuvenation biotechnology. The trick is to make this something that people are talking about and thinking about.

In any case, the Methuselah Generation filmmakers recently drew my attention to their Kickstarter fundraising page:

The Methuselah Generation is a 3D documentary about the science, philosophy, and implications of the coming age of extremely long-lived humans. It profiles the lives and work of scientists who are attempting to create new technologies that can bring about a new age in humanity, and explores their motivations and personal beliefs. Our film will ask (and attempt to answer) profound questions about longevity as it pertains to humanity, the environment and economics. And even if you don't believe that life extension is possible, the stories and the people involved in the science will fascinate you in this great cinematic treat.

Kickstarter is an all or nothing proposition: either they raise the minimum funding by the set date, $30,000 by December 26th in this case, or none of the funds are released. It's a good system for ensuring a certain minimum level of achievement for a donor's funds - if too little is raised to ensure a good shot at the project then your money is released to be used elsewhere.

On that note, I'm still awaiting the arrival of a Kickstarter for scientific research with some eagerness. There are a number of possible candidate ventures and prototypes in progress (such as SciFund, for example), but I don't think any have achieved the necessary level of validation in the marketplace. Crowdfunding clearly has an important role in the future of fields like biotechnology, where is very possible to perform useful research projects for a few tens of thousands of dollars. Building clearing houses for that funding process is a necessary step to see it gain more traction.

The Parkinson's research community may turn out to be an ally in efforts to develop mitochondrial repair technologies suitable for use in rejuvenation: "genetic mutations causing a hereditary form of Parkinson's disease cause mitochondria to run amok inside the cell, leaving the cell without a brake to stop them. ... Mitochondria, when damaged, produce reactive oxygen species that are highly destructive, and can fuse with healthy mitochondria and contaminate them, too ... Normally, when mitochondria go bad, PINK1 tags Miro, [a protein which literally hitches a molecular motor onto the organelle], to be destroyed by Parkin and enzymes in the cell, the researchers showed. When Miro is destroyed, the motor detaches from the mitochondrion. The organelle, unable to move, can then be disposed of: The cell literally digests it. But when either PINK1 or Parkin is mutated, this containment system fails, leaving the damaged mitochondria free to move about the cell, spewing toxic compounds and fusing to otherwise healthy mitochondria and introducing damaged components. ... The study's findings are consistent with observed changes in mitochondrial distribution, transport and dynamics in other neurodegenerative diseases ... Whether it's clearing out damaged mitochondria, or preventing mitochondrial damage, the common thread is that there's too much damage in mitochondria in a particular brain region. ... [Researchers are] interested in the possibility of helping neurons flush out bad mitochondria or make enough new, healthy mitochondria to keep them viable."

Link: http://www.sciencedaily.com/releases/2011/11/111110142104.htm

The latest Cryonics issue is out: "The 2011 4th quarter issue of Cryonics magazine is dedicated to the 'father of cryonics,' Robert Ettinger, who was cryopreserved on July 23, 2011. Alcor staff member Mike Perry contributes an historical piece on Ettinger and Mark Plus and Charles Platt write about his influence on contemporary cryonics, futurism, and the cryobiology community. Cryonics editor Aschwin de Wolf compiled Robert Ettinger's mature thoughts on the feasibility of 'mind uploading' and situates his outlook in a broader philosophical context. This issue also features a detailed article by the Alcor Board of Directors and Management about member underfunding and its associated challenges for Alcor's long-term financial health. Alcor member, and prolific science fiction writer, Gregory Benford is featured in this issue's member profile."

Link: http://www.alcor.org/magazine/2011/11/11/cryonics-4th-quarter-2011/

Armed with newer, cheaper, and better biotechnologies, researchers can measure ever more of the detailed effects of good health practices such as regular exercise, calorie restriction, and the like. It is possible now to examine the workings of metabolism in any specific part of the body in very great detail, all the way down to the molecular machinery in our cells, see how it changes with age, and see how those changes differ with different lifestyle choices. Or at least this can be done in mice - in humans, more statistical work is required to use today's technology to pull apart the differences between young and old, exercising and sedentary. The option to wait around for sizable portions of a human life span isn't there, after all; science moves faster than that.

Here is an open access paper that measures a little more of the effects of exercise, and along the way provides yet another compelling argument to be someone who exercises rather than someone who sits around growing ever more unfit with each passing year:

Healthy brain aging and cognitive function are promoted by exercise. The benefits of exercise are attributed to several mechanisms, many which highlight its neuroprotective role via actions that enhance neurogenesis, neuronal morphology and/or neurotrophin release. However, the brain is also composed of glial and vascular elements, and comparatively less is known regarding the effects of exercise on these components in the aging brain. Here, we show that aerobic exercise at mid-age [also] counters several well-established glial markers of brain aging. Similarly, we show that age-related changes in neurovascular morphology and function were reduced with exercise.

...

Thus, our results show that exercise can potentially mitigate progressive age-related changes in several key non-neuronal elements of the brain. Further, we show that these brain processes are still highly responsive to exercise in the midlife age range, consistent with studies showing that cognitive function can benefit from exercise even if initiated at later ages.

It's never to late to start on exercise. In the future, there will be rejuvenation biotechnologies capable of restoring the old to youthful health and vigor by repairing the low-level biological damage that causes aging. This will happen, I assure you - and it will be one of the least of the amazing new things to arrive in the years ahead. But human rejuvenation will almost certainly arrive later that either you or I desire, and until such time as it does become widely available the best things you can do for your own personal future of health and longevity are pretty primitive - lifestyle choices and supporting research and development.

All told, the better you do with the cards you have now, the more likely you are to live to benefit from the future of longevity-enhancing medicine. So do better.

Via EurekAlert!: researchers "created super strong, marathon mice and nematodes by reducing the function of a natural inhibitor, suggesting treatments for age-related or genetically caused muscle degeneration are within reach. It turns out that a tiny inhibitor may be responsible for how strong and powerful our muscles can be. ... By acting on a receptor (NCoR1), [researchers] were able to modulate the transcription of certain genes, creating a strain of mighty mice whose muscles were twice a strong as those of normal mice. ... By genetically manipulating the offspring of [mice and nematodes], the researchers were able to suppress the NCoR1 corepressor, which normally acts to inhibit the buildup of muscle tissues. ... In the absence of the inhibitor, the muscle tissue developed much more effectively. The mice with the mutation became true marathoners, capable of running faster and longer before showing any signs of fatigue. In fact, they were able to cover almost twice the distance run by mice that hadn't received the treatment. They also exhibited better cold tolerance. Unlike previous experiments with so-called super mice, this study addresses the way energy is burned in the muscle and the way the muscle is built. Examination under a microscope confirmed that the muscle fibers of the modified mice are denser, the muscles are more massive, and the cells in the tissue contain higher numbers of mitochondria - cellular organelles that deliver energy to the muscles. Similar results were also observed in nematode worms, allowing the scientists to conclude that their results could be applicable to a large range of living creatures."

