The liver is likely to be one of the earliest human organs grown to order from a patient's stem cells: liver tissue is already far more capable of regeneration than the tissues of other organs, and researchers have been making good progress in recent years in coaxing stem cells to form live tissue. As of today, a press report is doing the rounds to claim that a Japanese group have managed to grow a small functional mass of liver tissue - calling it a liver is no doubt considerably overstating the case, given the small size. Details are somewhat light on the ground, but we'll no doubt hear more soon.

Japanese researchers grow stem cell liver:

Japanese researchers have created a functioning human liver from stem cells, a report says. ... A team of scientists transplanted induced pluripotent stem (iPS) cells into the body of a mouse, where it grew into a small, but working, human liver, the Yomiuri Shimbun said.

A team led by professor Hideki Taniguchi at Yokohama City University developed human iPS cells into "precursor cells", which they then transplanted into a mouse's head to take advantage of increased blood flow. The cells grew into a human liver 5 millimetres (0.2 inches) in size that was capable of generating human proteins and breaking down drugs, the Yomiuri reported.

An abstract of Taniguchi's research was delivered to regenerative medicine researchers ahead of an academic conference next week, but Taniguchi declined to comment to AFP before the meeting.

The liver is a good example of an organ where the real challenges will lie in generating suitable blood vessels throughout the liver tissue and then integrating it with a patient's vascular system - being able to reliably build a mass of liver tissue from stem cells is but the first step on the path. Not that this is unknown; you might take a look at one of the more recent publications from Hideki Taniguchi's team, for example:

Generation of functional human vascular network:

One of the major obstacles in regenerating thick, complex tissues such as the liver is their need for vascularization, which is essential to maintain cell viability during tissue growth and to induce structural organization. Herein, we have described a method to engineer a functional human vascular network.

...

Vascularization is the key challenge to organ generation. We successfully generated human vascular networks inside a matrix. Integration of parenchymal cells using our engineering technique should facilitate future efforts to reconstitute vascularized human organ systems in vitro.

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

Andrew Weil, who is something of an apologist for aging, here holds forth on the merits of intermittent fasting (IF) - shown to improve health and extend life in laboratory animals through mechanisms that largely, but not entirely, overlap with those of calorie restriction: "An IF regime works, proponents say, because it aligns with our evolutionary history. Over the 250,000 years that Homo sapiens have been around, food supply has waxed and waned. We evolved to take advantage of this fact, building muscle and fatty tissue during times of abundance, then paring it back during lean ones. Fasting periods accelerate the clearing-out of waste left by dead and damaged cells, a process known as autophagy. A failure of autophagy to keep up with accumulated cellular debris is believed by many scientists to be one of the major causes of the chronic diseases associated with aging. Occasional fasting also seems to boost activity and growth of certain types of cells, especially neurons. This may seem odd, but consider it from an evolutionary perspective - when food is scarce, natural selection would favor those whose memories ("Where have we found food before?") and cognition ("How can we get it again?") became sharper. Research indicates that the benefits of IF may be similar to those of caloric restriction (CR) in which there are regular meals, but portions are smaller than normal. ... The positive effects of IF have been chronicled in a variety of animal and human studies, starting with a seminal experiment in 1946, when University of Chicago researchers discovered that denying food every third day boosted rats' lifespans by 20 percent in males, 15 percent in females. A 2007 review by University of California, Berkeley, researchers concluded that alternate-day fasting may: 1) Decrease cardiovascular disease risk. 2) Decrease cancer risk. 3) Lower diabetes risk (at least in animals, data on humans were less clear, possibly because the trial periods in the studies were not long enough to show an effect). 4) Improve cognitive function. 5) Protect against some effects of Alzheimer's and Parkinson's diseases."

