A novel approach in the tissue engineering of teeth is covered in this piece. It shows promise, but is still in the early stages of development in comparison to other methodologies in which researchers have actually created whole functional teeth:

[Researchers] investigated a process called mesenchymal condensation that embryos use to begin forming a variety of organs, including teeth, cartilage, bone, muscle, tendon, and kidney. In mesenchymal condensation, two adjacent tissue layers - loosely packed connective-tissue cells called mesenchyme and sheet-like tissue called an epithelium that covers it - exchange biochemical signals. This exchange causes the mesenchymal cells to squeeze themselves tightly into a small knot directly below where the new organ will form. By examining tissues isolated from the jaws of embryonic mice, [researchers] showed that when the compressed mesenchymal cells turn on genes that stimulate them to generate whole teeth composed of mineralized tissues, including dentin and enamel.

[The researchers then] set out to develop a way to engineer artificial teeth by creating a tissue-friendly material that accomplishes the same goal. Specifically, they wanted a porous sponge-like gel that could be impregnated with mesenchymal cells, then, when implanted into the body, induced to shrink in 3D to physically compact the cells inside it. They chemically modified a special gel-forming polymer called PNIPAAm that scientists have used to deliver drugs to the body's tissues. PNIPAAm gels have an unusual property: they contract abruptly when they warm. Ultimately, they developed a polymer that forms a tissue-friendly gel with two key properties: cells stick to it, and it compresses abruptly when warmed to body temperature.

[Researchers worked to] load mesenchymal cells into the gel, then implant the gel beneath the mouse kidney capsule - a tissue that is well supplied with blood and often used for transplantation experiments. The implanted cells not only expressed tooth-development genes; they also laid down calcium and minerals, just as mesenchymal cells do in the body as they begin to form teeth. In the embryo, mesenchymal cells can't build teeth alone - they need to be combined with cells that form the epithelium. In the future, the scientists plan to test whether the shrinking gel can stimulate both tissues to generate an entire functional tooth.

Link: http://www.seas.harvard.edu/news/2014/03/shrinking-gel-prompts-tooth-tissue-formation

Cross-links between proteins are formed by advanced glycation end-products and become a growing problem with advancing age. The best understood consequences are the degradation of elasticity in skin and blood vessels, but there are many other forms of harm that result from this interference with tissue structure. There is too little research presently taking place on methods of safely breaking cross-links, but this is something that the SENS Research Foundation seeks to change - the means to make an impact on aging here is one of the forms of rejuvenation treatment that might be developed comparatively rapidly, given the funding.

Here is an example of another form of harm created by cross-links, this time in the structure of tendons. The molecular structure of tissues determines their properties, such as mechanical strength and elasticity, and damage to that structure leads to loss of function:

Recent molecular modeling data using collagen peptides predicted that mechanical force transmitted through intermolecular cross-links resulted in collagen triple helix unwinding. These simulations further predicted that this unwinding, referred to as triple helical microunfolding, occurred at forces well below canonical collagen damage mechanisms. Based in large part on these data, we hypothesized that mechanical loading of glycation cross-linked tendon microfibers would result in accelerated collagenolytic enzyme damage.

This hypothesis is in stark contrast to reports in literature that indicated that individually mechanical loading or cross-linking each retards enzymatic degradation of collagen substrates. Using our Collagen Enzyme Mechano-Kinetic Automated Testing (CEMKAT) System we mechanically loaded collagen-rich tendon microfibers that had been chemically cross-linked with sugar and tested for degrading enzyme susceptibility. Our results indicated that cross-linked fibers were more than 5 times more resistant to enzymatic degradation while unloaded but became highly susceptible to enzyme cleavage when they were stretched by an applied mechanical deformation.

Link: http://dx.doi.org/10.1016/j.matbio.2013.11.005

The SENS Research Foundation (SRF) has enough of a budget these days to be funding a fair number of distinct research projects relevant to aging and longevity - too many for me to be familiar with all of them at this point. Some are fairly indirect, fundamental research that aims to build the foundations needed to even start in on projects that cut to the heart of the matter, the construction of rejuvenation biotechnologies that can reverse the course of degenerative aging. Bear in mind that as research progresses, it will not be the Foundation that funds or accomplishes the bulk of the work needed to make human rejuvenation a reality: these are still the early days, and it is as important to provide groundwork that opens the doors for other groups, or makes a field more financially attractive for development, as it is to make direct headway.

