Some enthusiasm from the research community: "induced pluripotent stem (IPS) cells [are] where I'm putting almost all of my chips these days, because it combines many of my interests - genomics, sequencing, epigenetics, synthetic biology, stem cells. I don't think people have fully appreciated how quickly adult stem cells and sequencing and synthetic biology have progressed. They have progressed by orders of magnitude since we got IPS. Before that, they basically weren't working. ... There is much to be worked out. But here's the leap. If you want to accelerate this, you have to pick an intermediate target that doesn't sound so scary. So you'll start out with bone marrow patients. And you're going to basically make a synthetic version of that patient's bone marrow using IPS, which is going to work much better than the diseased bone marrow. And once this works that's going to catch on like wildfire. And then you'll do skin, and then you'll do every other stem cell you can get. ... Will people who are, say, aging but not yet sick ever be able to use this technology? I don't consider this medicine, it's preventive. I expect somebody who is truly brave, who has nothing wrong with them other than maybe the usual aging, saying: 'I want a bone marrow transplant', or intestinal, or whatever. And it will gain momentum from there. ... Initially it will be wealthy people who will try this. Ironically, wealthy people are often willing to be the guinea pigs that are really in a sense the front line of new technologies. They're the foot soldiers. They're willing to put themselves at risk, and to spend money on it."

Link: http://www.technologyreview.com/blog/experimentalman/27164/

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

There are several rare conditions that present the appearance of accelerated aging, the changes they cause extending far enough down into the fundamentals of human biochemistry that there yet remains much to learn about their operation and some debate over whether they are in fact forms of greatly accelerated aging. The best known of these conditions are Hutchinson-Gilford Progeria (HGPS, or just progeria) and Werner syndrome; significant progress has been made in identifying their root causes over the past decade, but that is still a way removed from knowing whether there is any great relevance there insofar as concerns research into ordinary aging.

A recent open access paper takes a look at the question, though the bottom line at this time is that more time and greater understanding is needed:

Hutchinson-Gilford Progeria (HGPS) and Werner syndromes are diseases that clinically resemble some aspects of accelerated aging. HGPS is caused by mutations in the LMNA gene resulting in post-translational processing defects that trigger Progeria in children. Werner syndrome, arising from mutations in the WRN helicase gene, causes premature aging in young adults. What are the molecular mechanism(s) underlying these disorders and what aspects of the diseases resemble physiological human aging?

...

In both diseases recent evidence indicates that mutations in the genes responsible for these premature aging diseases result in increased DNA damage, particularly at telomeres. Although shortening and/or damage to telomeres is associated with proliferative arrest of cells in vitro, it remains unclear how accurately these diseases recapitulate the processes of tissue aging in humans. Here we discuss recent advances, using in vitro cell culture and mouse models of progeroid syndromes to highlight important questions that remain: A) what is the molecular mechanism of how such seemingly unrelated proteins cause similar degenerative diseases? B) are these mechanisms representative of normal aging?

Like a fair amount of nonetheless interesting research, work aimed at understanding accelerated aging conditions - and mining that knowledge for material that may prove useful in the development of ways to intervene in ordinary aging - is something of a sideshow. The trouble with science in general is that you have to spend time on the sideshows in order to confirm that they are in fact sideshows; every presently major field of endeavor in the life sciences started off small, unpromising, and prospective. I don't think the odds are good that something spectacular will result from investigations of progeria: you can't completely rule it out at this stage, but there are other places to concentrate resources that have a much higher expectation of value.

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

Via ScienceDaily: researchers "are applying new techniques and materials to come up with artificial blood vessels [that] will be able to supply necessary nutrients to artificial tissue and maybe even complex organs in the future. ... It seemed practically impossible to build structures such as capillary vessels that are so small and complex, especially the branches and spaces in between. But production engineering came to the rescue because rapid prototyping makes it possible to build workpieces specifically according to any complex 3-D model. Now, scientists [are] working on transferring this technology to the generation of tiny biomaterial structures by combining two different techniques: the 3-D printing technology established in rapid prototyping and multiphoton polymerization developed in polymer science ... A 3-D inkjet printer can generate 3-dimensional solids from a wide variety of materials very quickly. It applies the material in layers of defined shape and these layers are chemically bonded by UV radiation. This already creates microstructures, but 3-D printing technology is still too imprecise for the fine structures of capillary vessels. This is why these researchers combine this technology with two-photon polymerization. Brief but intensive laser impulses impact the material and stimulate the molecules in a very small focus point so that crosslinking of the molecules occurs. The material becomes an elastic solid, due to the properties of the precursor molecules that have been adjusted by the chemists in the project team. In this way highly precise, elastic structures are built according to a 3-dimensional building plan."

