Anthony Atala is one of the present luminaries of tissue engineering, or at least that part of the field focused on building replacement organs and pseudo-organs - the latter being tissue structures that are not exactly the same as what they replace, but still get the job done, such as the substitute bladder tissue manufactured by Tengion. Atala is also on the SENS Foundation research advisory board, and so can be seen to look favorably on the agenda of engineering longer healthy human life spans.

I notice that a recent article has Atala giving some thoughts on timelines for organ regrowth, which you might compare to similar thoughts from another figure in the field, and to speculative timelines for the use of animal organs, such as those grown in engineered chimeras. Researchers are usually fairly reticent to put times and timelines on the table in public, for all the obvious reasons, so I think it worth taking note when they do:

How Close Are We to Making Like Salamanders and Regenerating Our Own Organs?

Right now, more than 116,000 people are on the U.S. organ transplant waiting list. But what if they could just regrow their own livers, hearts, and kidneys, even 3-D print them? Anthony Atala, the director of the Wake Forest Institute for Regenerative Medicine, is working to make that a reality. Speaking today at Ciudad de las Ideas, an annual conference about big ideas held in Puebla, Mexico, and sponsored by Grupo Salinas, Atala asked, "If a salamander can do it, why can't we?"

So how long until regenerative medicine can make the agonizingly long transplant waiting list a thing of the past? Within the next decade, Atala predicts, "we will see partial replacements of [some] organs - not the entire replacement, but many times that's all we need." Of course, the very necessary regulatory process will have to be carried out before there is widespread use of regenerated organs. Atala notes that the average drug takes 15.5 years to be approved in the United States, and regenerative medicine is neither drug nor medical device, but a combination thereof, which makes approval even more complicated.

"Very necessary" is complete nonsense when describing the enormously restrictive and costly regulatory straightjacket fastened around modern medicine. The FDA is an ever-increasing dead weight that does little but slow down - or block entirely - important progress in medical science. Its existence makes every new medical technology vastly more expensive to develop, and in many cases regulators have closed the door entirely on lines of development because there is no way that benefits could be profitably realized.

Worse, regulators can declare entire potential fields of medicine forbidden, as is the case for applications of longevity science. Aging is not a defined disease for the FDA, and all that is not explicitly permitted is forbidden in their regulatory rubric - so there is no path to legally commercialize a therapy for aging in the US, even when it becomes technically possible to do so. Thus there is little to no funding for such development.

The medicines that might have been and the progress that might have happened is all invisible, of course, so few people pay any attention to it - the broken window fallacy again, where the harm done and costs incurred are swept under the carpet, so people can suggest that we are all better off for it. How much further might medical science have advanced if the ruinous cost of clinical trial after trial after trial, under far more onerous requirements than existed even a few decades ago, were instead funneled into more research?

To explain the seeming gap between accelerating progress in the laboratory and lagging slowness in clinical medicine, one only has to point to the regulators. They are to blame, and the rest of us for not doing something about this squalid situation.

Source:
http://www.fightaging.org/archives/2012/11/regenerative-medicine-timelines-from-anthony-atala.php

Oxidative stress is a term you'll see a lot when reading the literature of aging research. The more reactive oxidant compounds there are in a cell, the more they will react with important proteins, modifying them and thus causing cellular machinery to run awry or require repair. Aging is characterized by rising levels of oxidative stress, caused by things such as increased presence of metabolic byproducts that are ever more inefficiently removed, accumulating damage to mitochondria, and so forth.

This is still something of a high level picture, however, and there is still a lot of room left for researchers to expand the understanding of how exactly oxidative damage progresses, or how it contributes to specific manifestations of aging, such as increased cellular senescence. Hence we see work of this nature:

Protein damage mediated by oxidation, protein adducts formation with advanced glycated end products and with products of lipid peroxidation, has been implicated during aging and age-related diseases, such as neurodegenerative diseases.