Link: http://www.huffingtonpost.com/andrew-weil-md/fasting-health_b_1557043.html

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

This interview, machine-translated from the Russian, will be of interest to those who look into the history of transhumanist thought on the defeat of aging and radical life extension. It has deep roots back into the early 20th century, and one thread of these ideas was evolving through the ongoing disaster that was Russia of that century - the Russian cosmists are thought of as important predecessors to modern transhumanism, for example. These are some thoughts and recollections of someone who was publishing and thinking on the topic in the 1960s and later; note that the Russian end of the longevity science community are far from shy when it comes to talking about physical immortality as the end goal of medicine: "Meanwhile, today, in the [21st] century, when we talk about the necessity of victory over death, of making real the possibility of personal immortality and resurrection [of cryopreserved] people - people often do not even bother to think about it, but with some, or even masochistic pleasure begin to look for rebuttal. One would think, what to look for them? Why create additional obstacles? Chance of dying there at all. So there is nothing to lose. Is not it better to try to work together and find ways to avoid it? ... But, oddly enough, and sadly, no modern humanity, nor any single country (maybe with the exception of Japan, as far as I know), even such a purpose not intended. It's still pretty amazing! After all, people continue to die today, but no action is [taken]. How so? ... And yet ... There is no doubt the science over the past half century has leaped forward. Scientific and technological progress has radically changed many things in our lives. And the inspirational process is irreversible. You ask ... where the source of my optimism. He is in me and outside me. This is my inner conviction, supported by all the progressive tradition of Russian philosophical thought and [unstoppable] scientific thought."

Link: http://translate.google.com/translate?hl=en&sl=ru&tl=en&u=http%3A%2F%2Fm-batin.livejournal.com%2F144701.html

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

Researchers interested in finding genetic contributions to longevity generally start with some form of correlation study: trying to find commonalities between the genomes and epigenomes of long-lived individuals. So far, this has produced a great deal of data, much of which is unique to particular study populations - which suggests that there are many, many contributions to longevity buried in human genetic variations, and most are not all that important when considered in isolation. The odds of finding anything resembling a master switch for additional life span look remote at this point.

So the situation is complex, quite aside from the fact that it would still be a troublesome field of research even if the hunt was for one or more master switches. Researchers face an uphill struggle, as noted in a recent open access commentary, and thus have to be more inventive in their research:

It is a stroke of irony that lifespan - the principal phenotype used to search for aging genes - is a terrible phenotype for genetic analysis. Lifespan has relatively low heritability under most conditions, and it is affected by chronic, age-related diseases that confound its use as a biomarker of aging.

If the majority of aging genes are pleiotropic, as proposed by the evolutionary theory of aging, an opportunity is provided to identify these genes through the "back door," using phenotypes that are more amenable to genetic analysis.

To choose the pleiotropic phenotype for our studies, we went back more than 50 years to Williams, who, in his seminal paper, specified four "physiological expectations that follow from the theory," two of which we applied: "Rapid individual development should be correlated with rapid senescence," and, to specify a particular developmental phenotype, "The time of reproductive maturation should mark the onset of senescence." Therefore, to search for genes that regulate lifespan, we looked in the other direction - for genes that govern reproductive maturation.

The researchers then outline some of their investigations; when it produces candidate genetic variants, those variants still have to be confirmed in the same old standard, slow, and laborious way - animal studies of life span. In general the work of building a catalog of aging-related gene variants is slow going, and in the end will have far less practical application than other approaches to longevity science. This isn't to say that it shouldn't be done; all life science knowledge has value. But if the goal is to do something about the terrible cost of human aging, and do it as soon as possible, then approaches other than genetic investigation must have priority in the field.