Link: http://www.sciencedaily.com/releases/2011/09/110913122056.htm

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

Sir2 in yeast is one of the earliest discovered sirtuins, an important set of genes in the study of calorie restriction. Unfortunately that research has yet to generate a useful calorie restriction mimetic drug, and is looking less promising than it did initially. But here is an interesting result: "Activation of Sir2-orthologs is proposed to increase lifespan downstream of dietary restriction (DR). Here we describe an examination of the effect of 32 different lifespan-extending mutations and four methods of dietary restriction on replicative lifespan (RLS) in the short-lived sir2? yeast strain. In every case, deletion of SIR2 prevented RLS extension; however, RLS extension was restored when both SIR2 and FOB1 were deleted in several cases, demonstrating that SIR2 is not directly required for RLS extension. These findings indicate that suppression of the sir2? lifespan defect is a rare phenotype among longevity interventions and suggest that sir2? cells senesce rapidly by a mechanism distinct from that of wild-type cells. They also demonstrate that failure to observe life span extension in a short-lived background, such as cells or animals lacking sirtuins, should be interpreted with caution." Things are, as ever, more complex than we'd like in other words. One of the reasons that sirtuins haven't led directly to calorie restriction mimetics is that they are only one small part in a larger mechanism, and possibly not even a critical part - just the one that was easiest to notice.

Link: http://www.ncbi.nlm.nih.gov/pubmed/21902802

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

We age in part because a small number of important genes in our mitochondria are broken over time by the polluting effects of their day to day operation: broken genes mean the protein machines produced from their blueprints are also broken, or cannot be produced at all. Mitochondria are bacteria adapted to act as the power plants for our cells, swarms of them circulating inside every cell - and perversely the broken ones tend to win out in the ongoing, dynamic process of replication, damage control, and recycling of cellular machinery that takes place inside all of our cells. Cells can become overtaken by broken mitochondria, each herd of malfunctioning power plants spawned from one original chance breakage, and enough of these unfortunate cells produce a chain of unpleasant consequences throughout the body. Aging is damage, after all. This is a long story, and a better introduction than this can be found back in the archives, however.

SENS stands for the Strategies for Engineered Negligible Senescence, a detailed proposal for what must be done at the cellular and molecular level to reverse the damage of aging and thereby rejuvenate the old. SENS-related research is to vary degrees conducted in labs around the world, and where the research community isn't already large and hard at work - such as in the field of regenerative medicine - the SENS Foundation organizes and encourages research programs. One of the earliest SENS programs to move from concept to actual research, starting back when the initiative was conducted by the Methuselah Foundation, is MitoSENS: a way to use biotechnology to prevent mitochondrial damage from contributing to degenerative aging.

Mitochondrial genes are distinct from those in the nucleus of a cell, and as such are vulnerable. The available repair mechanisms are not as good as those in the nucleus, and the genes in each mitochondrion are right next door to power plant machinery that sustains the cell but also kicks out damaging reactive molecules. The MitoSENS strategy is twofold: (a) gene therapy to copy the few important mitochondrial genes into the cell nucleus, known as allotopic expression, and (b) one of a range of clever biotechnological strategies to get the protein machinery produced from those gene blueprints from the nucleus back out to the mitochondria where it is needed. You might look at the work of Corral-Debrinsky's group to see this in action in a real research program: when you have nuclear copies of mitochondrial genes, it doesn't matter if the more vulnerable mitochondrial versions suffer mishaps, everything continues as before.

A further good introduction to this topic and the work of the SENS Foundation is spurring this research can be found in video recorded at the recent SENS5 conference. Conference videos are being posted to the SENS Foundation YouTube channel as they are processed, and here is an educational presentation on the state of allotopic expression of mitochondrial genes:

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

One group of researchers believe that every tissue in the body is supported by a left-over population of fully pluripotent stem cells that might be easily accessible for use in therapies: "From the point of view of regenerative potential, the most important cells are pluripotent stem cells (PSCs). Such cells must fulfill certain in vitro as well as in vivo criteria that have been established by work with PSCs isolated from embryos, which are known as embryonic stem cells (ESCs). According to these criteria, pluripotent stem cells should: (i) give rise to cells from all three germ layers, (ii) complete blastocyst development, and (iii) form teratomas after inoculation into experimental animals. Unfortunately, in contrast to immortalized embryonic ESC lines or induced PSCs (iPSCs), these last two criteria have thus far not been obtained in a reproducible manner for any potential PSC candidates isolated from adult tissues. There are two possible explanations for this failure. The first is that PSCs isolated from adult tissues are not fully pluripotent; the second is that there are some physiological mechanisms involved in keeping these cells quiescent in adult tissues that preclude their 'unleashed proliferation', thereby avoiding the risk of teratoma formation. In this review we present an evidence that adult tissues contain remnants from development; a population of PSCs that is deposited in various organs as a backup for primitive stem cells, plays a role in rejuvenation of the pool of more differentiated tissue-committed stem cells (TCSCs), and is involved in organ regeneration. These cells share several markers with epiblast/germ line cells and have been named very small embryonic-like stem cells (VSELs). We suggest that, on one hand, VSELs maintain mammalian life span but, on the other hand, they may give rise to several malignancies if they mutate. We provide an evidence that the quiescent state of these cells in adult tissues, which prevents teratoma formation, is the result of epigenetic changes in some of the imprinted genes."