One of the Foundation's areas of interest is cancer and its causes, and this is where you'll find a lot of the more indirect work. There is a broad outline in WILT - whole body interdiction of lengthening of telomeres - as a path to build the ultimate cure for cancer, but it is also the case that a large amount of fundamental genetic science and tool-building is needed to validate and make progress on that path. For my money, I see cancer research as being in much the same state as stem cell research, by which I mean that a massive research edifice is already heading in roughly the right direction, making fair progress towards therapies that a few decades from now will be good enough to get by for the foreseeable future. Stem cells and cancer treatments are not presently set to be the limiting factors for the future of treating and reversing aging, in my opinion.

I'm not running the SRF, of course, and if you look over the Foundation's annual reports you'll see quite a lot of interest in specific tool-building at the intersection of genetics and cancer to arrive at more radical solutions for cancer than those pursued by the present mainstream. (The next generation of cancer therapies emerging from that mainstream are based on selective targeting of cancer cells, offering the promise of few side-effects and high effectiveness - which sounds pretty good to me). You can read an introduction to this area of work at the SENS website, and note that it may well also overlap with means of generating data relevant to questions on aging that are of greater interest than rejuvenation to the research mainstream, such as whether there is any merit at all in programmed aging theories, or whether there are any significant and widespread genetic contributions to longevity in humans.

One area of interest here is the generation and analysis of epigenetic data, something that I'm generally not so hot on as a point of relevance to human longevity, given its usual association with the development of drugs to slow aging or other ways to manipulate metabolism without addressing the underlying causes of dysfunction. Those are the slow roads, unlikely to produce great gains in healthy life span. But here is a piece by philanthropist Jason Hope on the way in which one SRF-funded research program is using epigenetic tools to arrive at a potentially better grasp on cancer at the opening stage, in its very earliest development:

Epimutations  -  Identifying Changes in Structures Controlling the Genetic Code

With funding from SENS Research Foundation, Albert Einstein College of Medicine (AECOM) Team members Dr. Vijg and Dr. Gravina have developed novel ways of identifying changes in the "scaffolding" that structures and controls the expression of the genetic code. These innovative approaches also help scientists determine if these changes in DNA are a response to environmental exposure or the result of damage to the scaffolding, leading to accumulating errors in the regulation of the DNA code. These methods may someday change the way doctors diagnose illnesses, such as cancer, and slow or reverse some of the debilitating effects of aging.

Dr. Gravina and the team tested the new evaluation method by analyzing DNA methylation in thousands of single liver cells, each from a different mouse. The researchers looked at specific locations in DNA scaffolding that control whether the genes are methylated or demethylated. This approach allowed scientists to compare the distinctive methylation and demethylation of individual cells with the widespread patterns of methylation occurring in a larger scale throughout the entire liver.

In other words, Dr. Gravina and his team found a way to determine whether changes in methylation were responses to environmental conditions common to many cells in the liver or were aberrant patterns unique to individual cells  -  widespread changes are likely the response to environmental stimuli whereas single cell deviations from the wider pattern are likely to be the result of damage to the epigenetic structure. The new approach developed with the support of SENS Research Foundation funding could be the foundation for new technologies for identifying cancers at their earliest stages.

You can probably see how this work will be of interest to researchers studying genetics and longevity, especially those who think that aging is a programmed set of epigenetic changes. As to cancer: the advantage of very early detection of cancer is that we don't need radical new technologies to eliminate early cancers with a high degree of reliability and comparatively little trauma. That goal is achievable with incremental advances in medical technology in the near term. Getting rid of very early stage cancer is very possible for many cancers even today, but the trouble is that by the time cancer is discovered it is almost always well past that stage. So there is a path here towards making the mainstream initiatives in targeted cancer treatment far, far more effective than would otherwise be the case. But again, I see this all happening on a good schedule with or without the help of the SRF: work on early detection of cancer is already an established line of research. This thus looks like tool-building, a process of making technologies that are needed for other Foundation work, and which also happen to have much broader applications in mainstream medicine.

Data on the degree to which various age-related conditions contribute to mortality is actually a lot less precise than most people assume it to be. Cause of death in old age is often either ambiguous or ambiguously recorded, leading to the need for estimation and correction via statistical methods. This opens the door to arguments as to the plausibility of data for any particular age-related condition, claiming that it is either more or less of a threat than previously thought. Here, for example, epidemiologists argue that Alzheimer's disease causes far more deaths than are officially reported as being due to this condition:

Data came from 2,566 persons aged 65 years and older (mean 78.1 years) without dementia at baseline from 2 cohort studies of aging with identical annual diagnostic assessments of dementia. Because both studies require organ donation, ascertainment of mortality was complete and dates of death accurate. Mortality hazard ratios after incident AD dementia were estimated per 10-year age strata from proportional hazards models. Population attributable risk percentage was derived to estimate excess mortality after a diagnosis of AD dementia. The number of excess deaths attributable to AD dementia in the United States was then estimated.