Increased protein modification has also been described upon replicative senescence of human fibroblasts, a valid model for studying aging in vitro. However, the mechanisms by which these modified proteins could impact on the development of the senescent phenotype and the pathogenesis of age-related diseases remain elusive.

In this study, we performed in silico approaches to evidence molecular actors and cellular pathways affected by these damaged proteins. A database of proteins modified by carbonylation, glycation, and lipid peroxidation products during aging and age-related diseases was built and compared to those proteins identified during cellular replicative senescence in vitro.

Common cellular pathways evidenced by enzymes involved in intermediate metabolism were found to be targeted by these modifications, although different tissues have been examined. ... An important outcome of the present study is that several enzymes that catalyze intermediate metabolism, such as glycolysis, gluconeogenesis, the citrate cycle, and fatty acid metabolism have been found to be modified. These results indicate a potential effect of protein modification on the impairment of cellular energy metabolism. Future studies should address this important issue by combining metabolomics and targeted proteomic analysis during cellular and organismal aging.

Link: http://dx.doi.org/10.1155/2012/919832

Source:
http://www.fightaging.org/archives/2012/11/work-on-better-understanding-oxidative-damage-in-aging.php

Last year a research group demonstrated that they could build tissue engineered sections of small intestine in mice. That same group is also working on producing structures of the large intestine using human cells, and here is an update on their progress:

[Researchers] have for the first time grown tissue-engineered human large intestine. ... Our aim is exact replacement of the tissue that is lacking. There are many important functions of the large intestine, and we can partially compensate for that loss through other medical advances, but there are still patients for whom this technology might be revolutionary if we can cross the translational hurdles. This is one of the advances that brings us toward our goal.

The human tissue-engineered colon includes all of the required specialized cell types that are found in human large intestine. The research team grew the tissue-engineered large intestine from specific groups of cells, called organoid units that were derived from intestinal tissue normally discarded after surgery. The organoid units grew on a biodegradable scaffold. After 4 weeks, the human tissue-engineered colon contained the differentiated cell types required in the functioning colon, and included other key components including smooth muscle, ganglion cells, and components of the stem cell niche. ... This proof-of-concept experiment is an important step in transitioning tissue-engineered colon to human therapy.

Link: http://eon.businesswire.com/news/eon/20121108006700/en/tissue-engineering/short-gut/complications-of-prematurity

Source:
http://www.fightaging.org/archives/2012/11/towards-tissue-engineered-large-intestines.php

We as a species are defined by our ability to create: given time we will build new wonders from all the matter we can lay our hands on. The true legacy of every generation is the new advances they create in technology - that progress in creation is the only thing likely be recalled in the distant future. Yet despite a history of creation piled upon creation, the urge to destroy is also strong; a certain love of destruction seems a hardwired part of human nature. See the broken window fallacy, for example, which is the 19th century formulation of an ancient truth: that people look upon the consequences of destruction selectively, and call it beneficial.

Suppose it cost six francs to repair the [window broken by a child], and you say that the accident brings six francs to the glazier's trade - that it encourages that trade to the amount of six francs - I grant it; I have not a word to say against it; you reason justly. The glazier comes, performs his task, receives his six francs, rubs his hands, and, in his heart, blesses the careless child. All this is that which is seen.

But if, on the other hand, you come to the conclusion, as is too often the case, that it is a good thing to break windows, that it causes money to circulate, and that the encouragement of industry in general will be the result of it, you will oblige me to call out, "Stop there! Your theory is confined to that which is seen; it takes no account of that which is not seen."

It is not seen that as [the owner of the window] has spent six francs upon one thing, he cannot spend them upon another. It is not seen that if he had not had a window to replace, he would, perhaps, have replaced his old shoes, or added another book to his library. In short, he would have employed his six francs in some way, which this accident has prevented.

The lesson of the broken window is that destruction is never beneficial. It is a cost, and that cost must be paid at the expense of some other benefit. This lesson is needed: the broken window fallacy was widespread two centuries ago and remains so now. You will hear commentary after every natural disaster suggesting that the resulting expenditures on repair will benefit the economy, for example.