Link: http://www.ncbi.nlm.nih.gov/pubmed/21339038

It is possible that important future biotechnologies to enhance human longevity might be built on top of a better understanding of the mechanisms that cause similarly sized species to have quite radically different life spans. It seems just as plausible as the idea of generating a family of age-slowing biotechnologies from a better understanding of human metabolism, though who is to say at this early stage in the game just how effective any final result might be. Still, research groups are successfully raising funds, sequencing genomes, and delving much deeper into the comparative biology of aging than has been the case in the past. For example:

The Long Life of Birds: The Rat-Pigeon Comparison Revisited

As a group, birds are long-living with their maximum lifespan potential (MLSP) being on average twice that of similar-sized mammals, and it can be much greater for some individual comparisons. The most common mammal-bird comparison in the scientific literature is the rat-pigeon comparison. The rat has a MLSP of 5 y, compared to 35 y for the similar-sized pigeon (both from the AnAge database: genomics.senescence.info). This seven-fold MLSP difference has the potential to give considerable insight into the processes that determine longevity. Importantly, this is many times the longevity difference generally achieved either by genetic manipulation or environmental manipulation (such as dietary restriction).

...

We have revisited the rat-pigeon comparison in the most comprehensive manner to date. We have measured superoxide production (by heart, skeletal muscle and liver mitochondria), five different antioxidants in plasma, three tissues and mitochondria, membrane fatty acid composition (in seven tissues and three mitochondria), and biomarkers of oxidative damage. The only substantial and consistent difference that we have observed between rats and pigeons is their membrane fatty acid composition, with rats having membranes that are more susceptible to damage.

That's a pretty good piece of supporting evidence for the membrane pacemaker hypothesis of aging: longer lived species are longer lived because their cellular membranes are more resistant to damage. This ties in nicely to the role of mitochondria and mitochondrial damage in aging: swarming mitochondria in cells churn out damaging free radicals as a consequence of their day to day operations, and as a consequence damage themselves in ways that spiral out to cause all sorts of harm in the long term. If a species is more resistant to that damage in the places where it matters the most, then it lives longer.

As I have said before, I tend to view this as support for the importance of mitochondrial repair research. If resistant mitochondria give pigeons even a fair chunk of that multiplier of seven over rat life spans, then how much further could the research community take things if armed with a way to completely fix the self-inflicted mitochondrial damage rather than just resist it?

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

A good example of what obesity does to your long term health: "Men who enter adult life obese face a life-long doubling of the risk of dying prematurely, new research has found. In a study presented today (Tuesday) at the International Congress on Obesity in Stockholm, researchers tracked more than 5,000 military conscripts starting at the age of 20 until up to the age of 80. They found that at any given age, an obese man was twice as likely to die as a man who was not obese and that obesity at age 20 years had a constant effect on death up to 60 years later. They also found that the chance of dying early increased by 10% for each BMI point above the threshold for a healthy weight and that this persisted throughout life, with the obese dying about eight years earlier than the non-obese. ... Body mass index (BMI) was measured at the average ages of 20, 35 and 46 years, and the researchers investigated that in relation to death in the next follow-up period. A total of 1,191 men had died during the follow-up period of up to 60 years. The results were adjusted to eliminate any influence on the findings from year of birth, education and smoking. ... At age 70 years, 70% of the men in the comparison group and 50% of those in the obese group were still alive and we estimated that from middle age, the obese were likely to die eight years earlier than those in the comparison group."

View the Article Under Discussion: http://www.eurekalert.org/pub_releases/2010-07/iaft-sfl071210.php

Read More Longevity Meme Commentary: http://www.longevitymeme.org/news/

Inevitably, researchers who focus on slowing aging through metabolic manipulation will uncover ingested compounds that alter metabolism in beneficial ways, and thus very modestly raise life expectancy. Here is an example in mice: "Recent evidence points to a strong relationship between increased mitochondrial biogenesis and increased survival ... Branched-chain amino acids (BCAAs) have been shown to extend chronological life span in yeast. However, the role of these amino acids in mitochondrial biogenesis and longevity in mammals is unknown. Here, we show that a BCAA-enriched mixture (BCAAem) increased the average life span of mice. BCAAem supplementation increased mitochondrial biogenesis and sirtuin 1 expression in primary cardiac and skeletal myocytes and in cardiac and skeletal muscle, but not in adipose tissue and liver of middle-aged mice, and this was accompanied by enhanced physical endurance. Moreover, the reactive oxygen species (ROS) defense system genes were upregulated, and ROS production was reduced by BCAAem supplementation. All of the BCAAem-mediated effects were strongly attenuated in [mice engineered to lack] endothelial nitric oxide synthase." Nitric oxide is important to stem cell and blood vessel function; it is interesting that this effect depends upon that component of metabolism.