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

Via EurekAlert!: "For the first time, we are showing evidence that vascular diseases are actually a kind of stem cell disease. ... It is generally accepted that the buildup of artery-blocking plaque stems from the body's immune response to vessel damage caused by low-density lipoproteins ... Such damage attracts legions of white blood cells and can spur the formation of fibrous scar tissue ... The scar tissue, known as neointima, has certain characteristics of smooth muscle, the dominant type of tissue in the blood vessel wall. Because mature smooth muscle cells no longer multiply and grow, it was theorized that in the course of the inflammatory response, they revert, or de-differentiate, into an earlier state where they can proliferate ... However, no experiments published have directly demonstrated this de-differentiation process ... researchers turned to transgenic mice with a gene that caused their mature smooth muscle cells to glow green under a microscope. In analyzing the cells from cross sections of the blood vessels, they found that more than 90 percent of the cells in the blood vessels were mature smooth muscle cells. They then isolated and cultured the cells taken from the middle layer of the mouse blood vessels. ... Notably, none of the new, proliferating cells glowed green, which meant that their lineage could not be traced back to the mature smooth muscle cells originally isolated from the blood vessels. ... We did further tests and detected proteins and transcriptional factors that are only found in stem cells. No one knew that these cells existed in the blood vessel walls because no one looked for them before. ... In the later stages of vascular disease, the soft vessels become hardened and more brittle. Previously, there was controversy about how soft tissue would become hard. The ability of stem cells to form bone or cartilage could explain this calcification of the blood vessels. ... Other tests in the study showed that the multipotent stem cells were dormant under normal physiological conditions. When the blood vessel walls were damaged, the stem cells rather than the mature smooth muscle cells became activated and started to multiply." Though if you want to consider root causes, look at mechanisms like accumulated damage to mitochondria that leads to a greater level of oxidized low-density lipoproteins in the blood.

Link: http://www.eurekalert.org/pub_releases/2012-06/uoc--trc053112.php

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

One of the costs of being sedentary is fiscal: the cost of medical services you would otherwise not have needed due to your increased risk of age-related disease. Here is another researcher running the numbers: "Physical inactivity is a recognized public health issue in Canada and globally ... A common approach for assessing the public health impact of physical inactivity is to measure the prevalence of the population not meeting physical activity guidelines. Recent surveillance data based on objective measures indicate that 85% of Canadian adults do not meet Canada's physical activity guidelines of 150 min/week of moderate-to-vigorous physical activity ... A second approach for assessing the public health impact of physical inactivity is to estimate the proportion of a disease within the population that is directly attributable to physical inactivity. For instance, 19% of the coronary artery disease cases in Canadian men are due to physical inactivity ... A third approach for assessing the public health impact of physical inactivity is to estimate the financial burden it places on the health care system and economy. The most recent Canadian estimates, based on 2001 data, suggest that the annual economic burden of physical inactivity is $5.3 billion. ... Similar to the 2001 estimates, the health care cost of physical inactivity in this report was estimated using a prevalence-based approach, which required 3 pieces of information: (1) the risks of chronic conditions in physically inactive individuals, (2) the direct and indirect costs of these chronic diseases, and (3) the prevalence of physical inactivity in the population. ... The estimated direct, indirect, and total health care costs of physical inactivity in Canada in 2009 were $2.4 billion, $4.3 billion, and $6.8 billion, respectively. These values represented 3.8%, 3.6%, and 3.7% of the overall health care costs." It is interesting to compare these numbers with research on individual lifetime medical cost differences that stem from being out of shape, and with some other number crunching on the economics of health and longevity.

Link: http://www.nrcresearchpress.com/doi/full/10.1139/h2012-061

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

You might recall research published a couple of months ago on calorie restriction and heart function. It illustrated (again) that people who practice calorie restriction over the long term have physiologically younger cardiovascular systems - meaning notably less low-level cellular damage and better function than their peers of a similar chronological age.

Heart rate variability (HRV) is a marker for cardiac autonomic functioning. The progressive decline in HRV with aging and the association of higher HRV with better health outcomes are well established. [Researchers] compared 24-hr HRV in 22 CR individuals aged 35 - 82 yrs and 20 age-matched controls eating Western diets (WD). The CR group was significantly leaner than the WD group. Heart rate was significantly lower, and virtually all HRV significantly higher in the CR than in the WD group. HRV in the CR individuals was comparable to published norms for healthy individuals 20 years younger.