What is the greatest ongoing disaster, the cause of the greatest destruction? The answer is degenerative aging. Aging destroys human capital: knowledge, skills, talents, the ability to work, the ability to create. It does so at a ferocious rate, a hundred thousand lives a day, and all that they might have accomplished if not struck down. If translated to a dollar amount, the cost is staggering - even shifts in life expectancy have gargantuan value. And why shouldn't they? Time spent alive and active is the basis of all wealth.

It is unfortunate, but many people advocate for the continuation of aging, for relinquishment of efforts to build medicines to extend health life. Among these are people who welcome aging and death because to their eyes it gives a young person the chance to step into a role vacated by an older person. This is another form of the broken window, however: the advocate for aging looks only at the young person, and dismisses what the older person might have done were they not removed from the picture by death or disability. So too, any apologism for aging based on clearing out the established figures because it provides a greater opportunity for younger people to repeat the same steps, follow the same paths, relearn the same skills, redo the same tasks ... these arguments are the broken window writ large.

Vast wealth and opportunity bleeds into the abyss on a daily basis, destroyed because the people who embody that wealth and opportunity decay and die. We would all be wealthier by far given the medical means to prevent these losses. In your thoughts on aging, don't ignore the vast invisible costs - the work never accomplished, the wonders never created, because those who could have done so never had the chance. The enforced absence of the age-damaged, the frail, the disabled, and the dead is in and of itself a form of damage; the loss of their skills and knowledge is something that must be repaired. That requires work and resources that might have gone to new creations, rather than catching up from loss.

So this continues, and the perpetual devotion of resources to repair and recover from the losses of death and disability is a great ball and chain shackled to our ability to create progress. But most people don't think of at all - it is invisible to them. Nonetheless, the costs of aging that we labor under are so vast that the introduction of ways to rejuvenate the old will lead to an blossoming of wealth and progress the likes of which has never before been seen.

Source:
http://www.fightaging.org/archives/2012/11/the-greatest-instance-of-the-broken-window-fallacy.php

This research result is noted because it stands in opposition to the present consensus on vitamin D and long term health in humans; the evidence to date supports a correlation between higher levels of vitamin D, a lower risk of age-related disease, and a longer life expectancy. But here we see the opposite result. This sort of outright contradiction is usually indicative of some greater complexity under the hood yet to be outlined and understood - and there's certainly no shortage of complexity in metabolism:

Low levels of 25(OH) vitamin D are associated with various age-related diseases and mortality, but causality has not been determined. We investigated vitamin D levels in the offspring of nonagenarians who had at least one nonagenarian sibling; these offspring have a lower prevalence of age-related diseases and a higher propensity to reach old age compared with their partners.

We [assessed] vitamin D levels, [dietary] vitamin D intake and single nucleotide polymorphisms (SNPs) associated with vitamin D levels. We included offspring (n = 1038) of nonagenarians who had at least one nonagenarian sibling, and the offsprings' partners (n = 461; controls) from the Leiden Longevity Study.

The offspring had significantly lower levels of vitamin D (64.3 nmol/L) compared with controls (68.4 nmol/L), independent of possible confounding factors. ... Compared with controls, the offspring of nonagenarians who had at least one nonagenarian sibling had a reduced frequency of a common variant in the CYP2R1 gene, which predisposes people to high vitamin D levels; they also had lower levels of vitamin D that persisted over the 2 most prevalent genotypes. These results cast doubt on the causal nature of previously reported associations between low levels of vitamin D and age-related diseases and mortality.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23128285

Source:
http://www.fightaging.org/archives/2012/11/lower-vitamin-d-levels-correlated-to-human-longevity.php

A low-cost, reliable method of measuring biological age is greatly sought after by the research community. People and laboratory animals age at different rates - by which I mean that they accumulate damage and changes characteristic of aging at different rates. Thus two individuals of the same species and same chronological age might have different biological ages thanks to life style, environment, access to medicine, and so forth.

