An article on the development of prosthetic organs, a field that continues to provide competition for regenerative medicine:

Proponents of biological organ replacements have recently been encouraged by the development of 3D tissue printing, which offers the tantalising possibility that we might build organs mechanically, layer by layer - a much faster process than growing them in the lab. But printing complex internal organs like the liver or heart is still some way off, and the technology will face similar issues to traditional tissue engineering when it comes to implanting. In the meantime, some scientists are pursuing a different approach, combining biological tissue with synthetic materials and/or mechanical and electronic components to create what could be called hybrid or even cyborg organs (cyborgans, if you will), which are more easily manufactured, longer lasting and more successful once implanted into the body.

On one level this means incorporating some biological material into a largely man-made device. French firm Carmat [has] begun animal trials on one of the world's most advanced designs for an artificial heart, which includes some biological elements.The two chambers inside the Carmat heart are each divided by a biomembrane that separates blood on side from hydraulic fluid on the other. Tiny motors controlled by an electronic sensor system pump the hydraulic fluid in and out of the chambers, in turn causing the membrane to pump the blood. To increase haemocompatiblity, the membrane is made from animal tissue that helps move the blood without damaging cells. Microporous biological and synthetic biomaterials also cover every other surface that comes in contact with the blood, in order to prevent material from sticking to them.

But scientists are also combining biological and synthetic materials in a more fundamental way, creating permanent artificial structures or scaffolds and then growing living cells around them. [Researchers are] already preparing to clinically trial blood vessels and tracheae (windpipes) made in this way, and [are] also developing urethrae, bladders and cardiac patches for healing hearts.

Link: http://www.theengineer.co.uk/medical-and-healthcare/in-depth/body-builders-developing-cyborg-organs/1016241.article

Source:
http://www.fightaging.org/archives/2013/05/the-state-of-electromechanical-and-bioartifical-organs.php

Many longevity mutations discovered in lower animals such as nematodes involve alterations to mitochondrial function - which only reinforces the apparent importance of mitochondria in determining life span. Mitochondria swarm within cells, working to produce the chemical energy stores used to power cellular operations. In doing so they emit reactive oxygen species, however, that can cause all sorts of harm to the molecular machinery of a cell if not neutralized by a cell's native antioxidants. It is damage to mitochondrial DNA, however, that seems to be one of the root causes of degenerative aging, via a Rube Goldberg sequence of consequences that causes cells to become dysfunctional mass exporters of reactive, harmful molecules.

From a practical therapy standpoint, the research community should be working on ways to repair, replace, or back up mitochondrial DNA in our cells if we want this contribution to aging to go away. That work is very poorly funded, however, in comparison to the benefits it might deliver. Meanwhile, examination of longevity mutations in lower animals continues to reinforce the fact that this is an important direction for therapies to treat and reverse aging.

Some mitochondrial longevity mutations work via hormesis; they cause a slight increase in the level of emitted reactive oxygen species, which in turn causes the cell to react with increased housekeeping and repair activities, resulting in a net gain - less damage over the long term translates into slower aging. Other mutations lower the level of emitted reactive oxygen species, which again means less damage over the long term. Yet more mitochondrial mutations extend life in less obvious ways, or cause mitochondrial dysfunction that appears at the high level to be broadly similar to that of longevity mutants, yet reduces life span. Once you start digging in to the mechanisms of the mitochondrial interior - the electron transport chain with it's multiple complexes - it's all far from simple

Here is an example of research into the mechanisms of mitochondrial longevity mutations in nematode worms:

Many Caenorhabditis elegans mutants with dysfunctional mitochondrial electron transport chain are surprisingly long lived. Both short-lived (gas-1(fc21)) and long-lived (nuo-6(qm200)) mutants of mitochondrial complex I have been identified. However, it is not clear what are the pathways determining the difference in longevity.

We show that even in a short-lived gas-1(fc21) mutant, many longevity assurance pathways, shown to be important for lifespan prolongation in long-lived mutants, are active. Beside similar dependence on alternative metabolic pathways, short-lived gas-1(fc21) mutants and long-lived nuo-6(qm200) mutants also activate hypoxia-inducible factor-1? (HIF-1?) stress pathway and mitochondrial unfolded protein response (UPRmt).

The major difference that we detected between mutants of different longevity is in the massive loss of complex I accompanied by upregulation of complex II levels, only in short-lived, gas-1(fc21) mutant. We show that high levels of complex II negatively regulate longevity in gas-1(fc21) mutant by decreasing the stability of complex I. Furthermore, our results demonstrate that increase in complex I stability, improves mitochondrial function and decreases mitochondrial stress, putting it inside a "window" of mitochondrial dysfunction that allows lifespan prolongation.