View the Article Under Discussion: http://dx.doi.org/10.1016/j.cmet.2010.08.016

Read More Longevity Meme Commentary: http://www.longevitymeme.org/news/

A study showed that mindfulness meditation training in no less than 8 weeks can improve a person's brain structure.

An Introduction to Mindfulness Meditation

In Buddhist tradition, mindfulness meditation has the aims of realizing the true nature of reality by focusing on a single object. The object of concentration can be any physical object, an imaginary picture or, more commonly, the person’s breathing. The primary objective of mindfulness meditation is to keep the mind consistently focused on the same object for the entire period.

There are different organizations that promote mindfulness meditation as a regular habit to maintain and improve brain health. It is a practice that does not require any expensive equipment to perform. All you need to have is a quiet and well ventilated place, and a basic knowledge of how mindfulness meditation works. The goal is to focus your mind on the realities of the ‘now’ and be mindful of your actions and thoughts at the present time. Different studies show that mindfulness meditation can improve a person’s mood, boost the immune system and alleviate stress.

The first step is to find a comfortable and quiet place where you can sit for an extended period of time. You can choose to sit on the most comfortable chair you have at home and keep your back, neck and head straight at all times. Leave all thoughts of the past behind you and try to stay focused in the present. Notice your breathing and feel the sensation of the air flowing in and out of your body. Try to observe how each breath is different from the previous and keep doing this until it becomes instantaneous and effortless.

You will begin to think about other things like your worries, fears, anxiety and other thoughts of the past. Try not to ignore them, instead make an effort to acknowledge them lightly. Try to remain calm and re-direct your attention and focus back on your breathing. Being pulled away from your focal point will always happen at first. But as you practice, you will soon begin to have more control over your mind and you’ll get pulled out less frequently each time.

Mindfulness Meditation to Improve Brain Health

A team of researchers from the Massachusetts General Hospital found that mindfulness meditation can improve a person’s brain structure in just 8 weeks of continuous practice. The researchers gathered a group of study participants who participated in an 8-week mindfulness meditation program and measured their brain regions associated with stress, empathy, sense of self and memory. The study was the first to investigate the effects of meditation on the gray matter of the brain.

Lead researcher Sarah Lazar from the MGH Psychiatric Neuroimaging Research program said that mindfulness meditation does not only give practitioners a sense of physical relaxation and peacefulness but they had also reported physical and cognitive improvements as long-term benefits. She added that their study shows that the claimed benefits may be due to the resulting physiological changes of mindfulness meditation. The study gives evidence that the practice does not only give practitioners a feeling of temporary peacefulness but that it benefits them by creating positive changes in the brain.

The previous studies conducted by Lazar’s team already showed structural differences between people who practice mindfulness meditation from those who have no history of practicing meditation. They had observed an improvement in the cerebral cortex and in areas linked to emotional and attention integration. But the previous studies lacked the evidence to show that the differences were produced by the practice of mindfulness meditation.

In their most recent study, the researchers took magnetic resonance (MR) images of the brain structure of 16 study participants before and after they were subjected to 8 weeks of mindfulness meditation; the program was created by the University of Massachusetts’ Center of Mindfulness. The study participants also received meditation guides in the form of audio recordings in addition to their weekly mindfulness meditation meetings that focused on nonjudgmental awareness of the state of mind, feelings and sensations. They were also asked to track the length of time that they practiced mindfulness meditation each day. In order to overcome the weakness of their previous study, the researchers used a control group and took MR images of their brain with the same time interval.

The study participants who participated in the mindfulness meditation program reported an average of 17 minutes of meditation in a day. Their responses to a mindfulness exam also showed improvements compared to their responses before participating in the program. The MR images also showed increased gray matter density in the hippocampus which is known to be important for memory and learning. Increase in density in areas linked to introspection, compassion and self-awareness were also observed. The control group did not experience any of these similar changes.

A neuroscientist from the University of Miami said that the results of the study put some light on the effects of mindfulness meditation to the brain. She added that the study showed that stress can be reduced for a short 8-week period of practicing mindfulness mediation and that it opens more opportunities to investigate better ways of effectively managing stress-related disorders.

Other Health Benefits of Mindfulness Meditation

Different studies have found that mindfulness mediation will not only give a feeling of peacefulness and relaxation but that it can also produce long-term effects to the person’s mental abilities. Mindfulness meditation can help people improve their intentional response to the present moment. This results to making better decisions and will allow them to respond more effectively to stress. In the past, mindfulness meditation lacked the scientific basis to prove its claimed benefits. But scientific studies are slowly producing evidences to show that mindfulness meditation can create positive changes in the brain

The various health benefits of mindfulness meditation include:

• development of self-acceptance
• better pain management for chronic health conditions
• increased self-awareness
• improved immune function
• reduced blood pressure
• more effective management of stress, anxiety, depression and other related symptoms.
• For chronic illness, studies had found that mindfulness meditation can help patient better manage episodes of pain and prevent resulting emotional complications like stress and depression.