Link: http://www.eurekalert.org/pub_releases/2011-11/epfd-tag110711.php

Michael Rae is the co-author of Ending Aging, a research assistant at the SENS Foundation, and a long-standing figure of note in the calorie restriction community: "I would say that one exciting recent development is that, with an increase in our research budget this year (based on performance last year and a more optimistic financial outlook from many of our donors), we've recently approved funding for several quite important and exciting research projects. One is a project whose ultimate aim is to tissue engineer a new thymus. The thymus is a gland located near the breast bone, where T-cells (an important immune cell) mature. The thymus shrinks with age, and the tissues on the outer layer of the organ where T-cells mature lose their architectural integrity, leading to a progressive failure to produce new T-cells to fight novel infections. The thymus engineering project, which is underway with SENS Foundation support at the Wake Forest University Institute for Regenerative Medicine by Dr. John Jackson and colleagues, is to use a trick that you may have heard of having been used to make a new rat heart using the tissue scaffolding of another's. ... The fifth SENS Conference was, indeed, quite amazing! Unlike the previous conference, this time much more of the work being presented had already been published; it was none the less remarkable to see just how much had been accomplished in the last year, from restoring cognitive function in a mouse model of Alzheimer's disease using a drug that boosted up the ability of their brains' lysosomes ('garbage disposal systems' as it were) to break down the sticky beta-amyloid protein [to] a just-begun study on a very bold and ambitious way [to] restore the loss of cells and degraded circuitry of the aging neocortex (the area of the brain where, arguably, our highest, most 'human' cognitive activity occurs)."

Link: http://www.digitaljournal.com/article/314216

Naked mole rats are of interest to researchers because they can live nine times as long as comparable rodent species: this implies that they are a good place to look for determinants of longevity and important mechanisms of aging. You can go far in biology by comparing similar species that nonetheless exhibit sharply defined differences in your area of interest. The naked mole rat genome was sequenced and published this year, but research into the genetics of aging in the species that predates the availability of the full genome is still arriving at the presses. For example, there is this open access paper:

RNA Sequencing Reveals Differential Expression of Mitochondrial and Oxidation Reduction Genes in the Long-Lived Naked Mole-Rat When Compared to Mice

The naked mole-rat is not only the longest-lived rodent, but has a much longer lifespan than expected for its relatively small body size and has been shown to be extremely resistant to neoplasia. Furthermore, since a number of other rodents including mice, rats and guinea pigs already have had their genome sequenced, the naked mole-rat is a prime candidate for comparative genomics studies. ... Using a combination of 2nd-generation sequencing platforms, [we] were able to compare gene expression between wild-derived mice and naked mole-rats without using a naked mole-rat reference genome.

Gene expression is the process by which proteins are produced from the DNA blueprint. How much of any given protein is produced at any given time, and how that changes over time and in response to circumstances, is at least as important as what the protein is. Examining different levels of protein production between neighboring species is a good way to narrow down the biological mechanisms that explain their differences. In this case:

Within over-expressed genes in the naked mole-rat, genes associated with oxidoreduction were strongly overrepresented as well as genes associated with mitochondria and more specifically mitochondrial matrix. Consistent with the free radical theory of ageing, the over-expression of genes related to oxidoreduction could protect the naked mole-rat from reactive oxygen species. [With caveats, and] in view of the hypothesis that mitochondria play a major role in mammalian ageing, these results point towards a putative role for oxidoreduction and mitochondrial alterations in the long lifespan of the naked mole-rat.

You might compare this view with the membrane pacemaker hypothesis, that has naked mole rat longevity stemming from the fact that vulnerable cell components such as mitochondria are have a composition that renders them resistant to damage caused by free radicals, the reactive byproducts of cellular-fuel-generation taking place within mitochondria. The mitochondria themselves are the first target for those free radicals, and if you look back in the Fight Aging! archives, you'll find an explanation as to how damage to mitochondria can spiral into damage throughout the body - and hence aging.

A good demonstration of the state of the art of tissue engineering: "Last spring, a research team at Japan's RIKEN Center for Developmental Biology created retina-like structures from cultured mouse embryonic stem cells. This week, the same group reports that it's achieved an even more complicated feat - synthesizing a stem-cell-derived pituitary gland. The pituitary gland is a small organ at the base of the brain that produces many important hormones and is a key part of the body's endocrine system. It's especially crucial during early development, so the ability to simulate its formation in the lab could help researchers better understand how these developmental processes work. ... The experiment wouldn't have been possible without a three-dimensional cell culture. The pituitary gland is an independent organ, but it can't develop without chemical signals from the hypothalamus, the brain region that sits just above it. With a three-dimensional culture, the researchers could grow both types of tissue together, allowing the stem cells to self-assemble into a mouse pituitary. ... Using this method, we could mimic the early mouse development more smoothly, since the embryo develops in 3-D in vivo. ... Fluorescence staining showed that the cultured pituitary tissue expressed the appropriate biomarkers and secreted the right hormones. The researchers went a step further and tested the functionality of their synthesized organs by transplanting them into mice with pituitary deficits. The transplants were a success, restoring levels of glucocorticoid hormones in the blood and reversing behavioral symptoms, such as lethargy."

Link: http://www.technologyreview.com/biomedicine/39108/

Tengion is one of the research groups attempting to tissue engineer replacement sections of intestine: "Tengion has demonstrated that smooth muscle cells seeded on its biological scaffolding and then implanted in rodents exhibit functional regeneration of both the inner lining of epithelial cells and the surrounding layers of small intestine smooth muscle cells in as little as eight weeks post-implantation. ... The regeneration of small intestine from smooth muscle cells using our technology platform represents an important step forward in the development of functional, regenerated organs. Our goal is to translate preclinical data and proof of concept findings into clinical programs that could represent a broad range of medical treatment possibilities for patients in need of new bladders, kidneys and other organs. ... In this preclinical study, patch and tubular constructs were implanted in rodent small intestines and histologically evaluated for evidence of regeneration of the neo-mucosa and muscle layers. In as little as eight weeks post-implantation, laminarly organized neo-mucosa and muscle layer bundles were demonstrated, supporting the approach of using autologous smooth muscle cells and biomaterial combination products to spur regeneration of the small intestine. Patients with short bowel syndrome have typically undergone extensive small intestine resectioning and may become dependent on parenteral nutrition, a costly treatment associated with multiple complications, and could potentially benefit from a regenerative medicine approach."