Link: http://dx.doi.org/10.1371/journal.pone.0059493

Source:
http://www.fightaging.org/archives/2013/04/mitochondrial-functional-mutations-and-worm-longevity.php

Some people are more predisposed to suffer Parkinson's disease than others, a fraction of those due to mutations in genes involved in mitochondrial quality control. The state of mitochondrial function shows up as an important component of many different conditions and indeed in aging itself. In Parkinson's disease it is thought that mitochondrial dysfunction contributes to the conditions in which the population of dopamine-producing neurons in the brain die off, producing the characteristic symptoms of the disease.

It may be that more of Parkinson's disease is genetic than was previously thought, and the odds of that being the case increase as the chain of molecular machinery involved in mitochondrial quality control is followed and new components identified. This sort of work also helps clarify the mechanisms associated with mitochondrial dysfunction in aging:

Mitofusin 2 (Mfn2) is known for its role in fusing mitochondria together, so they might exchange mitochondrial DNA in a primitive form of sexual reproduction. "Mitofusins look like little Velcro loops. They help fuse together the outer membranes of mitochondria. Mitofusins 1 and 2 do pretty much the same thing in terms of mitochondrial fusion. What we have done is describe an entirely new function for Mfn2."

Mitochondria work to import a molecule called PINK. Then they work to destroy it. When mitochondria get sick, they can't destroy PINK and its levels begin to rise. Once PINK levels get high enough, they make a chemical change to Mfn2, which sits on the surface of mitochondria. This chemical change is called phosphorylation. Phosphorylated Mfn2 on the surface of the mitochondria can then bind with a molecule called Parkin that floats around in the surrounding cell.

Once Parkin binds to Mfn2 on sick mitochondria, Parkin labels the mitochondria for destruction. The labels then attract special compartments in the cell that "eat" and destroy the sick mitochondria. As long as all links in the quality-control system work properly, the cells' damaged power plants are removed, clearing the way for healthy ones. "But if you have a mutation in PINK, you get Parkinson's disease. And if you have a mutation in Parkin, you get Parkinson's disease. About 10 percent of Parkinson's disease is attributed to these or other mutations that have been identified." The discovery of Mfn2's relationship to PINK and Parkin opens the doors to a new genetic form of Parkinson's disease.

Link: http://www.sciencedaily.com/releases/2013/04/130425142357.htm

Source:
http://www.fightaging.org/archives/2013/04/joining-the-dots-in-genetic-parkinsons-disease.php

The indy gene - named for "I'm not dead yet" - was one of the earliest longevity mutations to be uncovered in flies, and consequently is somewhat better studied than the many that have followed since then. Here is an open access paper on the subject:

Decreased expression of the fly and worm Indy genes extends longevity. The fly Indy gene and its mammalian homolog are transporters of Krebs cycle intermediates, with the highest rate of uptake for citrate. Cytosolic citrate has a role in energy regulation by affecting fatty acid synthesis and glycolysis. Fly, worm, and mice Indy gene homologs are predominantly expressed in places important for intermediary metabolism. Consequently, decreased expression of Indy in fly and worm, and the removal of mIndy in mice exhibit changes associated with calorie restriction, such as decreased levels of lipids, changes in carbohydrate metabolism and increased mitochondrial biogenesis. Here we report that several Indy alleles in a diverse array of genetic backgrounds confer increased longevity.

The paper is a good example of the way in which calorie restriction muddies the water of longevity studies; the effects of calorie restriction on life span are very strong in lower animals like flies and worms, and many past studies failed to fully account for differing dietary calorie intakes between populations of these animals. The authors of this paper point out a number of past papers with results that may tainted due to differing calorie intake, and note that their own work tries to control for this.

Link: http://www.frontiersin.org/Genetics_of_Aging/10.3389/fgene.2013.00047/full

Source:
http://www.fightaging.org/archives/2013/04/indy-mutations-and-fly-longevity.php

A range of research in laboratory animals associates alterations to the reproductive system with alterations in longevity. Nematode worms live longer if you remove their germ cells, for example. Transplanting younger ovaries into older mice extends life as well. There is some thought that these varied approaches work through common longevity mechanisms such as insulin-like signaling pathways, but that's by no means certain.

Here is another set of data to add to the existing research on this topic:

Reproduction is a risky affair; a lifespan cost of maintaining reproductive capability, and of reproduction itself, has been demonstrated in a wide range of animal species. However, little is understood about the mechanisms underlying this relationship. Most cost-of-reproduction studies simply ask how reproduction influences age at death, but are blind to the subjects' actual causes of death. Lifespan is a composite variable of myriad causes of death and it has not been clear whether the consequences of reproduction or of reproductive capability influence all causes of death equally.

To address this gap in understanding, we compared causes of death among over 40,000 sterilized and reproductively intact domestic dogs, Canis lupus familiaris. We found that sterilization was strongly associated with an increase in lifespan, and while it decreased risk of death from some causes, such as infectious disease, it actually increased risk of death from others, such as cancer.

Although a retrospective, epidemiological study such as this cannot prove causality, our results suggest that close scrutiny of specific causes of death, rather than lifespan alone, will greatly improve our understanding of the cumulative impact of reproductive capability on mortality. Our results strongly demonstrate the need to determine the physiologic consequences of sterilization that influence causes of death and lifespan. Shifting the focus from when death occurs to why death occurs could also help to explain contradictory findings from human studies.