Some interventions, such as calorie restriction, can slow the pace at which an individual ages, but measuring this slowing is a challenging process. Biological age is a simple concept at the high level, but finding a quick and reliable way to actually measure it has yet to happen. Thus while researchers would like to have rapid answers as to how effective any given method of slowing aging might be, they must wait and run long-lasting studies. The bottom line measure for any slowing of aging is to wait for the individuals in question to live out their lives and thus measure by effect on life span. Even in short-lived mice this can require years and thus a great deal of money. In longer-lived animals, ourselves included, it is simply impractical to run the necessary studies.

When it comes to the forthcoming generation of therapies capable of limited rejuvenation - by repairing some of the damage that causes degenerative aging - the situation is much the same, as is the need for a quick and easy measure of biological age. A therapy that actually produces some degree of rejuvenation should make a laboratory animal biologically younger than peers with the same chronological age. But how to measure that change without employing the lengthy and expensive wait-and-see approach?

Given the present state of affairs, any quick measure of biological age will speed research, making it very much faster and cheaper to assess varied means of extending healthy life. Some experiments that would presently require a year or more could be conducted in a few weeks or months: apply the therapy and evaluate the resulting changes in measures of biological age.

Several lines of research look promising when it comes to yielding a way to reliably and consistently evaluate biological age. One involves measurement of DNA methylation levels, and despite initial setbacks it may yet prove possible to tease out a useful measure from changes in the dynamics of telomere length. There are others. Here, for example, is a recent paper in which researchers present a method based on measurement of metabolite levels:

A metabolic signature predicts biological age in mice

Our understanding of the mechanisms by which aging is produced is still very limited. Here, we have determined the sera metabolite profile of 117 wild-type mice of different genetic backgrounds ranging from 8-129 weeks of age. This has allowed us to define a robust metabolomic signature and a derived metabolomic score that reliably/accurately predicts the age of wild-type mice.

In the case of telomerase-deficient mice, which have a shortened lifespan, their metabolomic score predicts older ages than expected. Conversely, in the case of mice that over-express telomerase, their metabolic score corresponded to younger ages than expected.

Importantly, telomerase reactivation late in life by using a TERT based gene therapy recently described by us, significantly reverted the metabolic profile of old mice to that of younger mice ... These results indicate that the metabolomic signature is associated to the biological age rather than to the chronological age. This constitutes one of the first aging-associated metabolomic signatures in a mammalian organism.

This might turn out to be an indirect measure of telomerase activity and little else, as over-specific matching is always a potential issue when searching for patterns in a large and complex system such as mammalian metabolism. Testing this metabolic signature against other means of accelerating or slowing aging in mice - such as calorie restriction - is thus one obvious next step.

Source:
http://www.fightaging.org/archives/2012/11/a-possible-metabolic-signature-of-biological-age-in-mice.php

Senescent cells are those that have left the cell cycle without being destroyed, either by the immune system or by one of the processes of programmed cell death. They remain active, however, exhibiting what is termed a senescence-associated secretory phenotype (SASP): these cells secrete all sorts of chemical signals that prove harmful to surrounding tissues and the body as a whole - through promotion of chronic inflammation, for example.

The number of senescent cells in tissue grows with age, and this increase in numbers is one of the root causes of aging. Researchers have demonstrated benefits in mice through destroying senescent cells without harming other cells. Regular targeted destruction of senescent cells could be the basis for therapies that remove this contribution to degenerative aging.

Any other approach would require understanding more about SASP and how to control or reverse the unpleasant effects of senescence - and here is an example of this sort of research, aimed at identifying controlling mechanisms with an eye to building therapies to reduce SASP:

With advancing age, senescent cells accumulate in tissues and the SASP-elicited proinflammatory state is believed to have a complex influence on age-related conditions. For example, two major SASP factors, IL-6 and IL-8, together with other SASP factors, attract immune cells to the tissue in which senescent cells reside; depending on the tissue context, this immune surveillance can promote processes such as wound healing, the resolution of fibrosis, and tumor regression. At the same time, SASP factors can compromise the integrity of the ECM, thus facilitating cancer cell migration. In addition, the systemic proinflammatory phenotype seen in the elderly is believed to affect a broad range of age-related pathologies, including diabetes, cancer, neurodegeneration and cardiovascular disease and contributes to an age-related decline of the adaptive immune system (immunosenescence).

