Fight Aging! Newsletter, May 12th 2014

May 12th 2014

The Fight Aging! Newsletter is a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: both the road to future rejuvenation and the present understanding of what works and what doesn't work when it comes to extending healthy life. Expect to see summaries of recent advances in medicine, news from the longevity science community, advocacy and fundraising initiatives to help advance rejuvenation biotechnology, links to online resources, and much more.

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  • SENS6 Rejuvenation Research Conference Presentation Videos
  • Longevity via Methionine Restriction Depends on Autophagy
  • Rejuvenation Biotechnology Update for Q2 2014
  • Digging into How Greater Mitochondrial Oxidative Stress Can Extend Life in Nematodes
  • Antioxidant Supplements Produce No Meaningful Benefits, But Hope Springs Eternal
  • Latest Headlines from Fight Aging!
    • GDF11 Reverses Some Aspects of Aging in Mice
    • Induced Pluripotency and Cellular Features of Aging
    • Cardiac BNP Gene Delivery as a Hypertension Treatment
    • Building Flesh and Blood
    • Halting Pancreatic Cancer Development
    • Considering the Choroid Plexus in Alzheimer's Disease
    • INDY Extends Longevity in Flies via Intestinal Stem Cells
    • More Work on DNA Methylation as a Biomarker of Aging
    • Reduced ISW2 Expression Extends Life in Yeast and Nematodes
    • Klotho Influences Cognition as Well as Aging


SENS, the Strategies for Engineered Negligible Senescence is a disruptive research and advocacy program that aims to build the foundations of rejuvenation treatments over the next few decades. It is the logical extension of the discovery over the past century of which forms of cellular and molecular damage characterize old tissues, and thus can be defensibly theorized to be the cause of aging. The key realization at the core of SENS is that researchers can work towards effective treatments for aging by repairing this damage even when they don't fully understand all the complex, intricate nuances of the progression from undamaged to damaged. To draw an analogy, you don't need a full molecular-scale model of rust progression to be able to effectively maintain metal structures: paint, oil, and regular inspection suffices. The knowledge necessary is much less encompassing and the costs much lower than those required to develop that full molecular-scale model.

So it is with aging, except vastly more complicated as a matter of research and development than dealing with rust on metal. We should expect it to cost a fantastic amount of money and time to develop a full understanding of aging, and the achievement of that goal lies a long way in the future. Meanwhile, repairing the damage we know about is a very viable large research program, something that could be brought to fruition at a cost of a billion dollars and ten to twenty years if all went much as expected.

SENS initiatives have nowhere near a billion dollars in funding at the present time. They are mostly coordinated by the fairly young SENS Research Foundation, with an annual budget that has grown to a little more than $4M, and include conferences that have been held every other year for more than a decade now. These events are attended by a range of noteworthy scientists from numerous fields of medical research, and the materials presented are always interesting.

The sixth conference was held at the end of last year, and as is usually the case it takes some months for videos of the presentations to be processed and uploaded to the SENS Research Foundation YouTube channel. I noted more presentations this year focused on the logistics of actually getting treatments to market, and it might be taken as an encouraging sign that more people think that it is worth spending time on planning at this stage. Two videos of interest are linked below, but there are a good fifty or so presentations to look through, so take some time and browse.

Legal problems of registering substances and therapies to cure aging

A number of compounds are known to have some anti-aging effects, reducing the rate of aging or extending the lifespan in animals and probably in humans. At the same time, these drugs are not widely marketed to the general public as cures against aging, which probably causes unnecessary losses of healthy life years for many people.

Health experts blame the international legal framework, which only allows registering drugs against certain diseases. This refers to Food and Drug Administration in the United States, and other national agencies which all follow the World Health Organization's guidelines for drug registration. As a result, some geroprotective substances are registered as either drugs against certain diseases (for example, diabetes) or food supplements.

One of the reasons named for this situation is that aging is not in the official list of diseases in the International Classification of Diseases. At the same time, there is a number of conditions which are not considered as diseases, like pregnancy, but there are medicines which are prescribed for these conditions.

Another problem is that most anti-aging drugs and therapies are supposed to have preventive rather than treating effects for a broad spectrum of diseases, and it would take long and expensive clinical trials to justify their beneficial effects. Registering geroprotective substances as medicines for more than one disease seems to be a workable solution. However, geroprotective effects can be more pronounced for some conditions, and much smaller for others, which would make it difficult for them to compete with drugs targeting specific diseases.

Another option is to promote the inclusion of aging into the official disease classifications which would require coordinated advocacy efforts at the global level. Alternatively, conditional registration of new drugs and therapies to cure and prevent aging should be developed and promoted. In any case, a system for testing drugs and therapies to cure aging effectiveness should be established.

In sum, the most promising strategies to ensure registration of new drugs and therapies to cure aging are: advocacy for acknowledging age related conditions like sarcopenia as treatable diseases; international lobbying to acknowledge aging as a treatable and partly preventable condition; promoting legal framework for conditional registration for the drugs and therapies to cure aging.

Accelerating translational research processes from bench to clinic

The productivity of medical innovation has been in decline, and this threatens the commitment of both public and private funders. However, there are both disruptive technologies and disruptive ideas that promise a turnaround. CASMI is exploring both, and developing testable models for change - including new open innovation-based discovery models, adaptive licensing of medicines, the use of real world data in development, and the personalisation of therapy on both genomic and behavioural grounds. With the support of SENS, CASMI is also investigating the translational issues facing cell therapy, so that the highly promising science delivers patient benefit as speedily and affordably as possible.


The practice of calorie restriction involves reducing dietary calorie intake while still obtaining optimal levels of necessary micronutrients. In near all species tested to date this greatly enhances health and slows all measures of aging. In mice, for example, maximum life spans of up to 40% greater than normal are exhibited in calorie restriction studies. In longer-lived species the degree of life extension obtained is smaller, but the health benefits still large. There is no medical technology at present that can provide anywhere near same degree of improvement in long and short term measures of health to humans, based on the evidence to date. Nonetheless, lifelong calorie restriction in humans is not expected to provide more than a 7% gain in life span.

The mechanisms of action by which calorie restriction works are much debated despite having been under intense investigation for more than a decade: inroads have been made and evidence gathered, but there is still plenty to argue over when it comes to which of the known mechanisms are more important. There is a strong case to be made for low levels of visceral fat tissue to be important in long-term health, however: if you simply surgically remove visceral fat from mice they live significantly longer. Another well studied mechanism is the metabolic reaction to low levels of methionine, an essential amino acid that is not manufactured in the body but must be obtained from diet. Methionine restriction that does not reduce calorie intake but in which diet is structured to include only minimal safe levels of methionine produces similar results to calorie restriction in rodents.

Autophagy is also known to be a mechanism of importance in calorie restriction and methionine restriction, both of which spur increased levels of autophagy. In fact there is some evidence to suggest that calorie restriction depends on autophagy to work its benefits. But what is autophagy? It is the name given to housekeeping processes that minimize the presence of damaged cellular components by recycling them. Many of the methods of extending life and slowing aging in laboratory animals discovered over the past twenty years have also been shown to involve increased levels of autophagy. If we consider that aging is just a matter of damage accumulation, then this makes sense.

In the paper quoted below researchers join another dot in this mass of evidence by showing that methionine restriction, like calorie restriction, requires autophagy to produce benefits - which goes some way to reinforcing its claim as one of the primary mechanisms involved in calorie restriction. This work was carried out in yeast, which is normally a good reason to wait until someone reproduces it in mammals before commenting, but in the case of calorie restriction there has been a very good correspondence between its behavior in yeast, flies, nematode worms, and mammals. As in one, so in all the others.

Lifespan Extension by Methionine Restriction Requires Autophagy-Dependent Vacuolar Acidification

Health- or lifespan-prolonging regimes would be beneficial at both the individual and the social level. Nevertheless, up to date only very few experimental settings have been proven to promote longevity in mammals. Among them is the reduction of food intake (caloric restriction) or the pharmacological administration of caloric restriction mimetics like rapamycin. The latter one, however, is accompanied by not yet fully estimated and undesirable side effects. In contrast, the limitation of one specific amino acid, namely methionine, which has also been demonstrated to elongate the lifespan of mammals, has the advantage of being a well applicable regime. Therefore, understanding the underlying mechanism of the anti-aging effects of methionine restriction is of crucial importance.

With the help of the model organism yeast, we show that limitation in methionine drastically enhances autophagy, a cellular process of self-digestion that is also switched on during caloric restriction. Moreover, we demonstrate that this occurs in causal conjunction with an efficient pH decrease in the organelle responsible for the digestive capacity of the cell (the vacuole). Finally, we prove that [this] autophagy-dependent vacuolar acidification is necessary for methionine restriction-mediated lifespan extension.


Methuselah Foundation and SENS Research Foundation are presently partnering to issue a quarterly update on rejuvenation biotechnology research to members of the 300, each of whom has committed to donating $25,000 over 25 years to help fund the development of effective treatments for degenerative aging. The last time I checked, there were in fact very nearly 300 members of the 300 - just a few places are left. It is a great initiative that helped launch the Methuselah Foundation more than ten years ago and raised the first significant funds for the Mprize for longevity science and early SENS research. You might read Michael Rae's 2004 essay "Why I Joined the Three Hundred" for more on that topic.

I am a member of the 300 myself, and consider it money well spent. The Methuselah Foundation has engineered a great deal of beneficial change in the aging research and related medical development communities over the years, all of it funded by philanthropic donations. It is no coincidence that prior to the Foundation's existence the research community and funding institutions were a mix of hostile and dismissive towards research aimed at extending healthy life spans, whereas today the prevailing culture is much more accepting of that goal. A lot of work behind the scenes aided in accomplishing that transformation.

The first edition of the present quarterly rejuvenation biotechnology newsletter was sent out back in January, so consider this a reminder if you didn't get around to reading it. Here is a link to the latest:

Rejuvenation Biotechnology Update, Volume 1 / Issue 2, April 2014

The Methuselah Foundation is thrilled to partner with SENS Research Foundation in order to bring out the most recent advancements in tissue engineering, regeneration, and rejuvenation research for members of The 300.

Because it doesn't take a scientist to understand the vital importance of investing in healthy life extension, these newsletters attempt to frame three significant studies from the past 3-6 months as accessibly and approachably as possible, describing how each one fits into the broader landscape of longevity research.

Long term human reconstitution and immune aging in NOD-Rag (-)- chain (-) mice.

This study shows that this strain of immune-deficient mice is able to receive a transplant of human immune stem cells, and to live longer-term with a "humanized" immune system where part of the immune cells in the mouse are derived from humans. One interesting aspect of this study is that it suggests that parts of the immune system might be able to be rejuvenated in a persistent way using human progenitor/stem cells. This is exciting because of the observation that the virus, cytomegalovirus or "CMV," appears to contribute to human immune senescence by reducing the proportion of naive T cells in aging. Moreover, thymic involution, the reduction in size and function of the thymus, has been observed in human aging. This is also assumed to contribute to reduced immune function in human aging.

The animal model in this paper could also be very useful as a tool for studying the effects of aging on the human immune system, while still using mice as the subjects, which are easier to use in research because of their small size, well known genetics, fast reproduction, and because they are mammals.

A novel in vitro three-dimensional bioprinted liver tissue system for drug development

In this study, the researchers used a proprietary 3D bio-printing technology to create liver constructs that simulate a human liver environment. They started by using hepatocytes (liver cells), and then added other cell types found or near in the liver. These cells began to integrate and interact with one another to create a kind of "simulated liver." They then tested this "liver simulation system" by testing for activity of a critically-important liver enzyme family involved in drug metabolism and detoxification of substances foreign to the body. They also tested whether these integrated cell systems would die quickly or live and function for a prolonged period of time, and they observed healthy, persistent functioning.

The drug development and approval process is immensely burdensome, time-consuming, and expensive. A very large proportion of this cost is due to the rigorous human testing that must be done to ensure the drug's safety. We're excited to see the advancement of biologically-relevant drug-testing systems by which drug companies can rigorously test small molecules without harm to living humans. These kind of "human simulations" can be valuable because they may dramatically reduce the cost of testing and ultimately deliver successful, safe drugs to people who need them, both more cheaply and more quickly.

Declining NAD(+) induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging

The subject of this study involved a compound intimately involved in the biochemistry of creating energy in our bodies. This particular compound is called "nicotinamide adenine dinucleotide", or "NAD+". NAD+ is well-known for its involvement in many biological processes involved in energy transfer, including those in the mitochondria. NAD+ has been observed to decline during advancing age, as is mitochondrial function. Knowing NAD+ is so closely involved in mitochondrial function suggests that if one were to replenish NAD+ in old age, one might also restore mitochondrial function. This might have quite a number of benefits, because doing so could enhance energy production in the body's cells, thereby possibly enhancing muscular function, brain function, and exercise output, among other things. For example, calorie restriction, which has been observed to "slow" various aspects of aging in many different organisms, appears to preserve both NAD+ concentrations and mitochondrial function during aging.

SENS Research Foundation (SRF) has a research program dubbed "MitoSENS" that addresses a different reason for age-related mitochondrial dysfunction. The present study focuses on a reversible decline in energy production capacity across most cells in the aging body due to altered metabolism, and reports that raising NAD+ in old mice improved mitochondrial function to that of young mice. SRF is more concerned about a tiny minority of cells in the body that harbor irreversible deletions in mitochondrial DNA, which push the cells into an abnormal metabolic state that ultimately causes them to poison far-flung cells all across the body. There is no reason to think that [a NAD+ boosting] treatment would have any positive effect on the underlying mitochondrial DNA deletions. If it did not, these may still need to be properly addressed to achieve persistent and complete human rejuvenation.


Nematode worms are one of the most studied types of organism, and many genetic alterations known to extend healthy life span by slowing aging were first demonstrated in the nematode species C. elegans. Numerous important low-level cellular processes and components are very similar in all animals, so studying the aging of worms is in fact a very cost-effective way to obtain insight into mammal biochemistry. Nematodes are very short-lived and comparatively cheap to maintain, and so much of the exploratory work in the aging research community takes place in these and other lower animals.

Over the course of recent decades it has become clear that mitochondria, the power plants of the cell, play an important role in degenerative aging. They emit damaging reactive oxygen species (ROS) in the course of turning food into chemical energy stores for the cell, and by a complicated process this starting point leads to the creation of a small population of dysfunctional cells that export toxic, broken proteins into their surroundings. This is one of the causes of aging.

Many of the ways of extending life in laboratory animals change the degree to which mitochondria generate reactive oxygen species, such as by disabling some portions of the intricate assembly of proteins inside each mitochondrion known as the electron transport chain. Interestingly in nematode worms there are examples of genetic and other changes that either lower or raise ROS output but in both cases induce life extension. The high level theory here is that less in the way of ROS emission means less damage to clean up, but modestly greater ROS production can boost the performance of cellular maintenance processes and thus more than offset the additional damage. The situation is probably more complex than this, however. The path between two points in a biological system is rarely a straight line.

Here researchers are tracing the mechanisms that connect increased ROS levels to greater life span in nematode worms, and joining more of the dots along the way:

What doesn't kill you may make you live longer

Programmed cell death, or apoptosis, is a process by which damaged cells commit suicide in a variety of situations: to avoid becoming cancerous, to avoid inducing auto-immune disease, or to kill off viruses that have invaded the cell. The main molecular mechanism by which this happens is well conserved in all animals, but was first discovered in C. elegans.

[Researchers] found that this same mechanism, when stimulated in the right way by free radicals, actually reinforces the cell's defenses and increases its lifespan. The findings have important implications. "Showing the actual molecular mechanisms by which free radicals can have a pro-longevity effect provides strong new evidence of their beneficial effects as signaling molecules. It also means that apoptosis signaling can be used to stimulate mechanisms that slow down aging. Since the mechanism of apoptosis has been extensively studied in people, because of its medical importance in immunity and in cancer, a lot of pharmacological tools already exist to manipulate apoptotic signaling. But that doesn't mean it will be easy."

The Intrinsic Apoptosis Pathway Mediates the Pro-Longevity Response to Mitochondrial ROS in C. elegans

The increased longevity of the C. elegans electron transport chain mutants isp-1 and nuo-6 is mediated by mitochondrial ROS (mtROS) signaling. Here we show that the mtROS signal is relayed by the conserved, mitochondria-associated, intrinsic apoptosis signaling pathway (CED-9/Bcl2, CED-4/Apaf1, and CED-3/Casp9) triggered by CED-13, an alternative BH3-only protein.

Activation of the pathway by an elevation of mtROS does not affect apoptosis but protects from the consequences of mitochondrial dysfunction by triggering a unique pattern of gene expression that modulates stress sensitivity and promotes survival. In vertebrates, mtROS induce apoptosis through the intrinsic pathway to protect from severely damaged cells.

Our observations in nematodes demonstrate that sensing of mtROS by the apoptotic pathway can, independently of apoptosis, elicit protective mechanisms that keep the organism alive under stressful conditions. This results in extended longevity when mtROS generation is inappropriately elevated. These findings clarify the relationships between mitochondria, ROS, apoptosis, and aging.


There comes a point in the study of antioxidant supplementation as a means to extend healthy life, after decades of work and thousands of scientific studies in which all the more rigorous results and meta-analyses indicate no effect or negative effects, at which one has to conclude than this is not merely an ambiguous or poorly understood outcome, but rather the case that in fact antioxidant supplementation has no effect or negative effects. Those studies in which some benefit is shown can be written off as the effects of inadvertent calorie restriction, an issue that is very prevalent in studies run prior to about ten years ago and still quite common now. Alternately, they used model organisms and other experimental situations in which the metabolic biochemistry was of little relevance to a healthy human.

Antioxidant therapies can be helpful in treating some medical conditions, and researchers are discovering that mitochondrially targeted antioxidants - still something that you can't obtain from a store - have some effect on health and longevity in addition to being a potential treatment for some degenerative eye conditions. But if you are taking commonplace antioxidant supplements in the hope of some benefit, then the overwhelming weight of evidence suggests that you are hoping in vain.

Hope springs eternal, of course, and the voice of the scientific community is soft in this matter when compared to the marketing efforts of companies selling antioxidants. The level of funding that flows into science from that direction also has its distorting effects. There are certainly scientists who talk about the present balance of evidence as ambiguous, and will cheerfully do so in a paper that lists scores of studies that show no great or relevant benefit.

From my point of view it seems as though focusing on the study of commonplace antioxidant supplements and health in this day and age is an avoidance of those fields of research that might actually meaningfully extend healthy human life spans. Antioxidants aren't going to achieve that goal, not even the impressive new mitochondrially targeted compounds. The way to the future is rather to be found via technologies such as gene therapy, the creation of engineered bacterial enzymes to clear out metabolic waste, immune therapies, stem cell treatments and other regenerative medicine, and a panoply of further modern approaches to repairing the damage of aging.

The following paper is largely a litany of antioxidant studies in which no relevant benefits were observed, and yet the researchers mark the field as ambiguous and finish with a comment that more work is needed to build a better way of delivering antioxidant supplements - quite missing their own conclusion, it seems. Hope springs eternal, but it is way past time to move on to better and more promising science in this modern age of biotechnology and progress.

Effect of Antioxidants Supplementation on Aging and Longevity

Organic compounds and structures composed of them are thermodynamically unstable in an oxygen-containing atmosphere. Molecular oxygen, in its triplet basal state, is rather unreactive due to the spin restriction. However, formation of oxygen free radicals and other reactive oxygen species (ROS) opens the gate for potentially deleterious oxidative reactions of oxygen. Seen from that perspective, the "Free Radical Theory of Aging" (FRTA), now more commonly termed the oxidative damage theory of ageing, seems to address a key facet of intrinsic biological instability of living systems. The basic idea of the FRTA is that free radicals and other ROS, formed unavoidably in the course of metabolism and arising due to the action of various exogenous factors, damage biomolecules, and accumulation of this damage are the cause of age-related diseases and aging.

If FRTA is true, antioxidants should slow down aging and prolong lifespan. This apparently obvious conclusion has stimulated enormous number of studies aimed at finding a relationship between levels of endogenous antioxidants and lifespan of various organisms on the effects of addition of exogenous antioxidants on the course of aging and lifespan of model organisms. Pubmed provides more than 13300 hits for conjunction of terms "antioxidant" and "aging or ageing." However, in spite of the plethora of studies, the answer to the question if exogenous antioxidants can prolong life is far from being clear.

Generally, the effects of antioxidant supplementation in model organisms are disappointing. Many studies showed no effect or even negative effects on the lifespan. Only in some cases considerable prolongation of lifespan was obtained and in organisms which are evolutionarily quite distant from mammals. In some cases, mean but not maximal lifespan was affected, which may be caused by reduction of mortality due to diseases rather than interference with the aging process itself. An apparently obvious conclusion from the plethora of studies could be that antioxidants cannot be expected to prolong significantly the lifespan, especially of mammals, which does not support the FRTA.

In summary, while beneficial effects of antioxidant supplements seem undoubtful in cases of antioxidant deficiencies, additional studies are warranted in order to design adapted prescriptions in antioxidant vitamins and minerals for healthy persons.


Monday, May 5, 2014

As you might know, in recent years researchers have joined the circulatory systems of old and young mice and seen that this causes stem cells in the old mice to return to work in greater numbers, somewhat reversing a number of measures of aging. Stem cell function declines with age in response to damage, and this reduces the risk of cancer due to damaged cells running awry. Thus there is a strong possibility that forcing old tissues to behave as though young by changing the signaling environment - such as by using young blood - will result in a greatly raised risk of cancer. This risk remains to be quantified.

Researchers are beginning to isolate specific signaling changes that lead to stem cell decline in aging, and the protein GDF11 is a promising start - though no doubt far from the only important signal. Boosting levels of GDF11 in old mice has already been shown to improve heart function. Here researchers find other benefits:

Injections of a protein known as GDF11, which is found in humans as well as mice, improved the exercise capability of mice equivalent in age to that of about a 70-year-old human, and also improved the function of the olfactory region of the brains of the older mice - they could detect smell as younger mice do. Studies examined the effect of GDF11 in two ways. First, by using what is called a parabiotic system, in which two mice are surgically joined and the blood of the younger mouse circulates through the older mouse. And second, by injecting the older mice with GDF11, which in an earlier [study] was shown to be sufficient to reverse characteristics of aging in the heart.

GDF11 is naturally found in much higher concentrations in young mice than in older mice, and raising its levels in the older mice has improved the function of every organ system thus far studied. "From the previous work it could have seemed that GDF11 was heart specific, but this shows that it is active in multiple organs and cell types. Prior studies of skeletal muscle and the parabiotic effect really focused on regenerative biology. Muscle was damaged and assayed on how well it could recover."

"The additional piece is that while prior studies of young blood factors have shown that we achieve restoration of muscle stem cell function and they repair the muscle better, in this study, we also saw repair of DNA damage associated with aging, and we got it in association with recovery of function, and we saw improvements in unmanipulated muscle. Based on other studies, we think that the accumulation of DNA damage in muscle stem cells might reflect an inability of the cells to properly differentiate to make mature muscle cells, which is needed for adequate muscle repair."

"We think an effect of GDF11 is the improved vascularity and blood flow, which is associated with increased neurogenesis. However, the increased blood flow should have more widespread effects on brain function. We do think that, at least in principle, there will be a way to reverse some of the cognitive decline that takes place during aging, perhaps even with a single protein. It could be that a molecule like GDF11, or GDF11 itself, could reverse the damage of aging."

It is worth noting that these results are all over the news at the moment, which I imagine has nothing to do with the merits of the science and everything to do with the fact that a company has been formed and is presently raising venture funding to commercialize this treatment. There is a sort of alchemy underway behind the scenes where influence and money is turned into press attention so as to obtain a better valuation.

Monday, May 5, 2014

Ordinary somatic cells can be reprogrammed into a state similar to that of embryonic stem cells, and the results are known as induced pluripotent stem cells (iPSCs). These can in theory be used to generate any type of cell, once a specific recipe of signals and environment is established for that cell type. One goal is to generate sources of patient-matched cells to order so as to facilitate regenerative therapies, but at this stage it is just as important to be able to generate cells for research - to build useful models of specific age-related and genetic conditions and thus rigorously investigate the underlying biochemistry.

It has been established that some properties exhibited by cells in old tissue are removed or lessened by the process of generating IPSCs. This is most interesting and probably a bonus when it comes to use in therapies, but quite inconvenient if your interest lies in building models of age-related or genetic conditions, as some of the basis for the condition is stripped out by the process of generating the cells that you want to use. Here is a discussion on this topic, in which researchers involved in studying Hutchinson-Gilford progeria syndrome (HGPS) seek ways to "re-age" the cells they are work with:

Age is the most important risk factor in many late-onset disorders such as Parkinson's disease (PD) as illustrated by the fact that PD patients do not develop symptoms until later in life. Therefore, it is imperative to consider age as well as genetic mutations when attempting to model these diseases in vitro.

Previously, it was unclear whether a donor cell from an old individual would maintain its age-associated properties following conversion into other cell fates ex vivo. However, recent studies have presented evidence that markers of cellular age, including mitochondrial fitness and telomere length, are reset to a young-like state when old donor fibroblasts are reprogrammed to iPSCs.

Indeed, our own study defines a broad set of age-associated markers, and we demonstrate the rejuvenation of old donor fibroblasts based on those markers. The corresponding iPSCs derived from old donors no longer exhibit features that distinguish old from young primary cells including abnormal nuclear morphologies, accumulated DNA damage, increased reactive oxygen specifies (ROS), reduced levels of a set of nuclear organization proteins, and loss of heterochromatin markers. We could not be sure, however, whether pluripotency simply suppresses "age" by downregulating age-related proteins such as progerin. Indeed HGPS iPSCs also show a loss of the age-associated markers at the pluripotency stage.

Therefore, iPSCs were differentiated into a fibroblast-like cell in order to match the phenotype of the donor fibroblasts used for reprogramming. We were able to show that similar to the pluripotency stage, iPSC-derived fibroblasts from old donors appear "young", suggesting that the cell's intrinsic molecular clock is reset following the reprogramming step. In contrast, HGPS iPSC-derived fibroblasts quickly upregulate progerin (the disease-causing protein) during differentiation, resulting in the re-induction of age-associated phenotypes. Based on these findings we hypothesized then that the difficulties of modeling late-onset disease in differentiated iPSCs could be caused by the fact that they are too "young" and that the implementation of defined genetic cues such as progerin overexpression may be sufficient to reintroduce age-associated markers.

Tuesday, May 6, 2014

The laboratory rat lineage used in this study, spontaneously hypertensive rats, was bred decades ago to exhibit high blood pressure, and predates modern genetic engineering methods. So I think there are fair odds that the beneficial results shown in this paper will hold up in normal rats or other models of hypertension.

Hypertension is a highly prevalent disease associated with cardiovascular morbidity and mortality. Recent studies suggest that patients with hypertension also have a deficiency of certain cardiac peptides. Previously we demonstrated that a single intravenous injection of the myocardium-tropic adeno-associated virus (AAV) 9-based vector encoding for proBNP prevented the development of hypertensive heart disease (HHD) in spontaneously hypertensive rats (SHRs). The current study was designed to determine the duration of cardiac transduction after a single AAV9 injection and to determine whether cardiac BNP overexpression can delay the progression of previously established HHD, and improve survival in aged SHRs with overt HHD.

To evaluate the duration of cardiac transduction induced by the AAV9 vector, we used four week old SHRs. Effective long-term selective cardiac transduction was determined by luciferase expression. A single intravenous administration of a luciferase-expressing AAV9 vector resulted in efficient cardiac gene delivery for up to 18-months. In aged SHRs (9-months of age), echocardiographic studies demonstrated progression of HHD in untreated controls, while AAV9-BNP vector treatment arrested the deterioration of cardiac function at six months post-injection (15-months of age).

Aged SHRs with established overt HHD were further monitored to investigate survival. A single intravenous injection of the AAV9-vector encoding rat proBNP was associated with significantly prolonged survival in the treated SHRs (613 ± 38 days, up to 669 days) compared to the untreated rats (480 ± 69 days, up to 545 days). These findings support the beneficial effects of chronic supplementation of BNP in a frequent and highly morbid condition such as HHD.

Tuesday, May 6, 2014

The ability to engineer blood vessel networks is one of the most important hurdles standing between the present state of the art in tissue engineering and the creation of large, functional tissue masses. Tissue of any meaningful size requires an intricate web of tiny blood vessels to support it, and that network must be tied into existing blood vessels in the body. The need for blood vessels is one of the reasons why decellularization of donor organs is a useful strategy at the present time: the extracellular matrix stripped of donor cells supplies the needed blood vessel structures, complete with chemical cues to guide new cells into the right places to reform the vessels.

In the case of organ engineering, one major obstacle keeping researchers from crafting functioning organs is the inability to ensure adequate blood supply to the nascent organ. Even if an entire organ can be constructed using all the appropriate cell types, its survival in the body depends on its access to oxygen and nutrients. Thin layers of tissue such as cartilage can get by with the simple diffusion of these life-giving compounds across tissue boundaries and do not require the construction of blood vessels to survive once implanted in a body. But more complex engineered tissues and organs require functional blood vessels to deliver oxygen and nutrients and to remove waste products.

But engineering functional blood vessel networks is not an easy task. Researchers must understand the mechanisms that drive the formation of blood vessels in order to guarantee consistent results and optimal survival of engineered tissues and organs. How do endothelial cells self-organize into functional networks? Do the cells require external cues to form stable vessels? How do they interact with neighboring cells to ensure expedient microvessel formation?

In 2008 [researchers] found that combining mesenchymal stem cells (MSCs) from human bone marrow with human endothelial cells prompted the formation of robust vascular networks. In some ways, this was a bit surprising, because the added stem cells were not really functioning in a typical stem-cell capacity. They were not differentiating into endothelial cells, nor were they being converted into the cell types that MSCs normally give rise to, such as bone, cartilage, or fat. Instead, they were somehow acting as "builders" to help organize the "building blocks" - the endothelial cells - into a functional network.

Recent work suggests that the interaction between [MSCs] and endothelial cells may also apply to blood-vessel cells derived from human induced pluripotent stem cells (iPSCs). [Human] iPSCs can generate both endothelial cells and pericytes, and that combining such iPSC-derived cells creates robust vessels. Because iPSCs can be derived from individual patients and tailored to their specific needs while minimizing the risk of immune rejection, this approach may help equip made-to-order iPSC-derived organs with the iPSC-derived blood vessels they need to survive.

Wednesday, May 7, 2014

Much of the cancer research community is focused on a search for specific proteins that will produce beneficial effects if levels are augmented or restricted. Here is an example of the sort of work presently taking place:

A research team [reports] that inhibiting a single protein completely shuts down growth of pancreatic cancer, a highly lethal disease with no effective therapy. Their [study] demonstrates in animal models and in human cancer cells that while suppressing Yes-associated protein (Yes) did not prevent pancreatic cancer from first developing, it stopped any further growth. "We believe this is the true Achilles heel of pancreatic cancer, because knocking out Yes crushes this really aggressive cancer. This appears to be the critical switch that promotes cancer growth and progression."

The study was conducted in mouse models of pancreatic ductal adenocarcinoma (PDAC), which accounts for all but five percent of human pancreatic cancers. These mice have a mutation in the KRAS gene, as well as a mutation in their p53 gene. "More than 95 percent of pancreatic cancer patients have a KRAS mutation and about 75 percent have a mutation in p53, so these mice provide a natural model of the human disease."

Because it has been very difficult to devise drugs that target either KRAS or p53, in this study the researchers looked for other potential druggable targets involved in uncontrolled growth of pancreatic cancer. They found that Yes was over-expressed in both mouse models and human samples of PDAC, and they discovered that the KRAS mutation found in most pancreatic cancer activates Yes.

Because Yes is over-expressed in other cancers, such as lung, liver and stomach tumors, researchers are already working on small molecule drugs that will inhibit activity of the protein and its partnering molecules. "KRAS and p53 are two of the most mutated genes in human cancers, so our hope is that a drug that inhibits Yes will work in pancreatic cancer patients - who have both mutations - and in other cancers with one or both mutations."

Wednesday, May 7, 2014

Amyloid levels in the brain are very dynamic, capable of changing rapidly. That amyloid builds up with age to contribute to the development of neurodegenerative conditions such as Alzheimer's disease points to a slow breakdown in the balance of generation and clearance. The choroid plexus is a filtration system for cerebrospinal fluid, and hence a place to look for failures, such as a progressive loss of the protein machinery needed to extract amyloid from the brain:

Accumulation of amyloid-beta peptides (Aβ) results in amyloid burden in normal aging brain. Clearance of this peptide from the brain occurs via active transport at the interfaces separating the central nervous system (CNS) from the peripheral circulation. The present study was to investigate the change of Aβ transporters expression at the choroid plexus (CP) in normal aging.

Morphological modifications of CP were observed by transmission electron microscope. Real-time RT-PCR was used to measure mRNA expressions of Aβ42 and its transporters, which include low density lipoprotein receptor-related protein-1 and 2 (LRP-1 and -2), P-glycoprotein (P-gp) and the receptor for advanced glycation end-products (RAGE), at the CP epithelium in rats at ages of 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33 and 36 months. At the same time, the mRNA expressions of oxidative stress-related proteins were also measured.

The results showed that a striking deterioration of the CP epithelial cells and increased Aβ42 mRNA expression were observed in aged rats, and there was a decrease in the transcription of the Aβ efflux transporters, LRP-1 and P-gp, no change in RAGE mRNA expression and an increase in LRP-2, the CP epithelium Aβ influx transporter. These results suggest the efficacy of the CP in clearing of Aβ deceases in normal aging, which results in the increase of brain Aβ accumulation. And excess Aβ interferes with oxidative phosphorylation, leads to oxidative stress and morphological structural changes. This in turn induces further pathological cascades of toxicity, inflammation and neurodegeneration process.

Thursday, May 8, 2014

Mutation of INDY, I'm Not Dead Yet, was one of the first longevity enhancing genetic alterations to be discovered in flies. Here researchers link this healthy life extension to preservation of intestinal stem cell function, work that has been helped along by the discovery in recent years of the great importance of the intestinal stem cell population and intestinal function in fly aging. One of the genes altered in that research to enhance stem cell function has now been linked to INDY:

The Drosophila Indy (I'm Not Dead Yet) gene encodes a plasma membrane transporter of Krebs cycle intermediates, with robust expression in tissues associated with metabolism. Reduced INDY alters metabolism and extends longevity in a manner similar to caloric restriction (CR); however, little is known about the tissue specific physiological effects of INDY reduction. Here we focused on the effects of INDY reduction in the Drosophila midgut due to the importance of intestinal tissue homeostasis in healthy aging and longevity.

The expression of Indy mRNA in the midgut changes in response to aging and nutrition. Genetic reduction of Indy expression increases midgut expression of the mitochondrial regulator spargel/dPGC-1, which is accompanied by increased mitochondrial biogenesis and reduced reactive oxygen species (ROS). These physiological changes in the Indy mutant midgut preserve intestinal stem cell (ISC) homeostasis and are associated with healthy aging. Genetic studies confirm that dPGC-1 mediates the regulatory effects of INDY, as illustrated by lack of longevity extension and ISC homeostasis in flies with mutations in both Indy and dPGC1. Our data suggest INDY may be a physiological regulator that modulates intermediary metabolism in response to changes in nutrient availability and organismal needs by modulating dPGC-1.

Thursday, May 8, 2014

The search continues for efficiently measured patterns of DNA methylation that correlate tightly to either chronological or biological age, with the latter being somewhat more useful than the former, as it could be used to rapidly evaluate the effectiveness of potential future rejuvenation treatments. Speed in evaluation is a driver of rapid progress, as it allows for more rapid exploration and avoidance of dead ends. Thus it is well worth keeping an eye on progress towards useful biomarkers of aging.

We perform a comprehensive analysis of methylation profiles to narrow down 102 age-related CpG sites in blood. We demonstrate that most of these age-associated methylation changes are reversed in induced pluripotent stem cells (iPSCs). Methylation levels at three age-related CpGs - located in the genes ITGA2B, ASPA and PDE4C - were subsequently analyzed by bisulfite pyrosequencing of 151 blood samples.

This epigenetic aging signature facilitates age predictions with a mean absolute deviation from chronological age of less than 5 years. This precision is higher than age predictions based on telomere length. Variation of age predictions correlates moderately with clinical and lifestyle parameters supporting the notion that age-associated methylation changes are associated more with biological age than with chronological age. Furthermore, patients with acquired aplastic anemia or dyskeratosis congenita - two diseases associated with progressive bone marrow failure and severe telomere attrition - are predicted to be prematurely aged.

Our epigenetic aging signature provides a simple biomarker to estimate the state of aging in blood. Age-associated DNA methylation changes are counteracted in iPSCs. On the other hand, over-estimation of chronological age in bone marrow failure syndromes is indicative for exhaustion of the hematopoietic cell pool. Thus, epigenetic changes upon aging seem to reflect biological aging of blood.

Friday, May 9, 2014

Researchers uncover a novel alteration of cellular metabolism that extends life in yeast and worms, and has similar effects in human cells as it does in nematode cells:

Epigenetics comprises multiple regulatory layers, including chromatin packaging - the orderly wrapping of DNA around histone proteins in the cell nucleus. By altering this DNA packaging, cells can control when and how genes are expressed. "Aging is, in part, the accumulation of cellular stress. If you can better respond to these stresses, this ameliorates the damage it can cause."

[Researchers] looked for chromatin-associated genes that could influence longevity by searching for genes that already were implicated in epigenetic regulation that might extend lifespan when deleted in the yeast, Saccharomyces cerevisiae. One such gene improved lifespan by about 25 percent. [The] team asked whether the gene ISW2 is part of previously identified longevity pathways, especially those associated with caloric restriction, a well-known strategy for extending lifespan. But pathways involving a form of chromatin modification (histone acetylation) came up empty, as did an alternate pathway involving growth control, suggesting ISW2 functions through a never-before-seen mechanism.

The team then looked for answers in the function of the ISW2 protein, and found that its absence alters the expression of genes involved in protecting cells from such stresses as DNA damage. Deletion of ISW2 increases the expression and activity of genes in DNA-damage repair pathways - an effect also seen during calorie restriction. The gene ISW2, it turns out, is involved in chromatin remodeling - it controls the spacing and distribution of the histone "spools" around which DNA wraps. Normally, ISW2 dampens stress-response pathways, possibly because overactivation of these pathways is deleterious early in life. Deletion or inactivation of the ISW2 gene activates those pathways, priming the cells to more effectively handle stress-associated genetic scars as cells age.

This effect is not limited to yeast. When [the team] reduced the levels of a related gene in the nematode worm, Caenorhabditis elegans, they observed a 15 percent improvement in longevity, which is similar in magnitude to the lifespan extension observed in other worm longevity pathways. Similarly, knocking down expression of a human homolog in cultured human cells boosted the expression of stress-response genes that, again, like yeast, occur in DNA-damage repair pathways.

Friday, May 9, 2014

A web of correlations exist between wealth, education, intelligence, and natural variations in human longevity. It is thus interesting to see that one of the genes associated with longevity and aging also has an effect on cognition - though not the effect that was initially expected:

Scientists have known for more than a decade that people and animals tend to live longer if they have high levels of Klotho in their bodies. And that led [researchers] to wonder whether a hormone that protects the body against aging might also protect the brain. So the team set out to see whether Klotho offered a way to "prevent the cognitive decline that comes with aging."

To find out, they studied more than 700 people between the ages of 52 and 85. About 1 in 5 of these people had a form of the Klotho gene that causes their bodies to produce high levels of the Klotho hormone. The team expected to find that people with high levels of the hormone experienced less cognitive decline than people with lower levels. "In fact what we found was not consistent with our hypothesis. We were completely surprised."

What they found was that the people with lots of Klotho experienced just as much cognitive decline as other people. Their brains weren't protected against aging at all. But their brains were different nonetheless. "Those that carried the genetic variant that increased their Klotho levels showed better cognitive performance across the lifespan." At any given age, people with lots of Klotho scored higher on tests of learning and memory, language and attention.

To learn more, the team began studying mice that had been genetically engineered to produce high levels of the mouse version of Klotho. "Elevating klotho made the mice smarter across all the cognitive tests that we put them through." A look at the brains of these mice suggested a reason. There was evidence that in areas involved in learning and memory, Klotho was causing a change that strengthened the connections between brain cells.


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