If there was a drug that did that, its financials would be staggering - and you'd never hear the end of it. It would be publicized and popularized in every corner of the world. But just ask someone to exercise a little willpower and planning in their diet to gain the same results ... and therein lies a lesson with regard to human nature.

I notice that the institutional publicity machine at Washington University in St.Louis has caught up with this research; if you'd like a little more commentary from the researchers involved, that's the place to look:

"This is really striking because in studying changes in heart rate variability, we are looking at a measurement that tells us a lot about the way the autonomic nervous system affects the heart," says Luigi Fontana, MD, PhD, the study's senior author. "And that system is involved not only in heart function, but in digestion, breathing rate and many other involuntary actions. We would hypothesize that better heart rate variability may be a sign that all these other functions are working better, too."

...

"Higher heart rate variability means the heart can adjust to changing needs more readily," says lead author Phyllis K. Stein, PhD. "Heart rate variability declines with age as our cardiovascular systems become less flexible, and poor heart rate variability is associated with a higher risk of cardiovascular death."

...

"The idea was to learn, first of all, whether humans on CR, like the calorie-restricted animals that have been studied, have a similar adaptation in heart rate variability," Fontana says. "The answer is yes. We also looked at normal levels of heart rate variability among people at different ages, and we found that those who practice CR have hearts that look and function like they are years younger."

...

"In many of our studies, we have found that a number of metabolic and physiologic changes that occur in calorie-restricted animals also occur in people who practice CR," Fontana says. And he says the finding that heart rate variability is better in people who practice CR means more than just that their cardiovascular systems are flexible. He says the better ratio suggests improved health in general.

"But we can't be absolutely positive that the practice of CR is solely responsible for the flexibility of the cardiovascular system," Stein says. "People who practice CR tend to be very healthy in other areas of life, too, so I'm pretty sure they don't say to themselves, 'Okay, I'll restrict my calorie intake to lengthen my life, but I'm still going to smoke two packs a day.' These people are very motivated, and they tend to engage in a large number of very healthy behaviors."

The point on calorie restriction practitioners practicing good health across the board is a fair one - peeling apart the beneficial effects of regular exercise from the beneficial effects of calorie restriction in humans, for example, is an interesting challenge. Still, it would be hard, I think, to find a population of humans who are exceptionally health-conscious without practicing calorie restriction and who nonetheless exhibit a youthful physiology to the degree seen in calorie restricted people. There are different classes of mechanism at work here.

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

Here is a study that points to amount of visceral fat as a dominant contribution to the risk of age-related type-2 diabetes - a condition rarely suffered by people who successfully avoid putting on weight over the years - something that doesn't just happen, but requires exercise and a sensible approach to diet and lifestyle. "A collaborative re-analysis of data from the InterAct case-control study [has] established that waist circumference is associated with risk of type 2 diabetes, independently of body mass index (BMI). Reporting in this week's PLoS Medicine, the researchers estimated the association of BMI and waist circumference with type 2 diabetes from measurements of weight, height and waist circumference, finding that both BMI and waist circumference were independently associated with type 2 diabetes risk but waist circumference was a stronger risk factor in women than in men. ... The prospective InterAct case-cohort study was conducted in 26 centres in eight European countries and consists of 12,403 incident [type 2 diabetes] cases and a stratified subcohort of 16,154 individuals from a total cohort of 340,234 participants with 3.99 million person-years of follow-up. ... These findings indicate that targeted measurement of waist circumference in overweight individuals (who now account for a third of the US and UK adult population) could be an effective strategy for the prevention of diabetes because it would allow the identification of a high-risk subgroup of people who might benefit from individualised lifestyle advice. ... Our results clearly show the value that measurement of [waist circumference] may have in identifying which people among the large population of overweight individuals are at highest risk of diabetes." A risk that is essentially yours to create, remove, or manage through the choices you make.