Link: http://www.marketwatch.com/story/tengion-organ-regeneration-platform-technology-demonstrates-ability-to-regenerate-small-intestine-in-preclinical-models-data-published-in-regenerative-medicine-2011-11-07

The best communities involved in advocacy and outreach are balanced somewhere between eagerness ("It's all so obvious, look what we could achieve!") and frustration ("But it's all so obvious - why don't they get it?"). Advocacy is hard despite its simplicity and time-worn, well-understood nature: it is hard because it is slow and incremental toil at the best of times, the human relations equivalent of banging two rocks together to make fire. You talk to people, you persuade people to your way of looking at things over and over and over again, making tiny little gains each time. For longevity science, the people willing to do this work are generally the bright sparks, the early adopters and foresightful folk who see the opportunity to defeat aging, see how plausible it is, and are full of enthusiasm for this goal. They are then run into the meatgrinder of tiny, incremental progress in persuading the world one person at a time.

Occasionally this isn't pretty, and hence the frustration. None of us are getting any younger, and while the science is so very obviously heading the right direction to produce working rejuvenation biotechnology, it is doing so very, very slowly. Only a minuscule fraction of the scientific community are working on relevant projects, there is next to no funding, and only a minuscule fraction of the public at large care one way or another. That needs to change, and changing it is slow going.

Here's some frustration from the Russian side of the community, translated, and further smoothed out by my edits:

It's aging that kills people. Also it's stupidity and greed that kill people. It exactly the stupidity and greed that prevents people from doing much to survive. The society spends an abysmally small amount of effort on life extension. Minimal interest and microscopic funding goes to studying of fundamental mechanisms of aging. Resources are being spent on any any old thing, but not on longevity. Years go by, and people become dung and rot in their graves. Because of their own stupidity and imbecility of others.

Almost everyone who comes to somebody's funeral should keep saying: "We are the sick people, we killed you by our passivity. Moreover, we keep on bringing death further on. The thought to identify the underlying reasons of death and to try to eliminate them doesn't even sneak into our empty minds. It's actually only money and pleasure that matter to us, and in indulging that we seek our own death."

I would have written "ignorance" in place of "stupidity," but Russian has a somewhat different set of overlapping meanings for words involving lack of knowledge, poor application of knowledge, and lack of intelligence. "Foolishness" or "unreasonableness" is as good a translation as "stupidity" from the original, I think. To my eyes people are rarely forthrightly stupid, but the small slice of attention that a person gives to matters outside his focus looks stupid from a distance - and most people give next to no attention to longevity science. That is foolish in this day and age, as it amounts to remaining blind to a tremendous opportunity just because you didn't take a small amount of time and effort to check on it.

There is a brass ring to be grasped: as someone who has spent a fair amount of time following the science and biotechnology, I can say with some conviction that it is clearly possible for us to engineer our way to agelessness in stages within a few decades from where we stand today. To do that, however, will require radical success in advocacy, fundraising, and growing the longevity science community over the next ten years.

Thus frustration stems from the size of the opportunity, the sheer obviousness of the imperative to defeat aging once you grasp it, and the feeling that the opportunity to achieve this goal in our lifetimes might be slipping from our grasp despite our progress to date. That's what things look like in the early stages of an exponential growth curve; it seems as though you'll never get there in time, but it takes off late in the game. Unfortunately it's also what things look like in the early stages of linear growth that will remain small - see the cryonics community, for example. We can't tell how the future will turn out, but we have to keep coming back to work at building it: the way to ensure the next few decades go badly for longevity science is to fail to try to do better.

You can't blame the rest of the world for not listening if you're not talking to them in the right way.

A good example of the next generation of targeted cancer therapies is outlined at the Technology Review: "scientists at the National Cancer Institute have developed a possible solution that involves pairing cancer-specific antibodies with a heat-sensitive fluorescent dye. The dye is nontoxic on its own, but when it comes into contact with near-infrared light, it heats up and essentially burns a small hole in the cell membrane it has attached to, killing the cell. To target the tumor cells, the researchers used antibodies that bind to proteins that are overexpressed in cancer cells. ... Normal cells may have a hundred copies of these antibodies, but cancer cells have millions of copies. That's a big difference. ... The result is that only cancer cells are vulnerable to the light-activated cascade. ... The researchers tested the new treatment in mice and found that it reduced tumor growth and prolonged survival. There are a few kinks to work out before the system can be adapted for humans, though. For instance, the researchers couldn't test the treatment's effect on large tumors, since killing off too many cells at once caused cardiovascular problems in the mice. Finding the right cancer-cell markers to pair with the dye may also prove difficult. For example, HER-2, one of the proteins targeted in the study, is only expressed in 40 percent of breast-cancer cells in humans. Still, the lack of toxicity associated with the treatment is a huge advantage,"

Link: http://www.technologyreview.com/biomedicine/39082/

A human interest piece on research into the genetics and biochemistry of centenarians amongst the Ashkenazi Jewish population: "Irving Kahn is about to celebrate his 106th birthday. He still goes to work every day. Scientists are studying him and several hundred other Ashkenazim to find out what keeps them going. And going. And going. ... The world's oldest stockbroker, he first went to work on Wall Street in 1928. ... Still, a man who at 105 - he'll be 106 on December 19 - has never had a life-threatening disease, who takes no cholesterol or blood-pressure medications and can give himself a clean shave each morning (not to mention a 'serious sponge bath with vigorous rubbing all around'), invites certain questions. Is there something about his habits that predisposed a long and healthy life? (He smoked for years.) Is there something about his attitude? (He thinks maybe.) Is there something about his genes? (He thinks not.) And here he cuts me off. He's not interested in his longevity. But scientists are. ... Pharmaceutical companies and the National Institutes of Health are throwing money into longevity research. Major medical centers have built programs to satisfy the demand for data and, eventually, drugs. Irving himself agreed to have his blood taken and answer questions for the granddaddy of these studies, the Longevity Genes Project at Albert Einstein College of Medicine in the Bronx, which seeks to determine whether people who live healthily into their tenth or eleventh decade have something in common - and if so, whether it can be made available to everyone else."