Link: http://dx.doi.org/10.1371/journal.pone.0061082

Source:
http://www.fightaging.org/archives/2013/04/sterilized-dogs-live-longer.php

It is worth keeping an eye on progress towards the creation of artificial cells and cell-like structures, as they are potentially useful in a very broad range of biotechnologies relevant to longevity science, regenerative medicine, and so forth. The first swarms of medical microrobots will quite likely be modified cells or artificial cells, packed with specific forms of molecular machinery to achieve some sort of effect in the body - such as manufacturing signaling compounds in response to local conditions, so as to steer the activities of surrounding cells.

A custom-built programmable 3D printer can create materials with several of the properties of living tissues. The new type of material consists of thousands of connected water droplets, encapsulated within lipid films. Because droplet networks are entirely synthetic, have no genome and do not replicate, they avoid some of the problems associated with other approaches to creating artificial tissues - such as those that use stem cells. Each droplet is an aqueous compartment about 50 microns in diameter. Although this is around five times larger than living cells the researchers believe there is no reason why they could not be made smaller. The networks remain stable for weeks.

"We aren't trying to make materials that faithfully resemble tissues but rather structures that can carry out the functions of tissues. We've shown that it is possible to create networks of tens of thousands of connected droplets. The droplets can be printed with protein pores to form pathways through the network that mimic nerves and are able to transmit electrical signals from one side of a network to the other."

Link: http://www.sciencedaily.com/releases/2013/04/130404142457.htm

Source:
http://www.fightaging.org/archives/2013/04/another-step-towards-early-artificial-cells.php

Few people seem terribly interested in noting the opportunity costs of aging, for all that a great deal of work goes into trying to build models for the direct costs. Insurers, government program administrators, and so forth, are all eager to put numbers to their potential future outlays - but they have fewer incentives to work on better numbers for the lost ability to earn that comes with advancing age. Here are some figures from a recent paper on dementia in the US, for example:

The estimated prevalence of dementia among persons older than 70 years of age in the United States in 2010 was 14.7%. The yearly monetary cost per person that was attributable to dementia was either $56,290 (95% confidence interval [CI], $42,746 to $69,834) or $41,689 (95% CI, $31,017 to $52,362), depending on the method used to value informal care. These individual costs suggest that the total monetary cost of dementia in 2010 was between $157 billion and $215 billion. Dementia represents a substantial financial burden on society, one that is similar to the financial burden of heart disease and cancer.

If you go digging around in US census data on income, or the quick summaries thereof, you'll see that median income sits somewhere a little under $40,000/year in the prime earning years of life. It tapers off to a little more than half of that for surviving members of the 75 and older demographic. So while one of seven completely median older people incurs costs of roughly $40,000/year for dementia, all seven completely median older people suffer an opportunity cost of roughly $20,000/year as a result of becoming old. A range of income that might have been earned if still healthy and vigorous is no longer within reach.

These are very rough and ready comparisons, but you can see that even piling in a bunch of other direct medical costs for the rest of the population - cancer, diabetes, cardiovascular disease, and the other common foes - the opportunity costs of being old still look sizable in comparison. In another study that gives average medical costs over time for people in Japan aged between 40 and 80 followed over 13 years, the average yearly expenditure was in the ~$3,500 range, rising to more like ~$25,000 in the last year prior to death. The error bars for casual use of any of the numbers mentioned in this post is large - probably a factor of two, given all of the oddities and politics that goes into medical expenditures and recording of income, and especially when comparing data between different regions on the world. But you can still draw very rough conclusions about relative sizes.

Lastly, I should note that all of the above only considers the living. Once you get to the age 75 demographic in the US, half of the original population is dead, give or take. The dead accrue even higher opportunity costs than those mentioned above, as they have (for the most part) lost all ability to earn or contribute to building new things.

So aging causes a largely unseen cost to go along with what is seen, the cost of what might have been but for disability and death. As is often the case, the cost of research and development to build the means of rejuvenation is small in comparison to what is lost to aging - and also in comparison to what is spent in coping with the aftermath of loss rather than trying to prevent it.

Source:
http://www.fightaging.org/archives/2013/04/on-costs-and-opportunity-costs-of-aging.php

Without the biotechnologies of human rejuvenation that could be created over the next twenty years given a fully funded crash program of development, we and our descendants will all die due to the effects of aging, exactly as did our ancestors. Aging to death has never been a choice - but now it is, and every needless day of delay comes at a cost of 100,000 lives. Everyone presently alive will suffer greatly due to aging and age-related conditions unless new medical technologies of the sort envisaged by the SENS Research Foundation are developed to repair and reverse the low-level biological damage that causes of aging. So why isn't this front and center on everyone's list of concerns? Why does longevity science and the elimination of age-related suffering barely even register in public eye?