Sources
altmedicine.about.com
eurekalert.org
studenthealth.ucsf.edu

Discuss this post in Frank Mangano’s forum!

Another Reason to Opt for Wheat Over White

Italian researchers find that women who eat white bread have two times the risk of heart disease than women who eat wheat.

When we were young and our folks asked us what bread we wanted our peanut butter and jelly on—white or wheat—our answer depended upon our mood at the time.  Did we want the white, which had a more bland taste but soaked up the jelly and peanut buttery goodness, or did we want the wheat, which had a more distinctive taste but didn’t marry with the PB and J quite as well as the white did?

Now that we’re older—and with any luck more health conscious than taste conscious—we hopefully choose wheat over white because it has the complex carbohydrates and fiber that white bread is void of, both of which are great for maintaining healthy weight levels and regularity.

But there’s another why white should always play second fiddle to wheat:  It may double your risk for heart disease.

In a new study published in the Archives of Internal Medicine, Italian scientists found that women who tended to eat high glycemic foods like white bread, pastries and ice cream had more than two times the risk of having heart disease later in life compared to women who ate foods low on the glycemic index.

Writing in the journal, Italian scientist Sabina Sieri and her colleagues said, “A high consumption of carbohydrates from high glycemic index foods, rather than the overall quantity of carbohydrates consumed, appears to influence the risk of developing coronary heart disease.”

The study of 32,500+ women also looked into the diets of over 15,100 men to see if their consumption of high glycemic foods affected their heart health.  But interestingly, no such linkage could be made between the kinds of carbohydrates men ate.  Researchers attribute the differentiation to the fact that men and women metabolize foods differently.

So, does this give men the green light to eat white bread and corn flakes whenever they want?  Alternatively, does this mean women should avoid white bread like the plague?

To both, the answer is no.  There’s nothing wrong with an occasional sandwich with white bread, so long as your bread options are more often than not 100 percent whole wheat.

And men, while your choice of bread may not influence your heart disease risk, a 10-year study conducted by Harvard researchers in 1994 found that men who ate high fiber breads like wheat had fewer heart attacks and fewer strokes than men who opted for white.

So when you’re out perusing the bread aisle and deciding what bread’s best, keep the white out of sight and make wheat your new favorite treat.

But buyer beware:  Don’t assume that brown in color means it’s wheat.  Many breads are made with refined flour; they’re just dyed brown with caramel color to make it look like they’re wheat. Read the ingredients label.  If the first listing doesn’t say “100 percent whole wheat,” put the brown down.

Sources:
vegetariantimes.com
msnbc.msn.com

Discuss this post in Frank Mangano’s forum!

A recent review paper: "Calorie Restriction (CR) research has expanded rapidly over the past few decades and CR remains the most highly reproducible, environmental intervention to improve health and extend lifespan in animal studies. Although many model organisms have consistently demonstrated positive responses to CR, it remains to be shown whether CR will extend lifespan in humans. Additionally, the current environment of excess caloric consumption and high incidence of overweight/obesity illustrate the improbable nature of the long-term adoption of a CR lifestyle by a significant proportion of the human population. Thus, the search for substances that can reproduce the beneficial physiologic responses of CR without a requisite calorie intake reduction, termed CR mimetics (CRMs), has gained momentum. ... The first results from a long-term, randomized, controlled CR study in nonhuman primates showing statistically significant benefits on longevity have now been reported. Additionally, positive results from short-term, randomized, controlled CR studies in humans are suggestive of potential health and longevity gains, while test of proposed [CR mimetics] have shown both positive and mixed results in rodents. ... Whether current positive results will translate into longevity gains for humans remains an open question. However, the apparent health benefits that have been observed with CR suggest that regardless of longevity gains, the promotion of healthy ageing and disease prevention may be attainable."

View the Article Under Discussion: http://www.ncbi.nlm.nih.gov/pubmed/20534066

Read More Longevity Meme Commentary: http://www.longevitymeme.org/news/

In recent years resveratrol has clearly fallen below the dividing line for work that is useful from a longevity perspective - if it could extend life significantly in mice, that would have been demonstrated by now. You might compare with the size of the effects on mouse lifespan for rapamycin to provide an example of a compound that is worth investigating. There is, however, a lot of money sunk into work on resveratrol and the underlying mechanisms of sirtuins, so don't expect that to halt any time soon. Research and developer institutions are prone to inertia, just like all other fields of human endeavor. In any case, here is some of the latest work on SIRT1: "If resveratrol needs SIRT1 to improve health, then animals lacking the gene should not get any benefits from the chemical. His lab published that experiment in yeast in 2003. But mice lacking SIRT1 die in the womb, or they are born with developmental defects such as blindness. To get around that problem, [researchers] engineered 'conditional knockout' mice whereby SIRT1 can be inactivated in adulthood. ... It took us two weeks to do the experiment in yeast, and five years in mouse, but finally we're there ... In normal mice, resveratrol combated the effects of a high-fat diet by boosting the efficiency of energy-generating organelles called mitochondria in skeletal muscle tissue. This effect vanished in adult mice without a working version of SIRT1. Yet SIRT1 wasn't responsible for all the beneficial effects of resveratrol ... Resveratrol stabilized the blood glucose levels of both normal and SIRT1-lacking mice on fatty diets. The chemical also improved liver health in mice without SIRT1. [The researchers also contend] that a lot the confusion over how resveratrol works comes down to dosage. At very high doses it binds other proteins besides SIRT1 ... For instance, a signalling protein called AMPK is also important to resveratrol's beneficial effects on metabolism. ... low doses of resveratrol boosted AMPK levels in various cells that expressed SIRT1, but not cells without the sirtuin. Much higher doses of resveratrol, however, activated AMPK irrespective of whether the cells expressed SIRT1."