Link: http://nymag.com/print/?/news/features/ashkenazi-jews-2011-11/

The future of your health is a matter of chance and likelihood: you have the power to shape that statistical landscape through good lifestyle choices and strategies such as helping to fund research into rejuvenation biotechnology and signing up with a cryonics provider - but nothing is a certainty. You can shift your chances, shift your life expectancy (itself a statistical measure), but you can't entirely remove happenstance and sheer bad luck. You are far better off by making and following good plans, but bad end results are still possible.

For example, even someone who signs up to be cryopreserved and does a good job of managing the organization of his own cryosuspension at the end of life can still be cut short by bad luck:

Alcor member A-1088, Dennis Ross, was pronounced legally dead on Sunday October 30, 2011. A neurocryopreservation, Mr. Ross became Alcor's 108th patient. Alcor received emergency notification that a member in the St. Petersburg, Florida area had been rushed to the hospital on Friday, October 28th and was diagnosed with a massive intracerebral hemorrhagic stroke due to a ruptured brain aneurysm.

Suspended Animation (SA) went to the hospital and began to prepare for a probable cryonics case. Through medical imaging on October 30, physicians determined the individual's brain damage was so extensive they declared him brain-dead. After the family decided to withdraw life support, SA performed field stabilization and attempted washout; however their success was limited due to the compromised blood flow of the brain. SA completed a neuroseparation before shipping the anatomical donation on dry ice to Alcor.

It's important to recognize that, despite best reasonable efforts, the possibility remains that we are going to be betrayed by our own biology in the end. The quote above is an unfortunate example of the type, in which the patient suffered a brain-damaging end of life incident that will greatly reduce the possibility of a good cryopreservation - and that despite high quality support from medical staff and everyone else involved in organizing the response. You'll recall that the point of cryonics is to preserve the fine structure of the brain, within which is the data that makes up the mind - keep that and none of the other damage matters in the long term. But the more neural damage that occurs prior to cooling, the worse the end result will be.

So the best preparation in the world can be sabotaged by the body breaking down in exactly the wrong way at the end of life. All we can do is strive to minimize the risks. In the case of cryonics, many of these late stage risks exist because Western legal systems make it impossible for people and services to collaborate in order to arrange the time and manner of death. Self-determination in end of life choices, and the ability to help people enact those choices, would make cryopreservation of the old and frail far less expensive and far less subject to risk of neural damage. This is just one of countless injustices and losses of freedom inherent in modern governance and law.

But back to the original point: the best we can do is to work to minimize risk. Risk cannot be removed entirely, and we all live in fragile bodies.

Yet another reason to try to minimize chronic inflammation, such as that generated by excess fat tissue: researchers "have shown that the development of osteoarthritis is in great part driven by low-grade inflammatory processes. This is at odds with the prevailing view attributing the condition to a lifetime of wear and tear on long-suffering joints. ... It's a paradigm change. People in the field predominantly view osteoarthritis as a matter of simple wear and tear, like tires gradually wearing out on a car. [It] also is commonly associated with blow-outs [such] as a tear in the meniscus - a cartilage-rich, crescent-shaped pad that serves as a shock-absorber in joints - or some other traumatic damage to a joint. ... [The] findings offer hope that by targeting the inflammatory processes that occur early on in the development of osteoarthritis - well before it progresses to the point where symptoms appear - the condition might someday be preventable. ... initial damage to the joint sets in motion a chain of molecular events that escalates into an attack upon the damaged joint by one of the body's key defense systems against bacterial and viral infections, the so-called complement system. This sequence of events involves activation of a chain reaction called the 'complement cascade,' and begins early in the development of osteoarthritis. ... An early clue regarding the complement system's key role in osteoarthritis came when [researchers] compared the levels of large numbers of proteins present in the joint fluid taken from osteoarthritis patients with levels present in fluid from healthy individuals. They found that the patients' tissues had a relative overabundance of proteins that act as accelerators in the complement cascade, along with a dearth of proteins that act as brakes."

Link: http://www.eurekalert.org/pub_releases/2011-11/sumc-orf110711.php

Here's a long and detailed post from the SENS Foundation on the recent demonstration of the benefits of senescent cell destruction: "studies involving the use of putative 'premature aging' models must be interpreted with caution ... In the case of this new report, however, while caution is still merited, the nature of the intervention used makes the study relatively free of such complications. The investigators did not simply modulate or normalize the very thing that the mutation (in this case, to the mitotic checkpoint component BubR1) itself disrupts, as in other widely-publicized studies involving putative 'accelerated aging'. Rather, the defective checkpoint system was left to proceed, and one of its downstream consequences, which was still under normal regulation - and one known to be directly induced by the normal degenerative aging process - was reversed at the structural level, by clearing out the p16Ink4a-positive senescent cells that had accumulated to an abnormal degree in their tissues. This left some aspects of the abnormal 'progeroid' phenotype in these organisms (the cardiovascular defects) intact, but illustrated the dysfunctional consequences of having tissues riddles with such cells. While still of abnormal origin, there is no strong reason to think that the ongoing effects of a rising burden of such cells would not be similar - and thus, that the effects of ablating such cells are uninformative about the effects of a similar intervention in 'normally' aging bodies. ... How might the results of this intervention be translated for human rejuvenation therapies? ... SENS Foundation is currently funding work by Dr. Kevin Perrot in Campisi's laboratory, screening compounds for their effectiveness in eliminating cells exhibiting the classical senescence-associated secretory phenotype."

Link: http://sens.org/node/2449

Video of presentations from the SENS5 conference continue to be posted to the SENS Foundation YouTube channel. Here are two of the latest.

Adipose tissue is at the nexus of processes involved in healthspan and metabolic dysfunction. Progression of age-related fat tissue dysfunction follows different trajectories across different fat depots, with fat becoming redistributed from subcutaneous to intra-peritoneal depots and ultimately ectopic sites, such as liver, muscle, and bone marrow. This is associated with insulin resistance, hypertension, atherosclerosis, strokes, myocardial infarction, cancer, and cognitive dysfunction. ... Senescent cells in adipose tissue could have profound clinical consequences because of their pro-inflammatory secretory phenotype, the large amount of adipose tissue in humans, and its central metabolic role.