Over an average of 8 years, 559 participants (21.8%) without dementia at baseline developed AD dementia and 1,090 (42.4%) died. Median time from AD dementia diagnosis to death was 3.8 years. The mortality hazard ratio for AD dementia was 4.30 for ages 75-84 years and 2.77 for ages 85 years and older (too few deaths after AD dementia in ages 65-74 were available to estimate hazard ratio). Population attributable risk percentage was 37.0% for ages 75-84 and 35.8% for ages 85 and older. An estimated 503,400 deaths in Americans aged 75 years and older were attributable to AD dementia in 2010.

[Thus] a larger number of deaths are attributable to AD dementia in the United States each year than the number (less than 84,000 in 2010) reported on death certificates.

Given that there were overall 2.5 million deaths in the US in 2010, with the largest attributed causes being cancer and heart disease, this paper is suggesting that a large systematic miscategorization exists, not just the need for a modest correction.

Link: http://dx.doi.org/10.1212/WNL.0000000000000240

Researchers review the evidence from animal studies suggesting that stem cell transplants are a beneficial treatment for degenerative disc disease. This is a treatment that has been available via medical tourism for some years now, though it is still only just entering clinical trials in the US:

Stem cell transplant was viable and effective in halting or reversing degenerative disc disease of the spine, a meta-analysis of animal studies showed, in a development expected to open up research in humans. Recent developments in stem cell research have made it possible to assess its effect on intervertebral disc (IVD) height. Not only did disc height increase, but stem cell transplant also increased disc water content and improved appropriate gene expression. "These exciting developments place us in a position to prepare for translation of stem cell therapy for degenerative disc disease into clinical trials."

The increase in disc height was due to restoration in the transplant group of the nucleus pulposus structure, which refers to the jelly-like substance in the disc, and an increased amount of water content, which is critical for the appropriate function of the disc as a cushion for the spinal column. What they found was an over 23.6% increase in the disc height index in the transplant group compared with the placebo group. None of the 6 studies showed a decrease of the disc height index in the transplant group. Increases in the disc height index were statistically significant in all individual studies.

"A hallmark of IVD degenerative disease is its poor self-repair capacity secondary to the loss of IVD cells. However, current available treatments fail to address the loss of cells and cellular functions. In fact, many invasive treatments further damage the disc, causing further degeneration in the diseased level or adjacent levels. The goal of tissue engineering using stem cells is to restore the normal function and motion of the diseased human spine."

Link: http://www.newswise.com/articles/stem-cell-transplant-shows-landmark-promise-for-treatment-of-degenerative-disc-disease-mayo-clinic

The immune system becomes unruly and ineffective in old age: on the one hand it generates ever greater levels of harmful chronic inflammation, while on the other it no longer has a sufficient population of effective cells able to tackle new threats, scan for cancerous cells, and eliminate senescent cells from the body. It becomes overactive and underachieving, and a sizable portion of the more obvious aspects of age-related frailty stem from the lack of a robust immune response.

Why does this happen? No doubt the normal culprits leave their mark: the forms of accumulated cellular and molecular damage that degrade tissues and cell populations, including those involved in generating and maintaining immune cells. Beyond this, however, there are problems that inevitably arise due to the evolved structure of the immune system: it has what are in effect built-in limits. The first is a limit to the number of immune cells that can be supported at any one time, as the potential supply of new cells diminishes to a trickle quite early in adulthood, as an organ necessary for their creation - the thymus - atrophies. The second limit of interest stems from the fact that the adaptive immune system devotes cells to remembering threats, and thanks to persistent threats like herpesviruses, ever more of the available cell population is devoted to memory rather than action. So the end result is an evolved system that is front-loaded for early success, but which systematically falls apart much later.

What can be done about this? Destroying unwanted and duplicative memory cells looks promising, as that will trigger replacement with fresh cells capable of action. Increasing control over stem cells offers the possibility of periodic infusions of large numbers of immune cells generated from a recipient's own cells. This would surmount the natural immune capacity at the upper end. Another approach that might achieve the same result is to restore the thymus, and thus restore a youthful flow of new immune cells. This would use the approaches of tissue engineering and regenerative medicine to either build a new thymus for transplantation, or regrow the existing thymus in situ.

The SENS Research Foundation has been putting a modest amount of funding into spurring greater progress towards thymic regeneration, and this year one of the young researchers in the undergraduate program will be working on this project, established in partnership with the Wake Forest Institute for Regeneration Medicine:

Julie Marco: SRF Undergraduate Research Scholar at the Wake Forest Institute for Regenerative Medicine

My early research experience investigating how age affects regeneration is what sparked my interest in the SENS Research Foundation (SRF). I wanted to be able to learn and see new techniques that are being used to try to help slow down or reverse the process of aging.