Here is a talk on this subject given at the Stanford Advancing Humanity Symposium last month by Maria Konovalenko of the Russian Science For Life Extension Foundation, an advocacy initiative:

In this talk I am sharing our wonder about why haven't the ideas of life extension won. It is not clear why isn't every person on Earth concerned with their longevity. There are several serious reasons that I mention in my presentation, but even all of them combined don't give the answer to this question. I am also looking at different possible scenarios of how the extending longevity ideas could rise to power.

Source:
http://www.fightaging.org/archives/2013/04/why-isnt-longevity-science-the-worlds-greatest-concern.php

This article looks past the immediate challenges of aging and early medical biotechnologies aimed at extending human longevity, and into the future of merged molecular manufacturing and biotechnology, when it will become possible to replace our biology with far more robust and long-lasting machinery:

If we're talking far-future, non-biological approaches to life-extension will win out over biological approaches, due mainly to their comparative advantages (e.g. ease of repair and modification). [I] think that the distinction between non-biological and biological systems (especially if Drexlerian nanotech - that is, using mechanosynthesis - is implemented with any ubiquity) will increasingly dissolve. If a system exhibits the structural, functional and operational modalities of a biological cell, tissue, organ or organism, yet consists of wholly inorganic materials, is it not closer to a biological system than to what we would typically consider a non-biological system? Either the distinction between the two will eventually dissolve, or we will use the term "biological" to designate systems exhibiting the structural, functional, and/or operational modalities of biological systems.

I make a distinction between life-extension therapies and indefinite-longevity therapies, and I'd like to elaborate more on this distinction here. Life-extension therapies extend longevity, but for various reasons fail to make it necessarily indefinite or unlimited. Often this is because such therapies aren't comprehensive - a given therapy solves one contributing factor of aging, but not all of them. Others, like SENS (which I'm in no way discounting), fix the major causes of damage, but use a different methodology for each respective source of damage or aging; the drawback of this approach is that if previously overshadowed causes of aging now begin to make a non-negligible impact on aging, in the absence of the more predominant causes, then we have no methodology to combat it. Because each strategy is tied intimately to the cause it seeks to ameliorate, the techniques often cannot be applied to the new source of molecular damage.

Indefinite or unlimited longevity therapies, on the other hand, use one comprehensive approach to mitigate all sources of aging. One example is Drexlerian nanotech (and to a shared but somewhat lesser extent Robert Freitas's nanomedicine - only because it has specifically-tailored strategies not dependent on the feasibility of Drexlerian molecular assembly or "mechanosynthesis", in addition to the more comprehensive ones). This approach fixes not the source of the damage but the damage itself, iteratively, and can thus be used to combat any source of molecular damage using the same tools, technologies and techniques. With such therapies we wouldn't need to come up with a second wave of strategies to combat those sources of aging that might crop up in the future, and which remained unnoticed until such a time only because their impact couldn't be seen (or allowed to take effect) while the first wave of sources was still predominant.

I'm not totally convinced that this last point is the case; I think it's more that a designed replacement for tissue can be made to have far fewer and more comprehensibly understood forms of aging (which can be repaired on an ongoing basis). But there will still be the unknowns, pushed into an ever-smaller corner, and ever less important. Yet by the time it is possible to build artificial tissue and cell replacements in this way, will we not have come to understand biology so well that the unknowns in biological aging are already equally small?

Link: http://lifeboat.com/blog/2013/04/longer-life-or-unlimited-life

Source:
http://www.fightaging.org/archives/2013/04/longer-life-or-unlimited-life.php

Advances in medical biotechnology happen constantly, and every field that is working towards long-term goals - such as, say, growing new organs from scratch or gaining sufficiently control over cells to repair and rejuvenate organs in situ - spins off new and incrementally better applications at each waypoint on the road. Every narrow field of applied life sciences has it's aura of new technologies and partial implementations.

So for the liver: one end goal would be the ability to simply grow livers on demand from a patient's own cells, another to reliabily trigger liver regrowth to the same degree as happens in lower animals. Still another is to repair damage and dysfunction globally in the liver's cells, so as to restore it to youthful capacity and function. The foundations for all of these goals are under construction, and along the way we see all sorts of interesting practical applications of biotechnology.

Here are a few such appications from recent news releases, with an emphasis on integration of biology with machinery, something that we'll be seeing a lot more of in the years ahead. These are first steps along a road that will see part-machine-part-biological tissues competing with artificially grown but otherwise wholly biological tissues, until such time as that distinction begins to blur at the edges with the advent of advanced forms of molecular nanotechnology.

Machine that preserves liver outside body offers new hope to transplant patients

At present, donated livers are cooled to 4C (39.2F) to preserve them, but this process does not stop them from deteriorating and they can only be stored for about 12 hours. The machine developed by scientists at Oxford University warms the organ to body temperature and circulates a combination of blood, oxygen and nutrients through it, allowing it to function just as it would inside a human body.