The loss of skeletal muscle is one of the most dramatic changes in the human body consequent to advancing age and is referred to as sarcopenia. It is a primary cause of age-related changes in muscle performance, functional status and metabolic homeostasis. In an effort to counter sarcopenia and its consequences, we have studied strategies to inhibit the muscle-enriched TGF-β superfamily member, myostatin. The purpose of this seminar is to demonstrate how antibody-directed approaches to myostatin have not only increased muscle mass in mouse models of aging and disease, but improved physical function and whole-body metabolism. Ultimately, strategies to disrupt myostatin may provide a means to extend healthspan.

A number of researchers have been working on ways to manipulate muscle growth through myostatin-connected mechanisms. For example:

The researchers tried to use one protein called follistatin to impede the action of another, myostatin, that's known to inhibit muscle growth. They injected the gene for follistatin into the right legs of six healthy monkeys and after eight weeks, their right legs had grown and were larger than their left legs. "We created a stronger muscle," said Brian Kaspar, the principal investigator for Nationwide's research institute. "We also showed that the muscle generated more force."

News of more incremental progress towards a cell transplant therapy to treat Parkinson's: "Parkinson's disease takes hold as cells that produce dopamine die off in part of the brain called the substantia nigra. This causes tremors, rigidity and slowness of movement, though patients may also experience tiredness, pain, depression and constipation, which worsen as the disease progresses. ... Brain cells that die off in Parkinson's disease have been grown from stem cells and grafted into monkeys' brains in a major step towards new treatments for the condition. US researchers say they have overcome previous difficulties in coaxing human embryonic stem cells to become the neurons killed by the disease. Tests showed the cells survive and function normally in animals and reverse movement problems caused by Parkinson's in monkeys. The breakthrough raises the prospect of transplanting freshly grown dopamine-producing cells into human patients to treat the disease. ... Previously we did not fully understand the particular signals needed to tell stem cells how to differentiate into the right type of cells. The cells we produced in the past would produce some dopamine but in fact were not quite the right type of cell, so there were limited improvements in the animals. Now we know how to do it right, which is promising for future clinical use."

Link: http://www.guardian.co.uk/science/2011/nov/06/stem-cells-brain-parkinsons-disease

Here's a better overview of recent research that demonstrates the benefits of destroying senescent cells: "Baker exploited the fact that many senescent cells rely on a protein called p16-Ink4a. He created a genetic circuit that reacts to the presence of p16-Ink4a by manufacturing an executioner: a protein called caspase-8 that kills its host cell. Caspase-8 is like a pair of scissors - it comes in two halves that only work when they unite. Baker could link the two halves together using a specific drug. By sneaking the drug into a mouse's food, he activated the executioners, which only killed off the cells that have lots of p16-Ink4a. Only the senescent ones get the chop. Baker tested out this system in a special strain of genetically engineered mice that age very quickly. It worked. The senescent cells disappeared, and that substantially delayed the onset of muscle loss, cataracts, and fat loss. Typically, around half of these mice show signs of muscle loss by five months of age. Without their senescent cells, only a quarter of them showed the same signs at ten months. Their muscle fibres were larger, and they ran further on treadmills. Even old mice, whose bodies had started to decline, showed improvements. ... There's been a question of whether senescent cells are important, since they're only a small proportion of cells. Our work indicates that a small number of these cells can have a big impact."

Link: http://blogs.discovermagazine.com/notrocketscience/2011/11/02/extending-healthy-life-by-getting-rid-of-retired-cells/

Cryonics industry figure Ben Best attended the fifth SENS conference that was held some weeks back in England, and his report can be read at Depressed Metabolism:

People who attend SENS conferences are the demographic that is the most receptive to cryonics of any identifiable group I have yet found. They are mostly scientists interested in intervening in the aging process.

...

great progress has been made in starting research programs on each of the SENS strategies, and by 2012 research on all the strategies is expected to be in progress.

...

In addition to my oral presentation on cryonics I also had a poster. Scientific conferences usually have poster sessions where scientists present research, reviews, or ideas in the form of a poster. Poster presenters stand by their posters at scheduled times to discuss their work on a one-to-one basis with individuals rather than to an audience. My poster dealt with challenging the concept of biological age and denying the possibility of a biomarker of aging that could determine biological age. I contended that biological age and biomarkers of aging assume a singular underlying aging process, which I denied on the grounds that aging is multiple forms of damage.

His view on biomarkers is an interesting one; you might look back in the Fight Aging! archives for a background on the search for biomarkers of aging - there are a good number of posts on the topic, and it's an area of research that has some importance to the future pace of progress. Absent good biomarkers, it's going to be hard to rapidly tell the difference between a working rejuvenation therapy and a non-working rejuvenation therapy - and time is in short supply.

I did want to draw you attention to a point from Best that I disagree with. He says:

I consider gene therapy to be an essential tool for the ultimate implementation of SENS, and a deficiency of SENS that there is so little attention paid to this technology. I don't see how SENS can be implemented by any means other than genetic re-programming. LysoSENS, for example, would require new genes to create new, more effective enzymes for the lysosomes. MitoSENS would require all mitochondrial proteins be made in the nucleus and imported into the mitochondria.

For mitochondrial repair, agreed, all of the most plausible paths look like gene therapy. The problem that MitoSENS seeks to solve is the accumulation of damage to mitochondrial DNA, and so that DNA either needs to be protected, repaired, or replaced. Fair enough. But I think there will be a wide range of other practical mechanisms for the delivery of necessary enzymes to lysosomes as a part of the LysoSENS program. Recent years have made it clear that biotechnologies other than gene therapy can target small molecules to specific cells and even specific portions of a cell, such as by hijacking normal protein targeting mechanisms or through carefully designed nanocarrier structures. I would agree that an ultimate implementation would be one that is always on - an unambigiously beneficial genetic change to allow lysosomes to digest what is presently indigestible and which will be passed on to future generations. But it seems far more likely that initial implementations will be periodic clinical treatments - injections and infusions - designed to flush the body's lysosomes with enzymes for a short period of time, and thereby clean them out. This would seem to be sufficient, given that we humans manage three decades of life at the outset without the obvious degenerations of aging starting to show up.