As an undergraduate student, I have had the honor of continuing to explore my research interests working at the Wake Forest Institute for Regenerative Medicine (WFIRM) under the mentorship of Dr. James Yoo on the skin bioprinting project - a project designed to create safer and scar-less treatments for people in need of skin grafts. Successful Dr. John Jackson. The thymus is the primary lymphoid organ for the production of T cells. It is comprised of two compartments, the cortex and the medulla. The T cells undergo maturation in the cortex section of the thymus and positive selection for a functional T cell receptor. The medulla is important for the negative selection of T cells to eliminate self-reactive T-cells and is also the region where mature T cells exit from the thymus.

As we age, the thymus decreases in immune function. This leads to a shift toward a greater and greater proportion of memory T cells compared to naïve T cells. In order to reverse this effect and enhance immune response, there is a need to regenerate thymus tissue and increase naïve T cell population. This project aims to regenerate the thymus using natural thymus scaffolds which have been reseeded with cells.

The prevailing wisdom is that the introduction of effective means to treat aging will reduce health care costs. After all, most expenditures are generated in the final stages of life, during the expensive and eventually futile process of trying to prevent the failure of constantly near-failing organs and systems. Operating a damaged machine is expensive and challenging: there is no way around that without repairing the damage. This is as true for us as for a car or a lawnmower, and the ability to repair the underlying causes of aging will indefinitely postpone the end stage of frailty and high mortality rates, and indefinitely prolong the low-cost stage of life in which little is spent on medicine.

At present, however, changes in life expectancy are not driven by treatments for aging. Rather there is an incidental increase due to generally better medicine throughout life, leading to a somewhat lower level of damage at a given age, and then there are improvements in the ability to postpone mortality without repairing the underlying causes of age-related disease. Better treatments for heart disease, stem cell therapies to temporarily revert some of the damage caused by aging, and so forth. So the dynamic is different, and leaves room to argue that increasing life expectancy under the present model of medical development can increase costs. Even so, it is clearly and obviously the case that adoption of the better approach - addressing the causes of aging - will lower costs.

It is still an open question whether increasing life expectancy as such causes higher health care expenditures (HCE) in a population. According to the "red herring" hypothesis, the positive correlation between age and HCE is exclusively due to the fact that mortality rises with age and a large share of HCE is caused by proximity to death. As a consequence, rising longevity - through falling mortality rates - may even reduce HCE. However, a weakness of many previous empirical studies is that they use cross-sectional evidence to make inferences on a development over time.

In this paper, we analyse the impact of rising longevity on the trend of HCE over time by using data from a pseudo-panel of German sickness fund members over the period 1997-2009. Using (dynamic) panel data models, we find that age, mortality and 5-year survival rates each have a positive impact on per-capita HCE. Our explanation for the last finding is that physicians treat patients more aggressively if the results of these treatments pay off over a longer time span, which we call "Eubie Blake effect". A simulation on the basis of an official population forecast for Germany is used to isolate the effect of demographic ageing on real per-capita HCE over the coming decades. We find that, while falling mortality rates as such lower HCE, this effect is more than compensated by an increase in remaining life expectancy so that the net effect of ageing on HCE over time is clearly positive.

Link: http://www.ncbi.nlm.nih.gov/pubmed/24585039

A small but significant number of cells become overtaken by damaged, dysfunctional mitochondria over a lifetime, and this process is one of the contributing causes of degenerative aging. Mitochondria are important to many cellular processes, and quality control mechanisms aim to either repair damage or remove and replace damaged mitochondria. Mitochondrial theories of aging postulate ways in which some forms of damage subvert quality control, allowing dysfunctional mitochondria to preferentially avoid recycling, leading to the end result described above.

This review paper looks at what is known of natural mitochondrial quality control mechanisms:

Repairing or disposing of a malfunctioning object is an everyday dilemma. Replacing an item may be quicker than repairing it, but may also be more costly. Cells are faced with the same options when their organelles are challenged. Ensuring the health of the mitochondrial network is of utmost importance for cellular health and, not surprisingly, mitochondrial quality control can take both the repair and disposal routes. Spectacular advances have been made in recent years and a picture is starting to emerge of what drives a cell to take one or the other path. Interestingly, mitochondrial quality control seems to be deficient in various medically relevant conditions, such as neurodegeneration and aging.

