Longevity Meme Newsletter, April 12 2010

April 12 2010

The Longevity Meme Newsletter is a weekly email containing news, opinions, and happenings for people interested in aging science and engineered longevity: making use of diet, lifestyle choices, technology, and proven medical advances to live healthy, longer lives. This newsletter is published under the Creative Commons Attribution 3.0 license. In short, this means that you are encouraged to republish and rewrite it in any way you see fit, the only requirements being that you provide attribution and a link to the Longevity Meme.



- The Era of Living Longer
- Spreading Recellularization
- Changes in DNA and Aging
- The Future of Cancer Therapies is Targeting
- Discussion
- Latest Healthy Life Extension Headlines


Of all the people throughout human history who lived to see age 65, half are alive today:


"This is the result of a grand increase in wealth across the world over the past two centuries: more people, higher living standards, technological innovation, and better medicine combining to yield a steady increase in human longevity. Slow and steady might be slow and steady, but it soon enough creates a world very different from that inhabited by our grandparents when they were young.

"Yet there is every reason to believe that what lies ahead is not more of the same, but a far more rapid leap in capabilities and outcomes. We don't stand on a flat slope of progress, but rather on the flatter, earlier sections of an exponential curve. The biotech revolution of the 21st century will do for our life spans what the computing revolution of the past fifty years did for human communications."


More research groups are now using the technique of recellularization to produce tissues and organs for transplant:


"Recellularization is a transplant preparation process that begins by stripping living cells from donor tissue - such as a heart valve, an entire heart, a trachea, and so forth - to leave behind the extracellular matrix as a scaffold. That scaffold is then seeded with the transplant recipient's own cells, which grow throughout its structure to reform the original tissue. This has proven to be an excellent way to prepare transplants that will not trigger immune rejection, even for xenotransplantation between species.

"Great shortages and delays exist for people who need organ transplants - largely imposed by regulatory bodies and laws that forbid an open market in body parts or paid agreements between donor and recipient. So organs that might otherwise have been used go to the grave, and funds that might have benefited the deceased's next of kin are spent on other things; yet another way in which unelected bureaucrats destroy value and ensure suffering in the field of medicine. One way in which recellularization might alleviate these human-caused issues is by opening the door to safe and widespread use of animal organs for transplant."


Nuclear DNA is well protected, but nonetheless changes happen with aging: mutations and epigenetic alterations in the way in which genes are transformed into proteins. Is this important in degenerative aging?


"Do changes in nuclear DNA significantly affect the course of aging? A good question, and one that is still open and energetically debated in the scientific community. How about epigenetic changes, mechanisms that alter the process of producing proteins from genetic blueprints without changing the genes themselves, such as those involving DNA methylation? Insofar as degenerative aging is concerned, are epigenetic changes a cause, a consequence of other, more fundamental changes, or a mix of both cases? These are also good questions, and still open to debate or new evidence."


Cancer therapies of the near future will be targeted biotechnologies that destroy only cancer cells, with few or no side-effects:


"A number of different technology platforms are under development within the paradigm of targeted cell killers. First is the nanoparticle: comparatively simple structures whose behavior researchers can expect to fully understand. They only do what they are designed to do, which is typically to act as an inert link between a homing device and a kill mechanism. Second is the engineered virus, altered natural self-replicators that are restricted to working their characteristic havoc only upon the target cell type. Thirdly, we have engineered immune cells. The immune system already tries to attack and destroy cancers, but some are invisible to it. If immune cells can be given the right biochemical tools to recognize the enemy, then they will fight and win.

"You might think of these strategies as falling on a scale of complexity: at the level of nanoparticles, researchers are working with systems simple enough for outcomes and side-effects to be confidently predicted or quickly established in the laboratory. Viruses are more capable and more complex, and the immune system yet more capable and complex. The trade off here lies in speeding development by use of an existing complex biological system that has already evolved to perform the task you have in mind versus the greater difficulty of predicting how that system is going to behave in the field as a therapy."