A review paper on one of the trailing areas of tissue engineering - lungs present a harder and more complex challenge than many other organs: "End-stage lung disease is a major health care challenge. Lung transplantation remains the definitive treatment, yet rejection and donor organ shortage limit its broader clinical impact. Engineering bioartificial lung grafts from patient-derived cells could theoretically lead to alternative treatment strategies. Although many challenges on the way to clinical application remain, important early milestones toward translation have been met. Key endodermal progenitors can be derived from patients and expanded in vitro. Advanced culture conditions facilitate the formation of three-dimensional functional tissues from lineage-committed cells. Bioartificial grafts that provide gas exchange have been generated and transplanted into animal models. Looking ahead, current challenges in bioartificial lung engineering include creation of ideal scaffold materials, differentiation and expansion of lung-specific cell populations and full maturation of engineered constructs to provide graft longevity after implantation in vivo. A multidisciplinary collaborative effort will not only bring us closer to the ultimate goal of engineering patient-derived lung grafts, but also generate a series of clinically valuable translational milestones such as airway grafts and disease models."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22026560

The aging of bacteria grants us insight into the very earliest evolutionary origins of aging: "When a bacterial cell divides into two daughter cells and those two cells divide into four more daughters, then 8, then 16 and so on, the result, biologists have long assumed, is an eternally youthful population of bacteria. Bacteria, in other words, don't age - at least not in the same way all other organisms do. ... [But] not only do bacteria age, but [their] ability to age allows bacteria to improve the evolutionary fitness of their population by diversifying their reproductive investment between older and more youthful daughters. ... Aging in organisms is often caused by the accumulation of non-genetic damage, such as proteins that become oxidized over time. So for a single celled organism that has acquired damage that cannot be repaired, which of the two alternatives is better - to split the cellular damage in equal amounts between the two daughters or to give one daughter all of the damage and the other none? ... bacteria appear to give more of the cellular damage to one daughter, the one that has 'aged,' and less to the other, which the biologists term 'rejuvenation' ... In a bacterial population, aging and rejuvenation goes on simultaneously, so depending on how you measure it, you can be misled to believe that there is no aging. ... We ran computer models and found that giving one daughter more the damage and the other less always wins from an evolutionary perspective. It's analogous to diversifying your portfolio."

Link: http://www.sciencedaily.com/releases/2011/10/111027150207.htm

So how are things coming along with the Open Cures project? (If this is new to you, please do follow that link to see what this is all about).

I should preface this post by noting that my work on any given project tends to take place in waves, and the past couple of months have been a trough of comparatively low activity for Open Cures. The earlier part of this year was a crest in which planning was accomplished, discussions held, an email group and web site site up, posts and articles written, and a few thousand dollars expended to test the waters for paid writing of protocol documents, largely through contractors with life science backgrounds met via the oDesk marketplace. A start, in other words, for something that I anticipate will run at a more modest rate for a number of years.

You never get as far as you'd like in any given period of time, of course, and the rest of the world rarely cooperates by conforming to initial expectations. Since the last update posted here, work on finding reliable authors and writing has proceeded at a slow but steady pace. I'm comfortable with my ability to source these folk now - there are a surprisingly large number of life science graduates and researchers offering their services on the global market for distance work. So the focus has been on establishing high quality baseline documents as examples, templates to help future writers toe the line, and similar issues. One of the slowdowns here has been a matter of dealing with the questions that bedevil the setup for any process: what exactly do we want the results to look like, what is the best way to obtain them, how does it all fall into place in detail.

From an operations perspective, I've shifted most of the ongoing publishing into the Open Cures Wiki: if I'd decided to do that at the outset it would have saved some time in setting up the website, but such is life. I'm presently within striking distance of finishing up the LysoSENS bacterial discovery protocol: a final and rewritten draft is in hand, just not yet posted, and the author will be fixing up the outline to conform with it. A protocol outline for the synthesis of SkQ1, the targeted mitochondrial antioxidant, was completed and posted last month and is awaiting expansion into a full document. There's a nice backlog of other items to be reworked into the final template, and a nice list of research results that I'd like to produce protocols to describe.

I had hoped that the LysoSENS bacterial discovery would prove to be a useful overture to the DIYbio community - it's an interesting project with bacteria and various chemical synthesis activities, well suited as a hobbyist project but one which can assist real, significant research. Watching and interacting with the DIYbio community has led me to think that I'm too early, however, and that they are not going to be particularly receptive any time soon for a range of reasons. Firstly, the movers and shakers are focused on growth and technology over specific projects; they are a small community still, and the most important things for them right now involve producing low-cost and open versions of common technologies (such as OpenPCR), and building shared laboratory spaces to help grow and solidify local groups (such as BioCurious).

Secondly, most of these folk are either disinterested or hostile towards engineered longevity and human rejuvenation as long-term goals. I would guess that this stems in part from the fact that this describes the population in general, and there's no particular reason that a selection of entrepreneurial life science folk should be any different, and in part from the plant biotech / third world farming assistance / environmentalist roots of a fair-sized fraction of the community. They have a tendency to look down on things that they can argue do not primarily help the poor and disadvantaged first; environmentalist hostility towards human longevity is well known and widespread.

Thirdly, the DIYbio community is somewhere between scared and terrified of the possibility of hostile government regulation arriving before they have a large enough community and mindshare to effectively resist it - so there is considerable self-censorship, caution, and opposition to any proposed work with animals, animal cells, or indeed anything that might touch on the heavy regulation that attends professional life science research on the medical side. Similarly, you won't win many friends by having the declared goal of working around the FDA as is the case for Open Cures - and for much the same reasons.

So, in short, I'm thinking that it's too early to expect useful allies there. That community needs to become larger, have listened to what the longevity advocacy community has to say for longer, and Open Cures needs more than just an idea and a website to demonstrate its solidity and useful nature. A nice library of protocols would be a good start, and that's underway at a modest, side-project sort of pace.

PCG-1 is known to be connected to the benefits of calorie restriction in a range of species, and here researchers are working with flies: "One of the few reliable ways to extend an organism's lifespan, be it a fruit fly or a mouse, is to restrict calorie intake. Now, a new study in fruit flies is helping to explain why such minimal diets are linked to longevity and offering clues to the effects of aging on stem cell behavior. Scientists [found] that tweaking a gene known as PGC-1, which is also found in human DNA, in the intestinal stem cells of fruit flies delayed the aging of their intestine and extended their lifespan by as much as 50 percent. ... While little is known about the biological mechanisms underlying this phenomenon, studies have shown that the cells of calorie-restricted animals have greater numbers of energy-generating structures known as mitochondria. In mammals and flies, the PGC-1 gene regulates the number of these cellular power plants, which convert sugars and fats from food into the energy for cellular functions. ... The researchers found that boosting the activity of dPGC-1, the fruit fly version of the gene, resulted in greater numbers of mitochondria and more energy-production in flies - the same phenomenon seen in organisms on calorie restricted diets. When the activity of the gene was accelerated in stem and progenitor cells of the intestine, which serve to replenish intestinal tissues, these cellular changes correspond with better health and longer lifespan."