Despite the great potential impact of the SASP on the biology of senescence and aging, the mechanisms that regulate SASP are poorly understood. ... Here, we report the identification of NF90 as an RNA-binding protein that binds to numerous mRNAs encoding SASP factors (collectively named SASP mRNAs) and coordinately influences their post-transcriptional fate in a senescence-dependent manner.

In young, early-passage, proliferating fibroblasts, high NF90 levels contributed to the repression of SASP factor production. This repression was elicited mainly via reduction in SASP factor translation ... By contrast, in senescent cells NF90 levels were markedly reduced, which allowed increased expression of numerous SASP factors. Our results are consistent with a role for NF90 as a coordinator of the inhibition of SASP factor production in early-passage, proliferating fibroblasts; in senescent cells, the lower levels of NF90 lead to SASP de-repression, permitting higher expression of SASP factors

Link: http://impactaging.com/papers/v4/n10/full/100497.html

Source:
http://www.fightaging.org/archives/2012/11/investigating-the-mechanisms-of-cellular-senescence.php

Myelin sheaths the axons of nerve cells, but the integrity of this sheathing degrades with age. Transplants of neural stem cells can be used to encourage myelin formation, and researchers are exploring this approach as a therapy for conditions involving more profound myelin loss.

There is always a demand in this sort of research for better and cheaper ways to obtain cells that have the desired effect. It is not trivial, for example, to isolate the right sort of neural stem cell, or establish a protocol for producing these cells from embryonic or induced pluripotent stem cells. A great deal of stem cell research these days involves the discovery of chemical signals, growth environments, and other necessary items to guide the growth of specific cell types.

Here is an example for myelin-forming cells, which will no doubt contribute to the next round of research and development of cell therapies aimed at regrowth of myelin:

Researchers have unlocked the complex cellular mechanics that instruct specific brain cells to continue to divide. This discovery overcomes a significant technical hurdle to potential human stem cell therapies; ensuring that an abundant supply of cells is available to study and ultimately treat people with diseases.

"One of the major factors that will determine the viability of stem cell therapies is access to a safe and reliable supply of cells. This study demonstrates that - in the case of certain populations of brain cells - we now understand the cell biology and the mechanisms necessary to control cell division and generate an almost endless supply of cells."

The study focuses on cells called glial progenitor cells (GPCs) that are found in the white matter of the human brain. These stem cells give rise to two cells found in the central nervous system: oligodendrocytes, which produce myelin, the fatty tissue that insulates the connections between cells; and astrocytes, cells that are critical to the health and signaling function of oligodendrocytes as well as neurons.

One of the barriers to moving forward with human treatments for myelin disease has been the difficulty of creating a plentiful supply of necessary cells, in this case GPCs. Scientists have been successful at getting these cells to divide and multiply in the lab, but only for limited periods of time, resulting in the generation of limited numbers of usable cells. ... Overcoming this problem required that [researchers] master the precise chemical symphony that occurs within stem cells, and which instructs them when to divide and multiply, and when to stop this process and become oligodendrocytes and astrocytes.

Link: http://www.urmc.rochester.edu/news/story/index.cfm?id=3669

Source:
http://www.fightaging.org/archives/2012/11/creating-myelin-producing-cells-to-order.php

One of the pleasant aspects of the repair approach to intervention in aging, such as that proposed in the Strategies for Engineered Negligible Senescence (SENS), is that all distinct forms of repair therapy can reasonably be expected to complement one another. Undergo a procedure to fix mitochondrial damage or break down an AGE such as glucospane, for example, and you are better off. Undergo both therapies and you will gain a commensurately greater benefit.