Researchers are confident they will be able to keep donor organs alive for 24 hours, and pre-clinical tests suggest it may be possible to preserve them for 72 hours or more. Modified versions of the portable device, which is the size of a supermarket shopping trolley, could also help transplants of other organs, including the pancreas, kidneys and lungs, and could be used to test the toxicity of new medicines.

Artificial human livers engineered for drug testing and discovery

Researchers have now made it possible for companies to predict the toxicity of new drugs earlier, potentially speeding up the drug development process and reducing the cost of manufacturing. The tool they have engineered to enable this is an artificial human liver piece, which mimics the natural tissue environment closely.

[These] liver tissue models for drug toxicity testing [consist of a ] three-dimensional porous scaffold that enables liver cells to spontaneously assemble into three-dimensional liver spheroids. These spheroids strongly resemble liver tissue. [By] seeding liver cells within a microfluidic system, the micro device is used to screen the liver's capacity to process different drugs and other compounds.

Using [a] microfabricated microporous membrane, the liver cells are sandwiched between the membranes, which can control the transfer of drugs, nutrients and oxygen to the cells, and provide more reliable and reproducible screening results. The membrane surface has been engineered to simulate liver cell interaction with [the extracellular matrix] and promote formation of liver tissues after the cells are seeded. Experiments have shown that the microporous membranes can maintain long-term liver cell functions for more than two weeks and will be useful for chronic liver toxicity testing, and industry-scale drug screening.

Team first to grow liver stem cells in culture, demonstrate therapeutic benefit

In a previous [study], investigators [were] the first to identify stem cells in the small intestine and colon by observing the expression of the adult stem cell marker Lgr5 and growth in response to a growth factor called Wnt. They also hypothesized that the unique expression pattern of Lgr5 could mark stem cells in other adult tissues, including the liver, an organ for which stem cell identification remained elusive.

[Researchers] used a modified version of [this method] and discovered that Wnt-induced Lgr5 expression not only marks stem cell production in the liver, but it also defines a class of stem cells that become active when the liver is damaged. The scientists were able to grow these liver stem cells exponentially in a dish - an accomplishment never before achieved - and then transplant them in a specially designed mouse model of liver disease, where they continued to grow and show a modest therapeutic effect. "We were able to massively expand the liver cells and subsequently convert them to hepatocytes at a modest percentage. Going forward, we will enlist other growth factors and conditions to improve that percentage. Liver stem cell therapy for chronic liver disease in humans is coming."

Source:
http://www.fightaging.org/archives/2013/03/disparate-liver-biotechnologies.php

You might look at this research on size and longevity in the context of what is known of growth hormone and aging. The presently longest lived mice, for example, are those in which growth hormone is removed or blocked, and they are small in comparison to their peers. Also worth considering are analogous rare human lineages with non-functional growth hormone receptors, such as those exhibiting Laron-type dwarfism.

Large body size is one of the best predictors of long life span across species of mammals. In marked contrast, there is considerable evidence that, within species, larger individuals are actually shorter lived. This apparent cost of larger size is especially evident in the domestic dog, where artificial selection has led to breeds that vary in body size by almost two orders of magnitude and in average life expectancy by a factor of two.

Survival costs of large size might be paid at different stages of the life cycle: a higher early mortality, an early onset of senescence, an elevated baseline mortality, or an increased rate of aging. After fitting different mortality hazard models to death data from 74 breeds of dogs, we describe the relationship between size and several mortality components. We did not find a clear correlation between body size and the onset of senescence. The baseline hazard is slightly higher in large dogs, but the driving force behind the trade-off between size and life span is apparently a strong positive relationship between size and aging rate. We conclude that large dogs die young mainly because they age quickly.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23535614

Source:
http://www.fightaging.org/archives/2013/04/within-a-species-larger-size-tends-to-mean-a-shorter-life.php

The smaller and shorter lived the animal, the easier it is to extend its life in the laboratory. This is in part because more experiments can run at lower cost, but also because it seems that many of the evolved, shared mechanisms for adjusting the pace of aging or degree of tissue maintenance in response to environmental circumstances (e.g. calorie restriction) have a larger effect in shorter-lived species.

Any given mechanism for lengthening life span can be triggered or partially triggered or gently influenced in numerous ways. A lot of present research is focused on enumerating these many methods, and then matching them up to the few known underlying mechanisms for lengthening life. So we see research publications like this one:

Although mitochondrial-derived oxygen radicals have been questioned as the main driving force for the aging process, changes in mitochondrial metabolism almost certainly play a role. Dietary restriction (DR), which extends lifespan, also delays the aging-induced electron transport chain dysfunction in rodents. DR increases the NAD/NADH ratio in many tissues, which stimulates mitochondrial tricarboxylic acid (TCA) cycle dehydrogenases that utilize NAD as a cofactor. The increased TCA cycle function likely necessitates increased anaplerosis, important for longevity.