Since the original observations that calorie restriction could extend lifespan, a close connection exists between energy metabolism and aging. Mitochondria, as an important source of reactive oxygen species, have long been considered a prime suspect for causing cellular aging. However, a different picture emerges from recent studies. In a screen for long-lived worm mutants, Andrew Dillin's lab found that creating imbalance in the assembly of respiratory chain subunits caused increased lifespan. That phenomenon was soon related to an activation of the mitochondrial unfolded protein response (UPR). Indeed, this increase in lifespan did not correlate to a reduced activity of the mitochondria, but to an activation of mitochondrial UPR, since increase in lifespan is blunted in mutants incapable of mounting a mitochondrial UPR. Thus, although direct causality between mitochondrial UPR induction and lifespan extension is not clearly established, it seems that mitochondrial quality control, more than mitochondrial activity, contributes to aging regulation. These observations, originally made in worms, could be extended to mice, where a large-scale genomic association study found that longevity was associated with variations in genes encoding mitochondrial proteins.

Link: http://dx.doi.org/10.12703/P6-15

I had just yesterday mentioned one of the ventures that researcher Alex Zhavoronkov is involved in, and today I hear that he and a team are launching In Silico Medicine in the US. No doubt the announcement was pushed forward to benefit from publicity associated with the recent launch of Human Longevity, as both groups are in the same business: the application of computing power, data analysis, and new genetic technologies to make inroads into treating aging.

Thus everything I said about Human Longevity applies here too. A great deal will be achieved in many areas of medical science through advances in genetics, but it doesn't seem likely to me that meaningfully extending healthy life spans over the next few decades will be among the plausible outcomes of genetic advances that focus on gathering and analyzing genetic data. Beyond a few very narrow and targeted applications, such as mitochondrial DNA repair or rescue, genetic and epigenetic engineering do not have much of a presence in a rejuvenation research portfolio focused on damage repair. Instead, genetics is the primary tool for slowing aging through manipulation of the operation of metabolism, a goal that is going to be very, very challenging and expensive to achieve safely. Even then that path cannot produce great gains in life span in the near term of the next few decades, and will not prove beneficial to people who are already old. So given the choice between rejuvenation and slowing aging, we should focus on rejuvenation. It should be more easily created, and requires only incremental new research rather than massive across-the-board advances in knowledge and biotechnology to achieve.

But these are all well worn arguments, made many times at Fight Aging! Clearly a lot of money is going to pour into work at the intersection of genetics and aging regardless of what think on the matter, and as I note above, the likely outcome is that noteworthy benefits will be realized in many areas of medicine. Just not, I expect, in human longevity. Here is a little from Zhavoronkov via email, and a pointer to the press materials for the launch of his company:

I got interested in aging when I was still a child and even before school was looking for ways to combat aging venturing from nutraceuticals and yoga to pharmaceuticals and neuroinformatics. Like many of you, when I met Aubrey de Grey, my life changed for the better as I saw his first comprehensive strategy to combat aging. But Aubrey's brilliant projects are stretched in time and we need to have a medium-term plan to be able to live until they bear dramatic longevity benefits. In Silico Medicine will help find these medium-term solutions and may even help with SENS research going forward by looking for molecules that activate the various endogenous mechanisms that are involved in damage repair. We would like to stand with Calico and Human Longevity Inc that recently stepped out to pursue a similar goal.

In Silico Medicine Inc. Launches in the US to Use Advances in Technology to Combat Aging and Age-related Diseases

One of the reasons why pharmaceutical companies failed to develop business models for increasing productive human longevity is because human lifespans are much longer than that of the many model organisms and it takes decades to evaluate the effects of any drug. Some of the known drugs have been on the market for many decades and only recently scientists started finding clues to their oncoprotective, cardioprotective and geroprotective effects. Moreover, many drugs that work on model organisms including mice do not have the same effects in humans. There is an urgent need for intelligent systems that will cost-effectively predict the effectiveness of the many drugs on the population, but also on the individual levels.

"We built our platform on years of experience of a large international team who specialize in using gene expression data from individual patient's tumor to predict the effectiveness of targeted compounds and improve clinical decision making. We are reinventing this system for drug discovery in cancer and aging," said Alex Zhavoronkov, PhD, the CEO of In Silico Medicine. "The recent wave of startups looking to employ big data to find solutions for aging, including Google's Calico and Human Longevity, should give everyone hope that we may see the time when both the medical institutions and pharmaceutical companies will start saving lives so every human being on the planet will benefit."

In Silico Medicine

Since 2008 the In Silico Medicine research team worked hard to develop a comprehensive database of tissue-specific gene expression profiles from a large number of healthy patients, who lost their lives in accidents. This database was thoroughly analyzed, categorized and annotated. In parallel, we constructed multiple databases of gene expression from many cancer biopsies, before and after treatment. We developed tools to map gene expression data onto signaling pathways and developed algorithms for evaluating the individual pathway activation strengths and to analyze and measure the state of the overall signaling pathway cloud.