Link: http://blogs.nature.com/news/2012/05/row-over-resveratrol-rumbles-on.html

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

The underlying infrastructural methods and technologies for working with stem cells are consistently improving - which lowers cost, thus allowing more research and development to take place. Here is an example: "researchers have proven that a special surface, free of biological contaminants, allows adult-derived stem cells to thrive and transform into multiple cell types. Their success brings stem cell therapies another step closer. An embryo's cells really can be anything they want to be when they grow up: organs, nerves, skin, bone, any type of human cell. Adult-derived 'induced' stem cells can do this and better. Because the source cells can come from the patient, they are perfectly compatible for medical treatments. ... We turn back the clock, in a way. We're taking a specialized adult cell and genetically reprogramming it, so it behaves like a more primitive cell. ... Before stem cells can be used to make repairs in the body, they must be grown and directed into becoming the desired cell type. Researchers typically use surfaces of animal cells and proteins for stem cell habitats, but these gels are expensive to make, and batches vary depending on the individual animal. ... human cells are often grown over mouse cells, but they can go a little native, beginning to produce some mouse proteins that may invite an attack by a patient's immune system. ... [A] polymer gel created by [researchers] in 2010 avoids these problems because researchers are able to control all of the gel's ingredients and how they combine. ... [Researchers] had shown that these surfaces could grow embryonic stem cells, [but] the polymer surface can also support the growth of the more medically promising induced stem cells, keeping them in their high-potential state. To prove that the cells could transform into different types, the team turned them into fat, cartilage and bone cells. They then tested whether these cells could help the body to make repairs. Specifically, they attempted to repair five-millimeter holes in the skulls of mice. The weak immune systems of the mice didn't attack the human bone cells, allowing the cells to help fill in the hole. After eight weeks, the mice that had received the bone cells had 4.2 times as much new bone, as well as the beginnings of marrow cavities. The team could prove that the extra bone growth came from the added cells because it was human bone."

Link: http://www.eurekalert.org/pub_releases/2012-05/uom-sse052312.php

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

A post at Extreme Longevity touches on an area of interest in aging research, and comes with a link to a PDF versions of the paper in question. It is another study confirming the link between levels of the protein p16INK4A and aging, something that has been known for some years. In particular, it shows up in the senescent cells that accumulate with age, something that researchers have managed to make use of: you might recall last year's study that showed beneficial effects from destroying senescent cells in rats. That research group used p16INK4A as a basis for their method of selective destruction, targeting only those cells that had become senescent and thus removing their contribution to the aging process.

It is worth noting that p16INK4A is a gene with a lot of aliases - which tends to happen when many different researchers have been working on the biochemistry independently. The official name is CDKN2A, or cyclin-dependent kinase inhibitor 2A, but it can be referred to as p16 as well. In any case, here is the Extreme Longevity post, a PubMed reference, and the PDF version of the paper:

In this study the researchers examined skin cells from middle aged people aged 43 to 63. They compared a group who had a strongly family history of extreme longevity to age-matched controls. They found that p16 expression in skin cells was significantly lower in the group that had the strong family history of longevity. They conclude "a younger biological age associates with lower levels of p16INK4a positive cells in human skin."

This study supports the idea that p16 expressing cells are linked to age both from a chronological as well as biological perspective. Work needs to be done to find a way to remove p16 positive cells from all tissues of the body on a regular basis. Such a therapy, if it existed, may act to reduce aging.

This all ties back in to cancer suppression versus tissue proliferation. Increased senescence in cells is one way of biasing the average over time to a lower rate of cancer - because the cells most likely to cause issues have been taken out of circulation and are no longer replicating. They should be destroyed by the immune system, but the immune system has its own age-related issues and falls down on that job, leaving the senescent cells to lurk and emit harmful signaling chemicals that damage surrounding tissue.

The flip side of the coin is that less replication among cells translates to less resilient tissues and organs, and thus faster aging. As mammalian biochemistry is set up by default, you can either be generating lots of fresh cells with a higher cancer risk, or aging faster due to poor tissue maintenance, but with a lower cancer risk. Biotechnology will let us escape from this Hobson's choice in due course - a method for tweaking the system associated with another cancer suppression gene to generate both less cancer and slower aging has been demonstrated in mice, for example. More and better technologies will emerge in human medicine in the fullness of time.