Link: http://www.newswise.com/articles/fruit-fly-intestine-may-hold-secret-to-the-fountain-of-youth

Via EurekAlert!: "Research into differentiation has led to a variety of breakthroughs as stem cell researchers harvest cells from one part of the body and genetically adapt them to fulfill a specialized role. However, if the implanted cells are too much like the cells of the targeted area they may not have the plasticity to engraft and repair the injured tissue. ... Stem cell differentiation and transplantation has been shown to improve function in conditions including degenerative diseases and blood supply disorders. However, the survival rate of transplanted cells in patients limits their overall effectiveness, which is a barrier to clinical use. ... To overcome this issue [researchers] explored de-differentiation, a process that reverts specialized, differentiated cells back to a more primitive cell. The team focused their research on multipotent stem cells, (MSCs) which can be altered into a variety of cell types through differentiation. Bone marrow MSCs have the potential to differentiate into each of the three basic types of lineage cells which form bone (osteocytes), cartilage (chondrocytes) and fat tissue (adipocytes). The team first differentiated bone marrow MSCs towards a neuronal lineage, but then removed the differentiation conditions, allowing the cell to revert back to a form with more basic cellular characteristics. Following this process the team recorded increased cell survival rates following transplants. In an animal model de-differentiated cells were found to be more effective in improving cognitive functions and in aiding recovery from strokes, compared to un-manipulated stem cells both in living specimens and in laboratory experiments."

Link: http://www.eurekalert.org/pub_releases/2011-11/w-rsc110111.php

At any given time a whole bunch of cells in your body need to be destroyed before they cause harm - cells that are past the productive stage of their life cycle and have become senescent, cells that are damaged and malfunctioning, and so forth. The majority of these cells are indeed destroyed, either by the immune system or through self-destruction mechanisms that evolved to trigger when vital cellular processes begin to run ragged. But this protective culling fails with age, and the accumulation of cells that should have been destroyed but were not is one of the driving forces of degenerative aging.

This fact is reflected in the proposed apoptoSENS research program, one of the seven branches of the Strategies for Engineered Negligible Senescence. Where the body isn't keeping up with cells that should be destroyed, appropriate forms of biotechnology can could be developed to perform this necessary work - and thereby remove and reverse this contribution to aging. The first array of therapies will probably look much like the targeted cell killing strategies under development in the cancer research community: using bacteria, viruses, nanoparticles, or the patient's own immune system to selectively seek out and destroy cells based on their surface markers.

I see that recent research adds weight to proposals for therapies that will eliminate senescent cells:

Scientists at the Mayo Clinic, in the US, devised a way to kill all senescent cells in [mice genetically engineered to age more rapidly than normal, and therefore accumulate senescent cells more rapidly than normal]. ... when they were given a drug, the senescent cells would die. The researchers looked at three symptoms of old age: formation of cataracts in the eye; the wasting away of muscle tissue; and the loss of fat deposits under the skin, which keep it smooth. Researchers said the onset of these symptoms was "dramatically delayed" when the animals were treated with the drug. When it was given after the mice had been allowed to age, there was an improvement in muscle function.

[The study] suggests if you get rid of senescent cells you can improve [physical traits] associated with ageing and improve quality of life in aged humans.

The caveat here is that these are not normal mice. Animals that suffer accelerated aging are used for the standard cost effectiveness reasons: the researchers were already working with the breed, effects will be easier to find, and can be found in a shorter period of time. Now that the researchers have an effect and a mechanism by which they can reliably destroy senescent cells, the next step is to repeat the study in ordinary mice and see what happens - which will of course take a few years if they want to evaluate the effects on life span as well as health, risk of age-related disease, and so forth.

Here's a link to the research paper and a little detail on how the authors are clearing out senescent cells:

Senescent cells accumulate in various tissues and organs with ageing and have been hypothesized to disrupt tissue structure and function because of the components they secrete. However, whether senescent cells are causally implicated in age-related dysfunction and whether their removal is beneficial has remained unknown. To address these fundamental questions, we made use of a biomarker for senescence, p16Ink4a, to design a novel transgene, INK-ATTAC, for inducible elimination of p16Ink4a-positive senescent cells upon administration of a drug.

The mice used were BubR1 mutants, and you can find an interesting article on that topic at the laboratory website.

An interesting open access review paper - the full thing is in PDF format only: "The development of materials and technologies for the assembly of cells and/or vesicles is a key for the next generation of tissue engineering. Since the introduction of the tissue engineering concept in 1993, various types of scaffolds have been developed for the regeneration of connective tissues in vitro and in vivo. Cartilage, bone and skin have been successfully regenerated in vitro, and these regenerated tissues have been applied clinically. However, organs such as the liver and pancreas constitute numerous cell types, contain small amounts of extracellular matrix, and are highly vascularized. Therefore, organ engineering will require the assembly of cells and/or vesicles. In particular, adhesion between cells/vesicles will be required for regeneration of organs in vitro. ... adhesive materials and technologies will work as 'glues' for assembling various kinds of cells. The adhesive materials should be degraded when cells themselves biosynthesize cell adhesion molecules ... Although integration of newly developed materials and technologies will be required for the regeneration of organs in vitro, this will ultimately lead to the creation of three-dimensionally engineered organs with functions similar to those of natural organs."

Link: http://dx.doi.org/10.1088/1468-6996/12/6/064703

Making therapies that can work in older patients despite their frailty and damage is an important part of progress in stem cell medicine of all sorts: "Age alone no longer should be considered a defining factor when determining whether an older patient with blood cancer is a candidate for stem cell transplantation. That's the conclusion of the first study summarizing long-term outcomes from a series of prospective clinical trials of patients age 60 and over ... the five-year rates of overall and disease-progression-free survival among mini-transplant patients were 35 percent and 32 percent, respectively. Patients in three age groups - 60 to 64, 65 to 69 and 70 to 75 - had comparable survival rates, which suggested that age played a limited role in how patients tolerate the mini-transplant. ... Conventional transplants, which are generally not perfomed on people over age 60 or others who are medically unfit, use high doses of total-body irradiation and potent chemotherapy to eliminate leukemic cells. The intense treatment destroys the blood and immune system and is fatal unless the patient is rescued by infusion of donor bone marrow or stem cells isolated from peripheral blood. The mini-transplant, in contrast, relies on the ability of donor immune cells to target and destroy the cancer - without the need for high-dose chemotherapy and radiation. Instead, low-dose radiation and chemotherapy is used to suppress the immune system rather than destroy it. This helps the body accept the donor stem cells, which then go to work to attack cancer cells - called the graft-vs.-leukemia effect - and rebuild the immune system."

