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

Here is a piece to act as fuel for people who like to argue policy and don't look much beyond the now. I think this is chiefly interesting for the potential support it gives to lifestyle differences between the genders as a noteworthy contributing cause to the fact that women live longer. Otherwise, it reinforces the point that differences in life expectancy at birth between regions or over time is not all that relevant to the intersection of medicine and aging - more attention should be given to statistics for life expectancy at 50 or 60.

Higher mortality rates among Americans younger than 50 are responsible for much of why life expectancy is lower in the United States than most of the world's most developed nations. The research [found] that excess mortality among Americans younger than 50 accounted for two-thirds of the gap in life expectancy at birth between American males and their counterparts and two-fifths between females and their counterparts in the comparison countries.

Most of the excess mortality of those younger than 50 was caused by noncommunicable diseases, including perinatal conditions, such as pregnancy complications and birth trauma, and homicide and unintentional injuries including drug overdose, a fact that she said constitutes a striking finding of the study. "These deaths have flown under the radar until recently. This study shows that they are an important factor in our life expectancy shortfall relative to other countries."

You get further in life by comparing what you have to what is possible, not with what other people have. But relativism of status, circumstances, and possessions is deeply set into the human mind. It's ever a struggle to get people to look beyond what is to see what might be.

Link: http://www.upenn.edu/pennnews/news/penn-study-links-us-mortality-rates-under-age-50-us-life-expectancy-lagging-other-high-income-c

Source:
http://www.fightaging.org/archives/2013/03/on-mortality-rates-and-life-expectancy.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

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

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

One of the root causes of aging is the formation of advanced glycation end-products (AGEs), something that happens much faster in a diabetic metabolism, but which nonetheless happens to all of us and causes progressively greater harm as the years pass. AGEs gum together and disable vital protein machinery, and also hammer on cell receptors in ways that cause chronic inflammation and other ills.

Past work on ways to break down AGEs - AGE-breaker drugs - largely occurred prior to the present rapid pace of development in biotechnology, and was both laborious and ultimately of little use in people despite promising animal studies. It turned out that the most important types of AGE in long-lived humans are not the same as in short-lived rodents, and thus drugs that help rats do little for people. However, one single form of human AGE - glucosepane - does make up the vast, overwhelming majority of AGEs in tissues such as skin. So it is a very viable, narrow target now that the research community knows enough to identify it as the primary target.

A safe way to remove glucosepane is needed in order to largely eliminate this contribution to degenerative aging. Sadly, as for much of the foundations of future rejuvenation therapies, little work and funding is directed to this end. This is thus one of the areas in which the SENS Research Foundation hopes to step in and spur greater interest and progress. Here are some notes on the current research programs funded by the Foundation to this end:

Chemical "crosslinking" of the structural proteins of our arteries slowly stiffens them with age, leading to more rigid blood vessels, rising "systolic" blood pressure (the first or top number in a blood pressure reading), and eventually to the loss of the ability of the kidneys to filter toxins from our blood, and a rising risk of stroke with age. Rejuvenation biotechnology can prevent these scourges at their source. New medicines that break apart these molecular "handcuffs" would allow the proteins of the arteries could move freely again, restoring the supple flexibility and cushioning capacity of aging arteries to youthful health and functionality. As a result, damage to the kidneys would be prevented, and strokes averted.

With a generous donation from software entrepreneur Jason Hope, SENS Research Foundation and the Cambridge University Institute of Biotechnology have established a new SENS Research Foundation Laboratory at Cambridge. With no one else taking on this challenging, critical research, the scientists in the Cambridge SENS lab will initiate work on biomedical solutions to glucosepane crosslinks starting from the ground up - with research to develop reagents that can rapidly and specifically detect proteins that have been crosslinked by glucosepane. The development of such reagents is an indispensible enabling technology for the development and testing of candidate glucosepane-breaking drugs.