In particular, rather than focusing on metabolic tinkering to incrementally improve matters, the better approaches would be to (a) repair the ability of the immune system to eliminate senescent cells at a youthful level, and (b) develop therapies to regularly completely sweep senescent cells from the body. The effects of reducing senescent cell numbers in rats were sufficiently good that more work will be devoted to that sort of strategy in the future - and a good thing too.

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

Following on from a recent post on the involution of the thymus in adults, the process by which it ceases to generate immune cells and atrophies, here is a another paper that considers some of the possible paths to interventions that maintain the thymus into old age. Given experiments in mice showing that transplant of a young thymus extends life, this seems worthy of further investigation: "The thymus is the primary organ for T-cell differentiation and maturation. Unlike other major organs, the thymus is highly dynamic, capable of undergoing multiple rounds of almost complete atrophy followed by rapid restoration. The process of thymic atrophy, or involution, results in decreased thymopoiesis and emigration of naïve T cells to the periphery. Multiple processes can trigger transient thymic involution, including bacterial and viral infection(s), aging, pregnancy and stress. Intense investigations into the mechanisms that underlie thymic involution have revealed diverse cellular and molecular mediators, with elaborate control mechanisms. This review outlines the disparate pathways through which involution can be mediated, from the transient infection-mediated pathway, tightly controlled by microRNA, to the chronic changes that occur through aging."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22539280

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

An article from the Wellcome Trust: "Researchers have been engineering cartilage in the laboratory for 15 years or more, but as yet the tissues they have created don't function properly in human joints. [Researchers] are taking a new approach to try to bridge the gap between laboratory-created cartilage and the tissue our bodies make. ... Biological texts show that these lab-grown tissues have the appearance, texture, and protein and mineral components of bone and cartilage. But once they are tested in an animal, these tissues simply don't behave quite like the natural tissues they are supposed to replicate. ... Joints are remarkable feats of engineering, but efforts to grow them in the lab have focused mostly on their biology. ... Biologists attempting to create cartilage and bone over the past 15 years have typically tested the mechanical properties of their laboratory-grown tissue - for example, whether it is rubbery and resilient enough when pressure is applied. ... Just because biological tests indicate a tissue looks like bone and feels like bone, doesn't actually mean it is bone ... This is where an engineering perspective becomes important. To look at how close a match these laboratory-generated tissues really are to native bone and cartilage, [researchers] supplemented the biological analyses with engineering tests, such as bio-Raman microspectroscopy. ... You shine a laser on the material, and the way the light scatters gives you an idea of the bonds between its components. Different mineral types form different bonds, so you get a much more precise picture of what is actually present. ... If a lab-grown tissue seems from some tests to be the real thing but isn't really, then it won't behave like it once it has been implanted in a human body. ... [The researchers aim] to use an engineering approach to create a whole osteochondral interface in which bone and cartilage transition seamlessly into each other like they do in the body. ... That's the only way it will effectively transmit loads to the underlying bone. And because bone will heal, it will heal the construct into the joint."

Link: http://www.wellcome.ac.uk/News/2012/Features/WTVM054966.htm

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

For some years researchers have been investigating the mechanisms of limb and organ regrowth in lower animals like salamanders, with an eye to finding out how easy or hard it would be to recreate those same capabilities in mammals - such as we humans. Do we retain the core mechanisms, lying dormant in our biochemistry, or have they been completely lost? Time and ongoing research will tell.

But these are not the only areas of regrowth wherein researchers might learn something of interest to regenerative medicine. Consider that elk regularly regrow their antlers, for example - not a simple organ by any means. Further down the scale of impressiveness, we might consider the many higher animals that regularly regrow feathers or coats of hair. Is there anything in their biochemistry that might be discovered and adapted to cause humans to regenerate in situations where they normally do not?

If you buy into the argument that salamander biochemistry is worth investigation, then it's hard to reject similar investigations in other species capable of the lesser forms of regrowth mentioned above. An open access paper is presently doing the rounds on this topic; you can read the summary in the release, or look at the paper itself:

Physiological Regeneration of Skin Appendages and Implications for Regenerative Medicine

The concept of regenerative medicine is relatively new, but animals are well known to remake their hair and feathers regularly by normal regenerative physiological processes. Here, we focus on 1) how extrafollicular environments can regulate hair and feather stem cell activities and 2) how different configurations of stem cells can shape organ forms in different body regions to fulfill changing physiological needs.

Regenerative medicine has great potential. The main challenge is how to elicit and harness the power of regeneration. Currently, the major issues are how to obtain stem cells, how to pattern stem cells into organized tissues and organs, and how to deliver stem cell products to patients. Although human beings have very limited powers of regeneration, many animals have robust regenerative powers, distilled and selected over millions of years of evolution. Here, we review fundamental principles of regenerative biology learned from nature in the hope that they can be applied to help the progress of regenerative medicine.

...