Unfortunately, this expectation of complementary therapies is very much not the case when it comes to attempts to slow down aging by genetic, epigenetic, or other metabolic manipulation. Metabolism is enormously complex, and even the well-studied phenomenon of calorie restriction isn't yet fully understood in terms of how the machinery of genes, proteins, and controlling signals all ties together to increase life span and improve health. Varied methods of extending life by slowing aging often turn out to operate on different portions of the same mechanism, or harmful when used together even though they are beneficial on their own.

One thing often tried by research groups that discover a novel way of slowing aging in laboratory animals is to try out the new method in calorie restricted animals: will the effects on life span complement one another and thus lead to a greater extension of life than is the case for either method on its own? Few presently known genetic alterations or other methods of slowing aging produce more than a 30% life extension in mice, and the standing record is 60-70% for growth hormone deficient mice - so at this point in time, it seems unlikely that any new life span record will be set through slowing aging without employing some complementary combination of techniques.

That this hasn't yet happened suggests that we shouldn't hold out much hope for the next five to seven years - there has, after all, been a lot of experimentation in mice over the past decade, and especially since the record set using growth hormone deficient mice. Unfortunately purely negative results don't tend to be published as often as positive results, so it's not a straightforward matter to find out which combinations of the various known methods to slow aging in mice have been tried only to fail.

Nonetheless, one example showed up recently in work on extending mouse longevity with AC5 knockout (AC5 KO) and calorie restriction, and here is a commentary on that research that clearly makes the point:

Models of longevity (Calorie Restriction and AC5 KO): Result of three bad hypotheses

Third Incorrect Hypothesis: The most widely studied model of longevity is calorie restriction (CR). Our hypothesis was that combining these two models would produce a super longevity model. Accordingly, we placed AC5 KO mice on CR. Within a month we found that all the AC5 KO mice on CR had died. Accordingly, we had to change our hypothesis to include that the AC5 KO and CR models share similar protective and metabolic mechanisms, which could mediate longevity and health, but when superimposed are actually lethal.

This might be taken as a cautionary note on metabolic manipulation as a path to slowing aging: there are pitfalls, it is enormously complicated, and there isn't much of a roadmap in comparison to the path to repair-based strategies of the sort outlined in the SENS vision.

Source:
http://www.fightaging.org/archives/2012/11/not-all-longevity-manipulations-play-nice-together.php

Myelin is the material sheathing axons in nerve cells. A number of conditions involve loss of myelin, such as multiple sclerosis (MS), but loss of myelin integrity occurs to a lesser degree for all of us as we age, and is thought to contribute to the characteristic cognitive decline of later years. Thus research into ways to regenerate myelin sheathing has broad potential application and is worth keeping an eye on:

We have identified a whole new target for drugs that might promote repair of the damaged brain in any disorder in which demyelination occurs. Any kind of therapy that can promote remyelination could be an absolute life-changer for the millions of people suffering from MS and other related disorders.

In 2005, [researchers] discovered that a sugar molecule, called hyaluronic acid, accumulates in areas of damage in the brains of humans and animals with demyelinating brain and spinal cord lesions. Their findings at the time [suggested] that hyaluronic acid itself prevented remyelination by preventing cells that form myelin from differentiating in areas of brain damage. The new study shows that the hyaluronic acid itself does not prevent the differentiation of myelin-forming cells. Rather, breakdown products generated by a specific enzyme that chews up hyaluronic acid - called a hyaluronidase - contribute to the remyelination failure.

This enzyme is highly elevated in MS patient brain lesions and in the nervous systems of animals with an MS-like disease. The research team [found] that by blocking hyaluronidase activity, they could promote myelin-forming cell differentiation and remyelination in the mice with the MS-like disease. Most significantly, the drug that blocked hyaluronidase activity led to improved nerve cell function. The next step is to develop drugs that specifically target this enzyme.

Link: http://www.sciencedaily.com/releases/2012/10/121031151611.htm

Source:
http://www.fightaging.org/archives/2012/11/promoting-remyelination-by-blocking-hyaluronidase.php