We then developed an annotated database of just over 150 targeted compounds acting on various molecular targets and network elements. We developed another set of algorithms to evaluate the activity of these drugs on the signaling pathway cloud to predict the effectiveness of these drugs on each patient's tumor. This research laid the foundation for the development of the OncoFinder, which was purchased by and is now the flagship product of the Hong Kong-based, Pathway Pharmaceuticals, the main research and business partner of In Silico Medicine.

In Silico Medicine took the concept of OncoFinder further, but instead of the normal and cancer cells, we evaluate the effects of various drugs on the pathway cloud constructed from gene expression and epigenetic data from cells taken from the old patients with those taken from the young patients with the intent to bring the state of the "old cells" as close to the signaling pathway cloud activation profile of the young cells.

These researchers propose that declining proteostasis with aging is something that starts abruptly in nematode worms, which they take as evidence for programmed aging - such as perhaps a coordinated lapse or other unfavorable change in cellular housekeeping and stress response mechanisms has evolved to occur comparatively early in life in this species:

Protein aggregation is associated with many age-related disorders, and increased protein oxidation, mislocalization, and aggregation are observed in aged organisms. Intuitively, these findings can be explained by a gradual decline in protein biosynthetic and quality control pathways and a progressive accumulation of protein damage. However, recent findings in Caenorhabditis elegans challenge this view, suggesting that a decline in proteome integrity may be the result of early programmed events rather than the consequence of a random and gradual accrual of molecular damage.

Here, we propose, from studies in Caenorhabditis elegans, that proteostasis collapse is not gradual but rather a sudden and early life event that triggers proteome mismanagement, thereby affecting a multitude of downstream processes. Furthermore, we propose that this phenomenon is not stochastic but is instead a programmed re-modeling of the proteostasis network that may be conserved in other species. As such, we postulate that changes in the proteostasis network may be one of the earliest events dictating healthy aging in metazoans.

Link: http://dx.doi.org/10.12703/P6-7

This review looks over progress in the use of stem cells treatments as a way to impact chronic inflammation and treat non-healing wounds:

A chronic wound develops when a wound fails to heal within an expected time frame and fails to achieve functional closure. There are many factors that impede healing, including co-morbid clinical conditions, aging, poor tissue perfusion, malnutrition, unrelieved pressure to the surface of the wound, immune suppression, malignancy, infection, obesity, and a number of medications. The usual patient with a nonhealing wound has a combination of several of the factors mentioned earlier, making any one therapeutic option unlikely to succeed.

One common thread with almost all nonhealing wounds is a persistent inflammatory state. Macrophages, known to mediate inflammation, influence healing in a positive way through increasing angiogenesis, decreasing bacterial loads, phagocytosing debris, and providing matrix deposition. If, however, a persistent inflammatory state develops in which the macrophages are dysregulated and become skewed toward a type I inflammatory phenotype, impeding progress toward wound repair and regeneration. Another potential explanation for the nonhealing wound is the presence of intrinsically dysfunctional or senescent cells that are incapable of responding to normal biochemical signals.

A number of treatment modalities are currently used to accelerate wound healing. The use of stem cell therapy has been hypothesized as a potentially useful adjunct for nonhealing wounds. Specifically, mesenchymal stem cells (MSCs) have been shown to improve wound healing in several studies. Immune modulating properties of MSCs have made them attractive treatment options. MSCs may be more useful if they are preactivated with inflammatory cytokines such as tumor necrosis factor alpha or interferon gamma.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3842880/

In a better world, the US research community would receive the same level of comparatively enthusiastic and well-informed public support for longevity science that is seen in Russia, while the Russian research community would enjoy the same greater level of access to funding as is found in the US. Or at the very least, the greater funding and greater public support would coincide, rather than each being in the most inconvenient location, as is the case at present.

I've kept half an eye on what is going on in the Russian longevity research community these past few years, ever since the advent of free and borderline usable automated translation tools. That community has its own enthusiastic advocates and organizations that are analogous in their roles to the Methuselah Foundation and SENS Research Foundation - working to generate greater public support and funding for their preferred means to extend healthy human life and eliminate age-related disease. The Science for Life Extension Foundation is one such group, and the UMA Foundation is another more recent addition to that network of people and organizations:

UMA Foundation

We believe scientists change the world. Not politicians, not oligarchs, scientists do. They create technologies that save people's lives, make our life style more comfortable, improve our health and make us age later. Thanks to scientists work we are able to see entire world in a life time, understand each other better, communicate and most wise of us - unite based on work for better world and added value.