Alteration of mitochondrial TCA cycle function influences lifespan in C. elegans. Malate, the tricarboxylic acid (TCA) cycle metabolite, increased lifespan and thermotolerance in the nematode C. elegans. The increased longevity provided by malate addition did not occur in fumarase (fum-1), glyoxylate shunt (gei-7), succinate dehydrogenase flavoprotein (sdha-2), or soluble fumarate reductase F48E8.3 RNAi knockdown worms. Therefore, to increase lifespan, malate must be first converted to fumarate, then fumarate must be reduced to succinate by soluble fumarate reductase and the mitochondrial electron transport chain complex II.

Lifespan extension induced by malate depended upon the longevity regulators DAF-16 and SIR-2.1. Malate supplementation did not extend the lifespan of long-lived eat-2 mutant worms, a model of dietary restriction. Malate and fumarate addition increased oxygen consumption, but decreased ATP levels and mitochondrial membrane potential suggesting a mild uncoupling of oxidative phosphorylation. Malate also increased NADPH, NAD, and the NAD/NADH ratio. Fumarate reduction, glyoxylate shunt activity, and mild mitochondrial uncoupling likely contribute to the lifespan extension induced by malate and fumarate by increasing the amount of oxidized NAD and FAD cofactors.

Link: http://dx.doi.org/10.1371/journal.pone.0058345

Source:
http://www.fightaging.org/archives/2013/03/malate-and-nematode-lifespan.php

A great many researchers are presently engaged in amassing data on human longevity. There are the longitudinal studies running for decades, familial studies searching for measures of inheritance in long-term health, the vast statistical epidemiological studies, and behind them all the growing databases of various biological measurements, taken in ever greater detail as the costs of doing so fall rapidly. This is all very interesting, and will ultimately lead to a complete (and very, very complex) vision of how human metabolism runs and alters throughout aging, from the uppermost and more familiar processes all the way down to cellular mechanisms and accrued damage.

But strangely, very little of this is strictly necessary in order to engineer far longer lives. We don't need to know much more than we do already about human biology in order to have a good shot at building functional rejuvenation biotechnologies. The differences between old tissues and young tissues are pretty well enumerated at this time: the remaining lack of knowledge relates to the (many, many) details of the intricate dance of molecular and epigenetic mechanisms involved in moving from young to old. That dance is what the majority of the aging research community - and the majority of funding - is involved in deciphering. But anyone with a bunch of money could short-cut all of that and stomp right down the path to rejuvenation therapies today, if they cared to do it. All that needs to happen is that the known differences between old tissue and young tissue be repaired - it doesn't matter how it happens, so long as you can repair it.

Think of it this way: a man could spend a very long time building the mathematical models needed to show exactly how paint cracks and flakes on a wall. In doing that he might learn a lot about how to create paint that lasts a little longer, or which materials make for longer-lasting painted surfaces. That's a life's labor right there. Or he could just take a day every now and then to sand off the wall and paint it over. This is essentially the same comparison between the relative amounts of labor involved in aging and longevity science - with the note that in this analogy the man needs to create the paint from scratch and chase down a horse and a tree to make the brush.

So longevity science is as much a matter of persuasion as getting the work done. We need to see more funding going to repainting and less to the general theory of decay in painted surfaces. It's very clear what needs to happen, but gathering the necessary large-scale funding for work on SENS-like rejuvenation biotechnology is a work in progress.

In any case, here's an interesting pair of papers resulting from some of the ongoing studies of human aging. Interesting doesn't necessarily mean progress towards longer lives, remember, but there's no harm in looking and learning. This first one, for example, makes one think about damage-based theories of aging - with the implication that people who live longer tend to be more robust in every way at every age, precisely because they are carrying less of a burden of damage. It is also worth looking back at unrelated work that speculatively suggests that intelligence (or better cognitive function, take your pick) correlates with longevity for genetic reasons rather than sociological or economic reasons. i.e. genes for intelligence confer greater resistance to low-level damage in cells and molecular machinery.

Familial Longevity Is Marked by Better Cognitive Performance at Middle Age: The Leiden Longevity Study

Decline in cognitive performance is a highly prevalent health condition in elderly. Offspring of nonagenarian siblings with a familial history of longevity have better cognitive performance compared to the group of their partners of comparable age. This effect is independent of age-related diseases and known possible confounders. Possible explanations might be differences in subclinical vascular pathology between both groups.

And here is another in a line of papers noting that long-lived humans appear to be subtly different in their lipid metabolism. These lipid metabolism differences are among the few that have been reliably showing up in different populations.

Metabolic Signatures of Extreme Longevity in Northern Italian Centenarians Reveal a Complex Remodeling of Lipids, Amino Acids, and Gut Microbiota Metabolism

Here using a combined metabonomics approach [we] report for the first time the metabolic phenotype of longevity in a well characterized human aging cohort compromising mostly female centenarians, elderly, and young individuals. With increasing age, targeted [profiling] of blood serum displayed a marked decrease in tryptophan concentration, while an unique alteration of specific glycerophospholipids and sphingolipids are seen in the longevity phenotype. We hypothesized that the overall lipidome changes specific to longevity putatively reflect centenarians' unique capacity to adapt/respond to the accumulating oxidative and chronic inflammatory conditions characteristic of their extreme aging phenotype.