In parallel, SENS Research Foundation is also providing funding to Dr. David Spiegel's group at Yale University, which has special expertise in making glycation crosslinks and which has recently been studying the mechanisms and chemical vulnerabilities of precursors of glucosepane. Dr. Spiegel's group has also recently published a report clarifying how the first generation crosslink-breaking drug worked. Once the Cambridge SRF lab has successfully established methods for identifying proteins that have been handcuffed together by glucosepane, Dr. Spiegel's group will use them to begin developing potential glucosepane-cleaving agents. Completing the cycle, candidate agents can then be tested at the Cambridge center - initially in tissue culture, and eventually in vivo.

Once developed, any glucosepane-labeling reagents that emerge from the first phase of this work will made available as openly as possible, to accelerate research into the role of crosslinks in disease and aging, and into ways to combat them.

Link: http://www.sens.org/research/research-blog/project-break-aging-arteries-free

Source:
http://www.fightaging.org/archives/2013/03/sens-research-foundations-age-breaker-research-programs.php

One of the root causes of aging is the formation of advanced glycation end-products (AGEs), something that happens much faster in a diabetic metabolism, but which nonetheless happens to all of us and causes progressively greater harm as the years pass. AGEs gum together and disable vital protein machinery, and also hammer on cell receptors in ways that cause chronic inflammation and other ills.

Past work on ways to break down AGEs - AGE-breaker drugs - largely occurred prior to the present rapid pace of development in biotechnology, and was both laborious and ultimately of little use in people despite promising animal studies. It turned out that the most important types of AGE in long-lived humans are not the same as in short-lived rodents, and thus drugs that help rats do little for people. However, one single form of human AGE - glucosepane - does make up the vast, overwhelming majority of AGEs in tissues such as skin. So it is a very viable, narrow target now that the research community knows enough to identify it as the primary target.

A safe way to remove glucosepane is needed in order to largely eliminate this contribution to degenerative aging. Sadly, as for much of the foundations of future rejuvenation therapies, little work and funding is directed to this end. This is thus one of the areas in which the SENS Research Foundation hopes to step in and spur greater interest and progress. Here are some notes on the current research programs funded by the Foundation to this end:

Chemical "crosslinking" of the structural proteins of our arteries slowly stiffens them with age, leading to more rigid blood vessels, rising "systolic" blood pressure (the first or top number in a blood pressure reading), and eventually to the loss of the ability of the kidneys to filter toxins from our blood, and a rising risk of stroke with age. Rejuvenation biotechnology can prevent these scourges at their source. New medicines that break apart these molecular "handcuffs" would allow the proteins of the arteries could move freely again, restoring the supple flexibility and cushioning capacity of aging arteries to youthful health and functionality. As a result, damage to the kidneys would be prevented, and strokes averted.

With a generous donation from software entrepreneur Jason Hope, SENS Research Foundation and the Cambridge University Institute of Biotechnology have established a new SENS Research Foundation Laboratory at Cambridge. With no one else taking on this challenging, critical research, the scientists in the Cambridge SENS lab will initiate work on biomedical solutions to glucosepane crosslinks starting from the ground up - with research to develop reagents that can rapidly and specifically detect proteins that have been crosslinked by glucosepane. The development of such reagents is an indispensible enabling technology for the development and testing of candidate glucosepane-breaking drugs.

In parallel, SENS Research Foundation is also providing funding to Dr. David Spiegel's group at Yale University, which has special expertise in making glycation crosslinks and which has recently been studying the mechanisms and chemical vulnerabilities of precursors of glucosepane. Dr. Spiegel's group has also recently published a report clarifying how the first generation crosslink-breaking drug worked. Once the Cambridge SRF lab has successfully established methods for identifying proteins that have been handcuffed together by glucosepane, Dr. Spiegel's group will use them to begin developing potential glucosepane-cleaving agents. Completing the cycle, candidate agents can then be tested at the Cambridge center - initially in tissue culture, and eventually in vivo.

Once developed, any glucosepane-labeling reagents that emerge from the first phase of this work will made available as openly as possible, to accelerate research into the role of crosslinks in disease and aging, and into ways to combat them.

Link: http://www.sens.org/research/research-blog/project-break-aging-arteries-free

Source:
http://www.fightaging.org/archives/2013/03/sens-research-foundations-age-breaker-research-programs.php