We think scientists work (especially young ones) is undervalued by our government and society. Many laws need improvement, too many labs need new equipment, new people, new ideas. Modernization and innovative technologies are impossible without fundamental science in Russia.

Today bio science not only can bring a fortune to researchers but make ones life fuller, bring creativity beyond even art and make young scientist name legendary. Join us! Apart from uniting on social media, we organize interesting conferences, events. We also help receiving funding for fundamental research and development and explain / explore some possible career paths in science in Russia.

While the declared mission is general improvement of the prospects for science and the scientific community in Russia, the specific projects funded by the UMA Foundation are largely focused on the life sciences and somewhat weighted towards longevity research and related projects. The Foundation was a sponsor of the 2012 Genetics of Aging and Longevity conference, for example. For this, we can look to the presence of Alex Zhavoronkov on the board: in addition to working with UMA Foundation he is a director of the UK Biogerontology Research Foundation, runs the International Aging Research Portfolio, and is a point of connection to other reaches of the longevity science community. Networking makes the world turn.

Mitochondria are bacteria-like organelles inside our cells tasked with the production of chemical energy stores, among other tasks. Like all organelles their collection of intricate protein machinery is wrapped by a membrane - or rather two membranes in this case, inner and outer.

The membrane pacemaker hypothesis advances the idea that membrane resistance to oxidative damage is an important determinant of differences in life span between species: there are correlations in the data from various different species. Mitochondria generate damaging reactive oxygen species as a consequence of their packaging of chemical energy stores, and are vulnerable to self-damage as a result. Some forms of that damage can spiral out to cause further harm that contributes to degenerative aging.

It is not yet completely clear that all these dots can actually be joined in the obvious way - that long-lived animals are long-lived because their mitochondria are more resistant to self-harm, and thus they suffer little from this cause of degenerative aging. Efforts to repair mitochondrial damage to see what happens may overtake efforts to build a better understanding, but work proceeds nonetheless. This paper is open access, but the full text is PDF format only at this point:

Mitochondria play vital roles in metabolic energy transduction, intermediate molecule metabolism, metal ion homeostasis, programmed cell death and regulation of the production of reactive oxygen species. As a result of their broad range of functions, mitochondria have been strongly implicated in aging and longevity. Numerous studies show that aging and decreased lifespan are also associated with high reactive oxygen species production by mitochondria, increased mitochondrial DNA and protein damage, and with changes in the fatty acid composition of mitochondrial membranes.

It is possible that the extent of fatty acid unsaturation of the mitochondrial membrane determines susceptibility to lipid oxidative damage and downstream protein and genome toxicity, thereby acting as a determinant of aging and lifespan. Reviewing the vast number of comparative studies on mitochondrial membrane composition, metabolism and lifespan reveals some evidence that lipid unsaturation ratios may correlate with lifespan. However, we caution against simply relating these two traits. They may be correlative but have no functional relation.

Link: http://dx.doi.org/10.1186/2046-2395-3-3

This open access study has something for everyone to argue about, no matter your previous position on diet and health. The basic idea that lower dietary protein levels are beneficial and increase life expectancy is straightforward and supported by research on calorie restriction and methionine restriction. But the results showing that low protein intake becomes disadvantageous and increases mortality in old age run contrary to past studies that demonstrated calorie restriction to be beneficial in old age.

This is not even to start in on talking about competing theories as to why animal protein may be worse for health over the long term than plant protein: because vegetarians tend to be more health-conscious in other ways; because of greater levels of dietary AGEs in cooked meat; because of greater methionine intake associated with meat eating; and so forth.

So this all suggests, as usual, that greater complexity is buried here. This is all interesting, but of course somewhat irrelevant to the future of longevity, which will arrive via new medical technology to repair the damage of aging, not via dietary changes. You'll want to click through and look at the infographic at the head of the paper for a better summary of the findings than the description in the abstract:

Mice and humans with growth hormone receptor/IGF-1 deficiencies display major reductions in age-related diseases. Because protein restriction reduces GHR-IGF-1 activity, we examined links between protein intake and mortality.

Respondents aged 50-65 reporting high protein intake had a 75% increase in overall mortality and a 4-fold increase in cancer death risk during the following 18 years. These associations were either abolished or attenuated if the proteins were plant derived. Conversely, high protein intake was associated with reduced cancer and overall mortality in respondents over 65, but a 5-fold increase in diabetes mortality across all ages.

Mouse studies confirmed the effect of high protein intake and GHR-IGF-1 signaling on the incidence and progression of breast and melanoma tumors, but also the detrimental effects of a low protein diet in the very old. These results suggest that low protein intake during middle age followed by moderate to high protein consumption in old adults may optimize healthspan and longevity.