Link: http://www.eurekalert.org/pub_releases/2011-11/fhcr-anl102611.php

In response to a news item posted yesterday, a commenter asks:

The fact that rejuvenation in mice seems to have been ten years away for around eight years now does not fill me with confidence. I understand of course that those estimates were for a scenario in which SENS had been adequately funded, and that it hasn't come remotely close. ... I want to know how far we are from actually achieving our goals given that funding is likely to continue to be inadequate. Fifteen years? Twenty? Fifty?

Which is a fair question. For reference, the fully funded SENS scenario called for a budget of $100 million per year over ten years the last time I checked, those funds spread between work on the seven categories of repair biotechnology required to prevent and reverse the degenerations of aging. That scenario is proposed to give a fifty-fifty shot at mouse rejuvenation by the end of the ten year period. As the clock keeps ticking without funding at that level materializing, one would expect the cost estimates to fall somewhat over time even if no-one is working on SENS: the cost of research and development in biotechnology is falling across the board, and in addition researchers benefit from a steady rate of progress throughout the fundamental life sciences. Some things that were obscure will become clear and some things that were hard will become easier because of progress in related areas of the broader field.

If SENS work stopped tomorrow and someone were to return to the drawing board ten years from now and run the numbers again, would rejuvenation in mice still be ten years and $100 million? Quite possibly yes on the ten years, and no on the $100 million - I think the cost would be significantly lower. But that doesn't mean it would take less time: as I've argued in the past there is a certain lower limit in the time taken for human endeavors. Organization of large projects, large-scale fundraising, and sequential tasks that depend upon one another can't be brought down below a certain minimum length of time for so long as there are humans in the decision loop. From this perspective, spending tens of millions of dollars on research in a few years is just as large and complex an undertaking as raising venture capital and starting a company - you can't expect to get much of anywhere without it taking a few years, no matter how good your tools and ideas are.

So watching estimated future costs ticking down is one form of progress - but not the one we want to see. The trouble with the question in the comment that I quoted above is that research funded at very low levels is inherently unpredictable:

I would say that the principal cause of uncertainty for the timeline leading to rejuvenation biotechnology - ways to repair and reverse the cellular and molecular damage that causes aging - is the fact that we lack a large, well-funded, well-supported research community at this time. Only comparatively small initiatives exist now, such as the SENS Foundation, and the actions, choices, and happenstance of individuals have large effects on the future timeline leading to the desired solid research community. That future community will be large enough that individual choices don't tend to have much of an effect on its progress one way or another, but here and now the element of chance is significant.

If funding of $100 million per year results in a big enough research group to allow for an averaging of the risks and reasonable predictions for a decade of work, then $1 million a year (the 2010 budget of the SENS Foundation) is far removed from predictability. If that continues for ten or twenty years, who can say what will result - certainly not fully implemented SENS, but my point is that no prediction of the actual resulting science and technology can be reasonable at these levels of funding.

The lesson to take away here is that we should view the SENS research program as a growth endeavor, and success in the long term goal of building a toolkit for human rejuvenation can only come through tremendous growth. These are still the early, formative years in a curve spanning decades. Present small scale work is accomplished to build the case beyond mere advocacy, to prove that the SENS vision leads to positive and useful results at every stage, and to attract greater levels of funding and support and greater numbers of researchers. Early outputs from SENS research will likely be technologies of use in producing therapies for end-stage age-related diseases, for example, or new science that contributes to these ends.

Over the last few years there have been a series of positive developments in stem cell research that suggest the age of a patient will not be a significant hurdle in generating useful cells for therapeutic use. Here is another: "Researchers were able to successfully transform cells from patients as old as 100 into stem cells virtually identical to those found in embryos. If these can be used to grow healthy tissue which can safely be transplanted into elderly patients it could open up new avenues of treatment for the elderly. ... This is a new paradigm for cell rejuvenation ... the age of cells is definitely not a barrier to reprogramming. ... scientists can use a method of taking normal cells from adults and reversing them to an unspecialised state, known as induced pluripotent stem cells (iPS), making them almost indistinguishable from embryonic stem cells. But experts are divided over whether the technique can work efficiently in elderly patients, who have the most to gain from the potential treatments, because their cells have deteriorated further. By adding two new ingredients, known as transcription factors, to the method of generating adult stem cells, they were able to overcome this hurdle and 'reset' many of the key markers of ageing in cells."

Link: http://www.telegraph.co.uk/science/science-news/8861115/Stem-cell-hope-for-elderly-patients.html

Some forms of naturally produced antioxidant in our cells can be manipulated to extend life - for example, mice engineered to produce more catalase at their mitochondria live longer. This can be taken as an indication of the importance of oxidative damage in the mitochondria as a cause of aging. Here is research in yeast to show that calorie restriction, another way of extending life, may also act partially through cellular antioxidants: "We are able to show that caloric restriction slows down ageing by preventing an enzyme, peroxiredoxin, from being inactivated. This enzyme is also extremely important in counteracting damage to our genetic material. ... active peroxiredoxin 1, Prx1, an enzyme that breaks down harmful hydrogen peroxide in the cells, is required for caloric restriction to work effectively. The results [show] that Prx1 is damaged during ageing and loses its activity. Caloric restriction counteracts this by increasing the production of another enzyme, Srx1, which repairs Prx1. Interestingly, the study also shows that ageing can be delayed without caloric restriction by only increasing the quantity of Srx1 in the cell. Repair of the peroxiredoxin Prx1 consequently emerges as a key process in ageing. ... Peroxiredoxins have also been shown to be capable of preventing proteins from being damaged and aggregating, a process that has been linked to several age-related disorders affecting the nervous system, such as Alzheimer's and Parkinson's. The researchers are accordingly also considering whether stimulation of Prx1 can reduce and delay such disease processes."

Link: http://medicalxpress.com/news/2011-10-longer-calories.html