The highlights and headlines from the past week follow below.

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Greater understanding of the immune system means a greater ability to reprogram its components - such as errant immune cells that cause autoimmune diseases. From EurekAlert!: a study "describes a unique therapeutic 'nanovaccine' that successfully reverses [type 1] diabetes (T1D) in a mouse model of the disease. In addition to providing new insight into diabetes, the research also reveals an aspect of the pathogenesis of the autoimmune response that may provide a therapeutic strategy for multiple autoimmune disorders. ... [Researchers] wanted to find a way to counteract the harmful autoimmune response without compromising general immunity. They discovered that our bodies have a built-in mechanism that tries to stop the progression of autoimmune diseases like T1D. Essentially, there is an internal tug-of-war between aggressive T-cells that want to cause the disease and weaker T cells that want to stop it from occurring ... The researchers also developed [a] nanotechnology-based 'vaccine' that selectively boosted the weak white blood T cells, enabling them to effectively counter the damage caused by their overactive T cell relatives. ... their nanovaccine blunted T1D progression in prediabetic mice and restored normal blood sugar in diabetic mice. ... If the paradigm on which this nanovaccine is based holds true in other chronic autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis, and others, [nanovaccines] might find general applicability in autoimmunity."

This seems like a logical next step for tissue printing technologies: "researchers have rigged up a device that can spray skin cells directly onto burn victims, quickly protecting and healing their wounds as an alternative to skin grafts. They have mounted the device, which has so far only been tested on mice, in a frame that can be wheeled over a patient in a hospital bed. ... A laser can take a reading of the wound's size and shape so that a layer of healing skin cells can be precisely applied. ... We literally print the cells directly onto the wound. We can put specific cells where they need to go. ... [Researchers] dissolved human skin cells from pieces of skin, separating and purifying the various cell types such as fibroblasts and keratinocytes. They put them in a nutritious solution to make them multiply and then used a system similar to a multicolor office inkjet printer to apply first a layer of fibroblasts and then a layer of keratinocytes, which form the protective outer layer of skin. ... The sprayed cells also incorporated themselves into surrounding skin, hair follicles and sebaceous glands, probably because immature cells called stem cells were mixed in with the sprayed cells."

Empires end when an entrenched elite can spend from the public purse and take on debt without immediate consequence or forethought, destroying the value of their currency in the process. Assuming (perhaps optimistically) that present economic empires survive the next couple of decades, a combination of foolish promises and increasing human longevity will be the rock that sinks them. From Reuters: "Like the subprime crisis faced by banks in 2008, the risk of people living for up to 20 years after retirement seems to have crept up on an industry based on using historical data to calculate people's chances of an early death. Now, pension funds and insurers say the mounting burden of protracted pensions payments is increasingly concentrated on a small group of providers: them. ... Nowhere better can the process be seen than in Britain, which is facing a crisis resulting from a combination of pension reforms and increased life expectancy. ... The many arguments in favor of a sovereign bond linked to longevity rest on one fundamental expectation: if pension providers can't pay, or become insolvent, governments will have to. Longevity bonds could make the process neater, and more politically palatable, than the collapse of a pension provider." The problem is not that some groups made bad bets, or that many people relied upon those bets being good. The problem is that these groups and their supporters can conspire with governments to bail themselves out with public funds and debt heedless of consequences.