Link: http://www.cell.com/cell-metabolism/fulltext/S1550-4131(14)00062-X?switch=standard

Technological progress happens in waves, and this is just as much the case in longevity science as elsewhere. Ideas spread within a community, and are acted upon by diverse groups around the same time. Funding is found, companies and laboratories are established, work is accomplished across a few years, and in the course of that new ideas arise. A few more years pass as new connections are forged and the new ideas digested, and then the cycle starts anew. This takes around a decade or so in a fast moving field, and we are, I think, at that overlapping time of the end of the current cycle and the beginning of the next.

The last cycle of development and research included the creation of the SENS research programs and the Methuselah Foundation, attempts to apply sirtuin research and the rest of the first batch of unsuccessful attempts to build calorie restriction mimetics, a great sea change in research community attitudes towards longevity science, and took place over a period in which the tools of genetics have shifted abruptly from costly to cheap.

Given a growing acceptance of the prospects for treating aging to extend healthy life, and the plummeting price of DNA sequencing and genetic engineering, it seems that we will see new large-scale initiatives established at the intersection of genetics and aging. My suspicion is that this is where Google's Calico venture will spend much of its time, for example. Hopefully I will be proven wrong on that count, however. It strikes me that outside of very narrow and specific applications of genetic engineering - such as the SENS approach of allotopic expression to eliminate mitochondrial damage as a cause of aging - focusing on gene sequencing in the context of life extension is very much a case of searching for the keys where the light is good, not in the dark where you dropped them.

Based on the large amount of data accumulated to date on the genetics of longevity, we should expect it to be a very complex domain. There will be thousands of contributing genes, every one of which has a tiny, near-insignificant effect on its own, an effect which is very dependent on other variations, and which will be different in every regional population and lineage. With very few exceptions, it has proven challenging to reproduce associations noted between specific genetic variations and human longevity: the association in one study population is non-existent in others, and wasn't large at all to begin with.

Similarly, manipulation of epigenetic patterns, the decorations on our genes that determine whether and how much of a protein is produced from its genetic blueprint, and which change rapidly in response to circumstances, is also an enormously complex undertaking. It is an extension of targeted drug discovery, really, where researchers aim for ever more precise ways to change the expression of specific genes so as to produce beneficial effects. Given so far unsuccessful struggle of the past decade to try to recapitulate even just a fraction of the benefits of the known and cataloged epigenetic changes that accompany calorie restriction - something that is not expected to extend life in humans by much more than five years - I'm not anticipating great benefits to longevity to arise from this path ahead, or at least not soon enough to matter.

But genetics is cheap now, and while human longevity may not benefit greatly over the next few decades, many other aspects of medicine will. So people will try:

In Pursuit of Longevity, a Plan to Harness DNA Sequencing

Dr. Venter announced on Tuesday that he was starting a new company, Human Longevity, which will be focused on figuring out how people can live longer and healthier lives. To do that, the company will build what Dr. Venter says will be the largest human DNA sequencing operation in the world, capable of processing 40,000 human genomes a year. The huge amount of DNA data will be combined with other data on the health and body composition of the people whose DNA is sequenced, in hopes of gleaning insights into the molecular causes of aging and age-related illnesses like cancer and heart disease.

Slowing aging, if it can be done, could be a way to prevent many diseases, an alternative to treating one disease a time. "Your age is your number one risk factor for almost every disease, but it's not a disease itself," Dr. Venter said in an interview. Still, his company will also work on treating individual diseases of aging as well. Human Longevity said it had raised $70 million, most of it from wealthy individuals, some of whom have backed his existing company, Synthetic Genomics.

My comments above aside, a rising tide floats all boats. If the next ten years brings ever-greater legitimacy for longevity science, and ever-greater public support for the goal of eliminating age-related disease from the human condition, then I'm fine with that even if a lot of the participants are barking up the wrong tree, or taking the slow and expensive road that generates data and little else.

As I note with great regularity, we don't actually need a complete understanding of aging in order to effectively treat it. Developing that complete understanding will cost far, far more to than to simply act on what we know already: list the known root causes of degenerative aging and repair them. Given that the research community already has a well-defined list of the differences between old tissues and young tissues, we can skip the exceedingly complex and expensive part of development in which it is determined exactly and in great detail as to how these changes progress and interact with our biology. Researchers know what the changes are, and there exist plausible plans to develop the means to revert these alterations. More knowledge is always good, but it isn't strictly necessary, and certainly isn't as important as saving lives through a greater focus on implementation of clinical therapies.