Source:
http://www.fightaging.org/archives/2013/03/a-few-recent-papers-on-human-longevity.php

An example of an application of induced pluripotent stem cells moving closer to use in humans. The transplant of new brain cells is a potential treatment for a range of neurodegenerative conditions:

Scientists have transplanted neural cells derived from a monkey's skin into its brain and watched the cells develop into several types of mature brain cells. [After] six months, the cells looked entirely normal, and were only detectable because they initially were tagged with a fluorescent protein. Because the cells were derived from adult cells in each monkey's skin, the experiment is a proof-of-principle for the concept of personalized medicine, where treatments are designed for each individual.

And since the skin cells were not "foreign" tissue, there were no signs of immune rejection - potentially a major problem with cell transplants. "When you look at the brain, you cannot tell that it is a graft. Structurally the host brain looks like a normal brain; the graft can only be seen under the fluorescent microscope."

The transplanted cells came from induced pluripotent stem cells (iPS cells), which can, like embryonic stem cells, develop into virtually any cell in the body. iPS cells, however, derive from adult cells rather than embryos. In the lab, the iPS cells were converted into neural progenitor cells. These intermediate-stage cells can further specialize into the neurons that carry nerve signals, and the glial cells that perform many support and nutritional functions. This final stage of maturation occurred inside the monkey.

Link: http://www.news.wisc.edu/21595

Source:
http://www.fightaging.org/archives/2013/03/testing-neurons-created-from-skin-cells-in-primates.php

All commonalities in cancer are interesting, as part of the high cost of dealing with cancer is based on the many, many different varieties and the great variability of its biochemistry even between individual tumors. Anything that is common between many types of cancer and between tumors offers a possibility of a lower-cost and broader therapy. The cell surface marker CD47 has shown up of late as a possible commonality, and work continues to see whether a therapy can be built on this:

A decade ago, [researchers] discovered that leukemia cells produce higher levels of a protein called CD47 than do healthy cells. CD47 [is] also displayed on healthy blood cells; it's a marker that blocks the immune system from destroying them as they circulate. Cancers take advantage of this flag to trick the immune system into ignoring them. In the past few years, [researchers] showed that blocking CD47 with an antibody cured some cases of lymphomas and leukemias in mice by stimulating the immune system to recognize the cancer cells as invaders. Now, [researchers] have shown that the CD47-blocking antibody may have a far wider impact than just blood cancers.

"What we've shown is that CD47 isn't just important on leukemias and lymphomas. It's on every single human primary tumor that we tested." Moreover, [the scientists] found that cancer cells always had higher levels of CD47 than did healthy cells. How much CD47 a tumor made could predict the survival odds of a patient. To determine whether blocking CD47 was beneficial, the scientists exposed tumor cells to macrophages, a type of immune cell, and anti-CD47 molecules in petri dishes. Without the drug, the macrophages ignored the cancerous cells. But when the CD47 was [blocked], the macrophages engulfed and destroyed cancer cells from all tumor types.

Next, the team transplanted human tumors into the feet of mice, where tumors can be easily monitored. When they treated the rodents with anti-CD47, the tumors shrank and did not spread to the rest of the body. In mice given human bladder cancer tumors, for example, 10 of 10 untreated mice had cancer that spread to their lymph nodes. Only one of 10 mice treated with anti-CD47 had a lymph node with signs of cancer. Moreover, the implanted tumor often got smaller after treatment - colon cancers transplanted into the mice shrank to less than one-third of their original size, on average.

Link: http://news.sciencemag.org/sciencenow/2012/03/one-drug-to-shrink-all-tumors.html

Source:
http://www.fightaging.org/archives/2013/03/more-on-cd47-as-a-potentially-broad-cancer-therapy-target.php

Metformin, used as a treatment for diabetes, is a weak candidate for a calorie restriction mimetic drug, one that causes some of the same metabolic changes (and thus hopefully health and longevity benefits) as calorie restriction. The evidence for health and longevity benefits actually resulting from this usage is mixed and debatable, however; certainly nowhere near as clear as for, say, rapamycin. Here researchers propose that metfomin's method of action stems in part from suppressing chronic inflammation, which is known to contribute to the progression of age-related frailty and disease:

[Researchers] found that the antidiabetic drug metformin reduces the production of inflammatory cytokines that normally activate the immune system, but if overproduced can lead to pathological inflammation, a condition that both damages tissues in aging and favors tumor growth. Cells normally secrete these inflammatory cytokines when they need to mount an immune response to infection, but chronic production of these same cytokines can also cause cells to age. Such chronic inflammation can be induced, for example by smoking, and old cells are particular proficient at making and releasing cytokines.