From the MIT Technology Review, a look at another form of first generation immune therapy aimed at cancer: "Last year marked a first for engineered antibodies - the European Commission approved a new cancer drug called Removab (catumaxomab), an antibody specially designed to grab both cancer cells and immune cells in such a way that the immune cell can kill the cancer cell. (The drug is undergoing testing for U.S. Food and Drug Administration approval.) Now a handful of similarly complex molecules, dubbed 'bispecific antibodies' for their ability to target two things at once, are in clinical trials. The two arms of these antibodies work together in different ways to treat cancer or other diseases, by bringing together two types of cells, as with Removab, by targeting two different types of receptors on the surface of a cell, or even using one arm to deliver drugs to specific cells targeted by the other. ... While the concept of bispecific antibodies has been around for decades, the approach has only recently shown clinical success. The field has been driven forward by new ways of designing and making the antibodies, which take advantage of advances in protein engineering, as well as the success of single-target antibodies, such as herceptin, that are already on the market." This is an example of the way in which targeting technologies and new strategies from the biotechnology labs are slowly filtering into the old school drug development pipeline.

Manipulating the machinery of mitochondria - the respiratory chain that turns food into the chemical ATP that is used to power cellular biochemistry - can extend healthy life in a variety of species. Here, researchers dig deeper into the mechanisms by which this happens, finding that there are more than one: "In Caenorhabditis elegans longevity is increased by a partial loss-of-function mutation in the mitochondrial complex III subunit gene isp-1. Longevity is also increased by RNAi against the expression of a variety of mitochondrial respiratory chain genes, including isp-1, but it is unknown whether the isp-1(qm150) mutation and the RNAi treatments trigger the same underlying mechanisms of longevity. We have identified nuo-6(qm200), a mutation [that] reduces the function of complex I and, like isp-1(qm150), results in low oxygen consumption, slow growth, slow behavior, and increased lifespan. We [compared] nuo-6(qm200) [to] nuo-6(RNAi) and found them to be distinct in crucial ways, including patterns of growth and fertility, behavioral rates, oxygen consumption, ATP levels, autophagy, [as] well as expression of superoxide dismutases, mitochondrial heat shock proteins, and other gene expression markers. RNAi treatments appear to generate a stress and autophagy response, while the genomic mutation alters electron transport and reactive oxygen species metabolism. ... Most importantly, we found that [the] lifespan increase induced by nuo-6(RNAi) is fully additive to that induced by isp-1(qm150), and the increase induced by isp-1(RNAi) is fully additive to that induced by nuo-6(qm200). Our results demonstrate that distinct and separable aspects of mitochondrial biology affect lifespan independently."

Via the Methuselah Foundation blog: "Today Methuselah Foundation launched the NewOrgan Prize, the Foundation's new longevity prize specifically focused on advancing the development of replacement tissues and organs for humans. Its goal is to accelerate advances in regenerative medicine, which will become the standard of care for replacing all tissue and organ systems in the body within 20 years, according to the U.S. Department of Health and Human Services. The first research team to construct a whole new complex organ (heart, kidney, liver, lung, pancreas) made from a person's own cells - one that is functionally equivalent and successfully transplanted - will be awarded the NewOrgan Prize. The goal of the Methuselah Foundation NewOrgan Prize is to achieve this medical breakthrough within the next 10 years. Today's launch is a call to action for competitors, candidates and contributors who want to participate in this crucial medical challenge aimed at extending healthy human life. ... Based on our success in spurring medical advances with incentives provided by the original Methuselah Mouse prize, we anticipate that over $10 million will be raised by the time the NewOrgan Prize criteria is met - and the prize presented - to the leading medical R&D team. At minimum, $1 million will be awarded to the research team that develops a whole new human organ that is functional and successfully transplanted."

One approach to stem cell therapy is to try to order existing stem cells to do more work, accomplished by introducing signaling molecules into the body - a drug, in other words. This methodology has reached the point of early clinical trials, as indicated in this press release: "Clinical-stage regenerative medicine company Juventas Therapeutics Inc. [has] started enrolling patients in a Phase 1 clinical trial to evaluate the safety and efficacy of its leading stem cell factor for treating heart failure. In preclinical studies of heart failure in pigs, JVS-100, as the factor is known, significantly increased cardiac function by promoting cell survival and increasing blood vessel formation in damaged hearts. JVS-100 works by encoding Stromal Cell-derived Factor-1 (SDF-1), a growth factor that in adults recruits stem cells from the bone marrow to create new blood vessels. The JVS-100-treated pigs showed significant improvements in cardiac function. ... We've led with heart failure because that's where our preliminary data was, and it's a great clinical opportunity. We also have strong data in the area of peripheral vascular disease and cosmetic wound healing. ... The factor can increase blood flow for patients who have peripheral vascular disease and accelerate wound closure and prevent scarring for patients who have had cosmetic surgery [so] we're looking to move both those toward clinic in the near future."