Link: http://www.eurekalert.org/pub_releases/2012-06/plos-wcl053112.php

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

The SENS Foundation Academic Initiative continues to grow, laying the foundation for the next generation of researchers working on rejuvenation biotechnology: "The Academic Initiative is likely to see another increased budget in 2013. We plan to offer at least as many scholarships and grants as we're offering this year, while we are nearly certain to expand our summer internship program, bringing in more interns overall and sending them to a greater number of labs. This year, some interns have been placed at the SENS Foundation Research Center, while others have gone to the Buck Institute for Research on Aging. We hope to place more interns at each location next year, and to add new locations. The Initiative's budget may not be the only thing that changes with the coming of the new year. SENS Foundation itself is still planning a revamp of its website, and the Academic Initiative won't miss that chance to have its own website enhanced further. Planning for our own next website has begun: long story short, it'll be simpler with less text and will offer very clear and immediate ways for students to get started. Some graphic design work that will go online with that new site is also underway. We'd like to finish by pointing out that we still have enough funding to continue to award materials grants throughout the summer and into the Fall 2012 semester. Since many students have extra time to put a proposal together over the summer, and since we're currently seeing a (likely summer-related) increase in interest in our grants, this is a particularly good time to apply."

Link: http://sens.org/node/2762

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

Microglia are immune cells that defend and clean up the brain and spinal cord. Like the rest of the immune system, they progressively fail in their work with age. Worse, like other immune system components, they begin to become actively harmful by causing chronic inflammation and other forms of damage instead of helping. Reversing that trend is one important line of research among many that, as they produce working medical technologies, will extend our healthy life spans.

Keeping the brain in good working shape is one of the most important goals of medical research. There is no short cut here by way of the comparatively advanced fields of stem cell medicine and tissue engineering - we can't look ahead to replacement brains in the next decade or two as we can for other organs. The brain has to be repaired in situ, completely and sufficiently for the long term: every form of age-related cellular damage either worked around or reversed. So microglia, as an important part of the existing maintenance systems in the brain, are of considerable interest. Can early successes be obtained by boosting their activity, or slowing or reversing their decline with age? The Longecity-funded research project on microglia transplants falls into this general area of research - something we'd like to see more of.

Following on from that topic, here is an open access review paper that provides an introduction to microglia in context of aging and neurodegeneration:

For many years, chronic neurodegenerative disorders of the central nervous system (CNS) were thought of in terms of primary neuronal dysfunction and loss with secondary glial and inflammatory responses. ... but of late this theory has required revision.

Microglia, which account for approximately 10% of the adult brain cell population, were first described by Pio Del Rio Hortega in 1919 ... However, it was not until the late 1980s that this field came of age when, using the new technique of immunohistochemistry, the McGeers showed that within the Alzheimer's disease (AD) brain there were large numbers of [activated] microglia. ... The pioneering work of the McGeers was to radically change how these diseases were seen as they went on to show that microglia were not only intimately bound to central inflammatory responses and antigen presentation, but in fact the whole innate immune system itself had a role to play in these CNS disorders.

Initial views on the role of microglia suggested that these cells were simply there to scavenge up debris and dead cells, while astrocytes fulfilled some supportive role in the CNS. However, microglia are now recognized to have a complex array of supportive and destructive roles in the CNS and that the balance between the two may be critical in driving some aspects of disease processes. Astrocytes are now seen as being fundamental in shaping and maintaining the developing and mature CNS, including a role in adult neurogenesis, axonal regeneration, and the [blood-brain barrier]. The dynamic interplay between all of these different CNS compartments is becoming more evident, such that some neurodegenerative disorders of the CNS may have a pathology as much in the glial cells as in the neurons themselves. This all means that understanding what happens in disease states is far more complex than originally conceived and that targeting each element of the interaction may be the route by which true disease modification can be achieved.

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