"We were surprised by our finding that metformin could prevent the production of inflammatory cytokines by old cells. The genes that code for cytokines are normal, but a protein that normally triggers their activation called NF-kB can't reach them in the cell nucleus in metformin treated cells. We also found that metformin does not exert its effects through a pathway commonly thought to mediate its antidiabetic effects. We have suspected that metformin acts in different ways on different pathways to cause effects on aging and cancer. Our studies now point to one mechanism."

Link: http://www.sciencedaily.com/releases/2013/03/130327093604.htm

Source:
http://www.fightaging.org/archives/2013/03/metformin-may-act-to-reduce-chronic-inflammation.php

Some publicity materials are presently doing the (late) rounds for a January review of progress in tissue engineering over the course of 2012. The review paper is open access, so I'm assuming that this is the standard process of picking a paper at some point after it is published and allowing open access for a while to draw some attention to the journal in question. Still, it's an interesting read, providing a perspective from inside the field on what is actually important enough to mention.

The merging of tissue engineering and regenerative medicine (TERM) forms an enormously broad, energetic, and important field of medical research. Not a week goes by without something new and vital happening in a regenerative medicine laboratory somewhere in the world, and vast sums of money flow into advancing the state of the art. Arbitrary tissues and organ structures grown from a patient's own cells are not so far ahead in the future now, and neither are ways to coerce the body to rebuild itself from the inside out. There is a certainly a sense of excitement among those involved.

Tissue Engineering and Regenerative Medicine: Recent Innovations and the Transition to Translation

The first challenge in conducting this review was the sheer number of recent publications in the TERM field. [The] number of TERM articles continues to rise with nearly 4000 original articles published in 2010, compared to a mere 360 a decade earlier. This can be partially attributed to the increasing use of the same common terminology, particularly for the more recent "regenerative medicine." Still, there is no doubt that our field is expanding and capturing a larger portion of the work done across the biomedical sciences.

Many seemingly discordant lines of research have now become intertwined in TERM and constitute the fabric of our field, with these concepts arising from the blurring of boundaries between traditional disciplines. While this point is sometimes easy to forget, much of what we now consider commonplace in TERM was only a short time ago separated by barriers of dogma and discipline. As these lines continue to blur, and multi-disciplinary research becomes more the rule than the exception, our field is experiencing tremendous growth.

The pace of growth is now so fast that it impossible for most of us to keep up with the field as a whole, or even a small subset of it. For example, a TERM search specific to "cartilage" returns more than 450 articles published in 2011 alone, meaning that one would need to read more than one article per day just to stay abreast of this small portion of the TERM terrain.

We found considerable innovation in a number of traditional TERM fields, but also new ideas that are beginning to take hold in emerging focal areas. For instance, in the realm of tissue replacement, we are now seeing not just scaffolds of ever-increasing complexity derived from standard engineering methods, but also complex scaffolds predicated on natural designs (and native tissues themselves, once decellularized). In the broader field of regenerative medicine, we are seeing developmental biology begin to address not just the formation of tissues, but the specific role that endogenous stem cells play in both generative and regenerative processes. Integrating these basic science findings with novel materials that specifically recruit endogenous populations may provide a next wave in smart biomaterials for tissue repair. Likewise, new cell sources, most prominently iPSCs, have come to the fore, making autologous cell-based therapies for any tissue a real possibility.

Finally, our objective screen showed that ours is truly a translational field, and that TERM advances are being reduced to clinical practice at an ever-increasing rate. [Both] the quantitative nature of these outcome measures and levels of evidence in support of these applications are advancing as well. Together, these advances are now beginning to change the lives of small subsets of the population, and in the future, these novel approaches will be able to address a host of diseases and instances of tissue degeneration that were heretofore untreatable.

Source:
http://www.fightaging.org/archives/2013/03/a-late-tissue-engineering-year-in-review-for-2012.php

An interesting piece on the use of scaffold materials to guide regrowth in regenerative medicine:

A research group [is] weaving nanoscale nerve-guide scaffolds from a mixture of natural chitosan and an industrial polyester polymer, using a process called electrospinning. The raw materials are dissolved in solvents and placed into a syringe, the needle of which is attached to a high-voltage supply. Charged liquid is then expelled from the needle towards an earthed collector plate. Like a spark between a cloud and a lightning conductor, the liquid stretches out to the collector, and the molecules within it form into a solid but incredibly thin thread.

The resulting minuscule fibres accrete into a dense mesh whose texture is similar to that of the body's own connective tissue. In laboratory tests, prototype nerve guides built from this nanomaterial sustained the growth of new neural cells, produced no immune reactions and were much stronger and more flexible than commercial collagen tubes. By adjusting the electrospinning process, the orientation of the nanofibres can be controlled to build scaffolds suitable for cultivating cells that need precise alignment, such as elongated muscle fibres and heart tissue.

Link: http://www.economist.com/news/technology-quarterly/21573056-biomedical-technology-tiny-forms-scaffolding-combining-biological-and-synthetic

Source:
http://www.fightaging.org/archives/2013/03/on-nanoscale-featured-scaffolds-in-regenerative-medicine.php