A good review paper: "Our understanding of autophagy has expanded greatly in recent years, largely due to the identification of the many genes involved in the process, and to the development of better methods to monitor the process, such as GFP-LC3 to visualize autophagosomes in vivo. A number of groups have demonstrated a tight connection between autophagy and mitochondrial turnover. Mitochondrial quality control is the process whereby mitochondria undergo successive rounds of fusion and fission with a dynamic exchange of components in order to segregate functional and damaged elements. Removal of the mitochondrion that contains damaged components is accomplished via autophagy (mitophagy). Mitophagy also serves to eliminate the subset of mitochondria producing the most reactive oxygen species, and episodic removal of mitochondria will reduce the oxidative burden, thus linking the mitochondrial free radical theory of aging with longevity achieved through caloric restriction. Mitophagy must be balanced by biogenesis to meet tissue energy needs, but the system is tunable and highly dynamic. This process is of greatest importance in long-lived cells such as cardiomyocytes, neurons, and memory T cells. Autophagy is known to decrease with age, and the failure to maintain mitochondrial quality control through mitophagy may explain why the heart, brain, and components of the immune system are most vulnerable to dysfunction as organisms age."

Cytomegalovirus (CMV) is one of the reasons our immune systems decay with aging: too many immune cells become specialized to deal with CMV, leaving too few to deal with everything else. New research "explains how a virus that has already infected up to 80 percent of the American population can repeatedly re-infect individuals despite the presence of a strong and long-lasting immune response. The research involves cytomegalovirus (CMV), which infects 50 percent to 80 percent of the U.S. population before age 40. ... For most people, CMV infection goes undetected and they do not become seriously ill. ... When most viruses infect a host, the immune system remembers the disease and protects against re-infection. This is the case with smallpox, seasonal strains of flu and several other viruses. This immune system reaction is also the reason why vaccines made with weakened or dead viruses work against these pathogens. In the case of CMV, the body's immune system is continuously stimulated by ongoing, low-level persistent infection, but yet CMV is still able to re-infect. This research explains how CMV is able to overcome this immune response so that re-infection occurs. ... The results of this study primarily illustrate the significant barriers to creating a vaccine that will prevent CMV infection." But a vaccine won't do much for people already burdened by an CMV-focused immune system. What we want is a way to use targeted cell killing strategies to destroy CMV-related immune cells and free up space for more useful immune cells.

Rapamycin recently showed promise as a potential treatment for Alzheimer's disease, and here more researchers are working on that: "A few weeks after a report that rapamycin, a drug that extends lifespan in mice and that is currently used in transplant patients, curbed the effects of Alzheimer's disease in mice, a second group is announcing similar results in an entirely different mouse model of early Alzheimer's. ... The second report [showed] that administration of rapamycin improved learning and memory in a strain of mice engineered to develop Alzheimer's. The improvements in learning and memory were detected in a water maze activity test that is designed to measure learning and spatial memory. The improvements in learning and memory correlated with lower damage in brain tissue. ... Strikingly, the Alzheimer's mice treated with rapamycin displayed improved performance on the maze, even reaching levels that were indistinguishable from their normal littermates. Levels of amyloid-beta-42 were also reduced in these mice after treatment, and we are seeing preserved numbers of synaptic elements in the brain areas of Alzheimer's disease mice that are ravaged by the disease process."



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