Using the episodic regeneration of skin appendages as a clear readout, we have the opportunity to understand and modulate the behavior of adult stem cells and organ regeneration at a level heretofore unknown. Through this work, we hope to be able to establish or improve the stem cell environment so it can be applied to regenerative medicine.

In conclusion, we think it will be very productive to learn how nature manages the physiological regeneration process. This is a reprogramming process in which the genetic and epigenetic events converge to generate complex functional forms, depending on the physiological need in different parts of the body and at different stages of life. Principles learned from regenerative biology can then be applied toward regenerative medicine.

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

No-one should be surprised by the plausibility of rejuvenation biotechnology, as old people create young children, and only a tiny hint of the damage that makes people old seeps through that process. So we know that there exist ways for cells and larger structures to extremely effectively manage their level of damage - and some of the explorers in stem cell science have already recreated these processes outside their normal context. Here is a further exploration of what happens when old animals create young animals: "Although the body is constantly replacing cells and cell constituents, damage and imperfections accumulate over time. Cleanup efforts are saved for when it really matters. ... I have a daughter. She is made of my cells yet has much less cellular damage than my cells. Why didn't she inherit my cells including the damaged proteins? That's the process I'm interested in. ... A few days after conception, the cells in the embryo all look the same - they are unspecified stem cells that can develop into any bodily cell type. As the process of cell specification (differentiation) begins, they go from being able to keep dividing infinitely to being able to do so only a limited number of times. This is when they start cleansing themselves. ... Quite unexpectedly we found that the level of protein damage was relatively high in the embryo's unspecified cells, but then it decreased dramatically. A few days after the onset of cell differentiation, the protein damage level had gone down by 80-90 percent. We think this is a result of the damaged material being broken down. ... In the past, researchers have believed that the body keeps cells involved in reproduction isolated and protected from damage. Now it has been shown that these types of cells go through a rejuvenation process that rids them of the inherited damage." Can this process be isolated and applied safely to ordinary cells elsewhere in the body? Time will tell, but it's a worthy goal to aim for given its demonstrated effectiveness.

Link: http://www.physorg.com/news/2011-09-body.html

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

A few years ago, researchers demonstrated a way to reverse some of the effects of Alzheimer's disease - a method that, interestingly, didn't involve targeting buildup of beta amyloid, presently the mainstream focus of the Alzheimer's research community.

HDAC2 regulates the expression of a plethora of genes implicated in plasticity - the brain's ability to change in response to experience - and memory formation. ... Several HDAC inhibitors are currently in clinical trials as novel anticancer agents and may enter the pipeline for other diseases in the coming two to four years. ... The researchers conducted learning and memory tasks using transgenic mice that were induced to lose a significant number of brain cells. ... after taking HDAC inhibitors, the mice regained their long-term memories and ability to learn new tasks. In addition, mice genetically engineered to produce no HDAC2 at all exhibited enhanced memory formation.

There are a few other studies out there to place question marks next to the primacy of amyloid in Alzheimer's disease - but you have to weigh them against the huge number of studies suggesting that it is important. But it's certainly the case that, given the ability, we would want to remove all such buildups of metabolic byproducts that appear with age. Young people don't have them, old people have them, ergo they may be part of the problem - and given limited information and large resources, why not work toward reversing all changes?

Here's a recent update on HDAC2 research. To my eyes, the most promising aspect of this work is not that it will necessarily lead to a viable therapy - the odds are always low for every research program - but that it shows Alzheimer's to be a reversible disease until quite late in the game.

The researchers found that in mice with Alzheimer's symptoms, HDAC2 (but not other HDACs) is overly abundant in the hippocampus, where new memories are formed. HDAC2 was most commonly found clinging to genes involved in synaptic plasticity - the brain's ability to strengthen and weaken connections between neurons in response to new information, which is critical to forming memories. In the affected mice, those genes also had much lower levels of acetylation and expression. .. The researchers then shut off HDAC2 in the hippocampi of mice with Alzheimer's symptoms, using a molecule called short hairpin RNA, which can be designed to bind to messenger RNA - the molecule that carries genetic instructions from DNA to the rest of the cell. With HDAC2 activity reduced [genes] required for synaptic plasticity and other learning and memory processes [were] expressed. In treated mice, synaptic density was greatly increased and the mice regained normal cognitive function.

...

The researchers also analyzed postmortem brains of Alzheimer's patients and found elevated levels of HDAC2 in the hippocampus and entorhinal cortex, which play important roles in memory storage.

...

The findings may explain why drugs that clear beta-amyloid proteins from the brains of Alzheimer's patients have offered only modest, if any, improvements in clinical trials ... The new study shows that beta amyloid also stimulates production of HDAC2, possibly initiating the blockade of learning and memory genes. ... We think that once this epigenetic blockade of gene expression is in place, clearing beta amyloid may not be sufficient to restore the active configuration of the chromatin.

Which all sounds to me very much like real progress in understanding the mechanics of Alzheimer's, if it's all validated by the research community - incremental, true, but progress nonetheless.

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm