Fight Aging! Newsletter, March 14th 2016

March 14th 2016

Fight Aging! provides a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress towards the medical control of aging in order to prevent age-related frailty, suffering, and disease, as well as improvements in 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 medical research, news from the scientific community, advocacy and fundraising initiatives to help speed work on the repair and reversal of aging, links to online resources, and much more.

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  • An Unexpected Benefit of Cellular Senescence
  • Gene Mutation Cuts Risk of Heart Attack in Half in Humans
  • Electrical Stimulation as a Basis for Some Forms of Compensatory Therapy for Age-Related Degeneration
  • Does Calorie Restriction Slow Aging or Postpone Aging?
  • Recent Advances in Anti-Amyloid Passive Immunization
  • Latest Headlines from Fight Aging!
    • Targeting Hepatic Stellate Cells to Reverse Liver Fibrosis
    • Microglia Play an Important Role in Neuroplasticity
    • Enhanced FGF Signaling Reverses the Diminished Neurogenesis Observed in Old Mice
    • Reversal of Periodontitis Achieved via Inhibition of C3
    • Slow Progress Towards Printed Tissue that Incorporates a Functional Blood Vessel Network
    • Injectable Scaffolding Gel Improves Regeneration of Blood Vessels and Muscle Tissue
    • Progress in Engineering Small Sections of Eye Tissue
    • AGE Accumulation and Decline in Motor Function
    • Speculation on Mitochondrial Damage and Cancer in Aging
    • Inhibition of Cystathionine Beta-Synthase Greatly Reduces Cell Death Following Stroke


Researchers have found that, unusually, entering a senescent state actually improves some measures of performance in the beta cells of the pancreas responsible for producing insulin. Senescent cells are those that have removed themselves from the cycle of replication, either because they have reached the Hayflick limit, or prior to that point in reaction to molecular damage or a toxic local environment. A senescent cell may destroy itself via programmed cell death mechanisms or it may be destroyed by the immune system, but while it remains in place it behaves badly, secreting a harmful mix of molecules that change surrounding cellular behavior and remodel tissue structures. Aging brings a growing number of these senescent cells in all tissues, lingering long past the point at which they should have been destroyed. Their harmful effects grow sizable and contribute to the pathology of most age-related conditions. Thus cellular senescence is a cause of aging, age-related disease, and death. Even if all of the other mechanisms that cause aging were hand-waved away, increasing numbers of senescent cells alone would be enough to kill us eventually.

Biology is complex, however, and it is rare for any given process to do just one thing, or for any mechanism to be important in just one way. Evolution likes reuse, and cellular senescence has a variety of forms and has evolved into a variety of roles. It may have started as a process of embryonic development, a way to halt growth in order to define the shape of extremities such as fingers. The transient creation of senescent cells is also involved in wound healing, however, and senescence in response to damage and toxins likely serves to reduce the risk of cancer, or at least initially. Large numbers of senescent cells cause significant chronic inflammation, among other issues, and that eventually overwhelms any cancer-prevention benefit resulting from preventing replication in cells at a greater risk of suffering cancerous mutations.

Given all of this, it shouldn't be completely surprising to find more places and circumstances in the body in which cellular senescence produces benefits along the way towards ultimately helping to kill us. That we find such benefits isn't a good reason to pull back from efforts to produce therapies that can clear senescent cells from the body, and thereby prevent their contribution to aging, of course, but they do serve to remind us that nothing is ever simple when it comes to living organisms.

Cellular Aging Process Unexpectedly Enhances Insulin Secretion

New research shows that a cellular program that causes aging can also bring unexpected benefits in the function of pancreatic beta cells and the production of insulin in mice and humans. The researchers examined the activity of a gene named p16, which is known to activate a program called senescence in cells. Senescence prevents cells from dividing, and is therefore important in preventing cancer. The activity of the p16 gene increases in human and mouse pancreatic beta cells during aging and limits their potential to divide. This activity is thus seen as having a negative effect - the lack of ability of these cells to divide can contribute to diabetes, since beta cells are the cells responsible for secreting insulin when blood glucose levels are high, and their loss causes diabetes. However, it was unknown whether senescent beta cells could continue functioning at all.

To their surprise, the researchers discovered that during normal aging, p16 and cellular senescence actually improve the primary function of beta cells: the secretion of insulin upon glucose stimulation. Because insulin secretion increases during the normal aging of mice and is driven by elevated p16 activity, some of these cells actually start to function better. The researchers further found that activation of p16 and senescence in beta cells of mice that suffer from diabetes enhanced insulin secretion, thereby partly reversing the disease and improving the health of the mice. Similar experiments conducted in human cells strongly suggest that senescence-induced enhancement of insulin secretion is conserved between mice and humans, and point to the p16 gene as its main driver in both organisms.

p16Ink4a-induced senescence of pancreatic beta cells enhances insulin secretion

Cellular senescence is thought to contribute to age-associated deterioration of tissue physiology. The senescence effector p16Ink4a is expressed in pancreatic beta cells during aging and limits their proliferative potential; however, its effects on beta cell function are poorly characterized. We found that beta cell-specific activation of p16Ink4a in transgenic mice enhances glucose-stimulated insulin secretion (GSIS). In mice with diabetes, this leads to improved glucose homeostasis, providing an unexpected functional benefit.

Expression of p16Ink4a in beta cells induces hallmarks of senescence - including cell enlargement, and greater glucose uptake and mitochondrial activity - which promote increased insulin secretion. GSIS increases during the normal aging of mice and is driven by elevated p16Ink4a activity. We found that islets from human adults contain p16Ink4a-expressing senescent beta cells and that senescence induced by p16Ink4a in a human beta cell line increases insulin secretion in a manner dependent, in part, on the activity of the mechanistic target of rapamycin (mTOR) and the peroxisome proliferator-activated receptor (PPAR)-γ proteins. Our findings reveal a novel role for p16Ink4a and cellular senescence in promoting insulin secretion by beta cells and in regulating normal functional tissue maturation with age.


It has to be said, it is pretty rare for researchers to find a genetic effect as large as a halving of disease risk in human studies. We'll have to see if this particular case holds up in replication studies, but for the moment researchers are claiming that a mutation in the angiopoietin-like 4 (ANGPTL4) gene reduces risk of heart attack by 50%, and that to initial inspection this mutation doesn't seem to bear any detrimental side-effects. If this is in fact the case, we can add this to the growing list of potentially desirable gene therapies that are now well within the technical capabilities of most laboratories in this new age of CRISPR and low-cost, reliable genetic editing. At this point there are probably a score or more speculative changes that may be worth carrying out on the basis of animal studies or the existence of healthy human mutants, but only two or three, such as myostatin knockout, that are backed by sufficient evidence and experience to seem viable and low risk for immediate clinical translation.

Somewhere out there, right now, people with an interest, people with scientific knowledge, and people with money are exchanging missives and chewing over business plans that involve producing and selling packages of gene therapies for human enhancement. Some of these will include viable compensatory treatments for specific aspects of age-related degeneration; myostatin knockout to reduce loss of muscle mass and strength in aging, for example, or adding lysosomal receptors to increase cellular maintenance and slow loss of organ function. As the cost of gene therapy continues to fall, even as its reliability and capabilities increase by leaps and bounds, we're going to see the same thing happen for this field as happened for stem cell research fifteen years ago. Many groups and clinics will choose to circumvent the more restrictive regulatory systems of the US and Europe. They will offer therapies in other regions based on the technical ability to do so, and where there is a reasonable expectation of success and benefit. My prediction is that this process of commercial and medical exploration will be well underway five years from now.

Mutated gene safeguards against heart attacks

For the large-scale study at hand, the scientists analyzed 13,000 different genes from a pool of 200,000 participants - both heart attack patients and healthy control persons. They were on the lookout for correlations between gene mutations and coronary artery disease. For a number of genes, the researchers registered a correlation, including the ANGPTL4 (angiopoietin-like 4) gene. In addition, subjects with the mutated ANGPTL4 gene had significantly lower triglyceride values in their blood. "The blood fat triglyceride serves as an energy store for the body. However, as with LDL cholesterol, elevated values lead to an increased risk of cardiovascular disease. Low values, by contrast, lower the risk. For most patients the focus still lies on cholesterol. A differentiation is always made between the healthy HDL and the harmful LDL cholesterol variants. However, in the mean time we know that the HDL values always run inversely proportional to those of the triglycerides and that HDL itself actually tends to behave in a neutral manner. The triglycerides, on the other hand, are the second important blood fat, alongside the harmful LDL cholesterol. The only reason HDL blood values are still measured is because, together with HDL and triglyceride values, they can be used to derive the LDL values, which cannot be measured directly."

The current study now shows that the concentration of triglycerides in the blood are influenced not only by nutrition and predisposition, but also by the ANGPTL4 gene. "At the core of our data is the lipoprotein lipase (LPL) enzyme. It causes the decomposition of triglycerides in the blood." Normally, ANGPTL4 hems the LPL enzyme, causing blood fat values to rise. The mutations identified by the researchers disable the function of this gene and thereby ensure that the triglyceride value drops significantly. "At the same time, we discovered that the body does not even need the ANGPTL4 gene and manages wonderfully without it. It seems to be superfluous." Shutting down the gene or inhibiting the LPL enzyme in another manner may ultimately protect against coronary disease. "Based on our results, medications now need to be developed that neutralize the effect of the ANGPTL4 gene, thereby reducing the risk of a heart attack. Other researchers have already done this successfully in animal tests. They drastically reduced the blood fat levels in monkeys that received a neutralizing antibody against ANGPTL4. This feeds the hope that antibody preparations with a similar effect can soon be used successfully in humans."

Coding Variation in ANGPTL4, LPL, and SVEP1 and the Risk of Coronary Disease

Through large-scale exomewide screening, we identified a low-frequency coding variant in ANGPTL4 that was associated with protection against coronary artery disease and a low-frequency coding variant in SVEP1 that was associated with an increased risk of the disease. Moreover, our results highlight LPL as a significant contributor to the risk of coronary artery disease and support the hypothesis that a gain of LPL function or loss of ANGPTL4 inhibition protects against the disease.

ANGPTL4 has previously been found to be involved in cancer pathogenesis and wound healing. Previous functional studies also revealed that ANGPTL4 regulates plasma triglyceride concentration by inhibiting LPL. The minor allele at p.E40K has previously been associated with lower levels of triglycerides and higher levels of HDL cholesterol. We now provide independent confirmation of these lipid effects. In vitro and in vivo experimental evidence suggests that the lysine allele at p.E40K results in destabilization of ANGPTL4 after its secretion from the cell in which it was synthesized. It may be that the p.E40K variant leads to increases in the enzymatic activity of LPL because of this destabilization. Previous, smaller studies produced conflicting results regarding p.E40K and the risk of coronary artery disease; we now provide robust support for an association between p.E40K and a reduced risk of coronary artery disease.

To provide confirmatory orthogonal evidence that a loss of ANGPTL4 function is associated with a decreased risk of coronary artery disease, we searched for loss-of-function mutations in this gene. We found that ANGPTL4 loss-of-function mutations were associated with substantially lower triglyceride levels (35% lower than in persons who were not carriers of a loss-of-function mutation), and we also found that these loss-of-function alleles were associated with a 53% lower risk of coronary artery disease. The identification of additional ANGPTL4 inactivating mutation carriers provides further evidence of the association between a loss of ANGPTL4 function and lower triglyceride levels and a reduced risk of coronary artery disease.


Functional electrical stimulation has been used as the basis for therapies and prosthetics in cases of paralysis. In theory it can help slow degeneration of paralyzed limbs by exercising muscles, or in some lesser cases bypass damaged nerves sufficiently well to allow very limited function of otherwise paralyzed muscles. As prosthetic systems become more sophisticated, "limited function" increases in scope: consider the proof of concept from last year in which a paraplegic with spinal cord injury walked a few steps. This is still a long way from robust methods of bypassing damaged nerves, however. It is most likely that progress in regenerative medicine will enable repair of even very severe nerve damage before artificial nerve bypasses arrive at the point of enabling paraplegic patients to use their paralyzed limbs in a natural way.

Elsewhere, electrical stimulation of various sorts is used in a variety of therapies for a variety of conditions, and has been for some time - though the evidence for benefits and understanding of mechanisms involved is lacking in many cases. Looking forward to the future, some research groups are exploring the role of electric fields and signals in tissue growth, in regeneration, and in related uses in tissue engineering, as well as potentially providing a basis for selectively disabling cancer cells. But for today I'll point out a few recent research articles that focus firstly on whether or not electrical stimulation of muscles can be of use as a compensatory treatment for age-related muscle wasting, and secondly on electrical stimulation of the brain as a way to increase neuroplasticity - again a way to compensate in part for losses that occur due to aging. As is frequently the case in research, these are not approaches that address any of the root causes of degeneration, but rather try to add more capacity or resilience to impacted tissues. This will always be an inferior approach, capable of producing only lesser benefits, but the cost-benefit analysis for undertaking the work may still be favorable in many cases.

Brain Boost: ONR Global Sponsors Research to Improve Memory through Electricity

Researchers have significantly boosted the memory and mental performance of laboratory mice through electrical stimulation. The study involved the use of Transcranial Direct Current Stimulation, or tDCS, on the mice. A noninvasive technique for brain stimulation, tDCS is applied using two small electrodes placed on the scalp, delivering short bursts of extremely low-intensity electrical currents. "We already have promising results in animal models of Alzheimer's disease. In the near future, we will continue this research and extend analyses of tDCS to other brain areas and functions."

After exposing the mice to single 20-minute tDCS sessions, the researchers saw signs of improved memory and brain plasticity (the ability to form new connections between neurons when learning new information), which lasted at least a week. This intellectual boost was demonstrated by the enhanced performance of the mice during tests requiring them to navigate a water maze and distinguish between known and unknown objects. Although tDCS has been used for years to treat patients suffering from conditions such as stroke, depression and bipolar disorder, there are few studies supporting a direct link between tDCS and improved plasticity. More important, the researchers identified the actual molecular trigger behind the bolstered memory and plasticity - increased production of brain-derived neurotrophic factor (BDNF), a protein essential to brain growth. BDNF is synthesized naturally by neurons and is crucial to neuronal development and specialization.

Biology of Muscle Atrophy and of its Recovery by FES in Aging and Mobility Impairments: Roots and By-Products

We have presented strong evidence that the atrophy which accompanies aging is to some extent caused by loss of innervation. We compared muscle biopsies of sedentary seniors to those of life long active seniors, and show that these groups indeed have a different distribution of muscle fiber diameter and fiber type. The senior sportsmen have many more slow fiber-type groupings than the sedentary people which provides strong evidence of denervation-reinnervation events in muscle fibers.

In extreme examples of muscle degeneration accompanying nerve disconnection, we have gathered data supporting the idea that electrical stimulation of denervated muscles can retain and even regain muscle. We show here that, if people are compliant, atrophy can be reversed. A further example of activity-related muscle adaptation is provided by the fact that mitochondrial distribution and density are significantly changed by functional electrical stimulation (FES) in horse muscle biopsies relative to those not receiving treatment. All together, the data indicate that FES is a good way to modify behaviors of muscle fibers by increasing the contraction load per day. Indeed, it should be possible to defer the muscle decline that occurs in aging people and in those who have become unable to participate in physical activities. Thus, FES should be considered for use in rehabilitation centers, nursing facilities and in critical care units when patients are completely inactive even for short periods of time.

Molecular and Cellular Mechanisms of Muscle Aging and Sarcopenia and Effects of Electrical Stimulation in Seniors

One of the problems associated with aging is that some people cannot move because of pathological conditions like pain, osteoarthritis and so on. Is there an alternative approach instead of physical exercise for these people? Researchers designed a specific way of analyzing electrical stimulation to address the question: can electrical stimulation mimic the effect of physical exercise? In particular, a stimulator for neuromuscular electrical stimulation was designed, especially suiting the requirements of elderly people with diminished fine motor skill. What was demonstrated is that electrical stimulation did improve muscle performance. The increase in muscle strength was associated with an increase of muscle fibers and most importantly with an increase of fast fibers, which are related to the power of the skeletal muscle. We asked: what is the mechanism associated with this increase of muscle strength and increase in muscle mass?

Since IGF-1 is one of the factors that are activated during physical exercise, we verified whether electrical stimulation was able to induce an increase in IGF-1 expression. At first, we analyzed the expression of the different types (isoforms) of IGF-1. All of them were up regulated after electrical stimulation. Then we analyze some downstream pathways activated by IGF-1. We demonstrated that electrical stimulation stimulates not only anabolic pathways, but negatively modulates muscle catabolism. Another component that we analyze is collagen expression. There is remodeling, not only during physical exercise but also in electrical stimulation of extracellular matrix (ECM). Of note histology did not reveal any accumulation of fibrotic tissue in electrical stimulated muscles. To further support the morphological evidences, we analyzed one of the important controllers of fibrosis, namely miR29. The electrical stimulation regulates miR29, which might block the accumulation of fibrosis. We then analyzed the number of satellite cells that can be activated by electrical stimulation. We wanted to verify whether electrical stimulation, similarly to exercise, can increase the activity of these cells. Electrical stimulation indeed increased the number of satellite cells.

In conclusion, what we demonstrated is that electrical stimulation, which can be applied to people that cannot carry out normal physical activity, modulates similar factors associated with physical exercise. All of these data might help to design therapeutic strategies to counteract muscle atrophy associated with aging.


The practice of calorie restriction has been shown to reliably and robustly extend life in a variety of species. It has been used for decades now as a tool to investigate the relationships between metabolism, genetic variation, cellular biochemistry, and aging. Does the life extension produced in response to calorie restriction mean that it slows aging, postpones aging, or both? What does the distinction between slowing and postponing aging even mean at the most detailed level of consideration? Attempting to answer this question means engaging with definitions of aging, whether statistical or physiological, that are all still fairly open to debate. This is well illustrated by the open access paper linked below.

Over the past twenty years researchers have discovered and demonstrated many interventions that extend healthy, mean, and maximum life spans in varied combinations and degrees in short-lived species such as nematode worms, fruit flies, and mice. The plasticity of life span in response to altered environmental, genetic, and metabolic states is inversely related to the unmodified life expectancy of the organism in question. The longer the life span, the less it changes. So while nematodes that normally live for a few weeks have been engineered to gain as much as a tenfold increase in length of life, in mice that normally live a few years the record for artificial life extension stubbornly remains stuck at the 60-70% increase achieved more than a decade ago. The researchers involved used genetic knockout of the growth hormone receptor, and by good fortune there is a small human population descended from a comparatively recent ancestor who have inherited a very similar loss of function mutation. They, much as expected, don't seem to have any obvious gain in life expectancy. We are a long-lived species in comparison to mice, and therefore our plasticity of life span in response to these sorts of alterations is much lower.

Why does plasticity of longevity scale in this way? Calorie restriction may provide the answer. The calorie restriction response most likely evolved very early in the history of life because it provides survival advantages in periods of famine. Famine takes place on seasonal or shorter time frames, and a season is a sizable chunk of the life of a mouse, but much less so for a human. Thus only the mouse evolves the ability to greatly extend life when calorie intake falls, despite the fact that both mice and humans exhibit quite similar short-term alterations in metabolic state in response to calorie restriction. Calorie restriction in mice can extend life by 40% or more, while in humans it certainly doesn't produce anywhere near that gain. There is no rigorous estimate for longevity added in humans practicing calorie restriction, and such an estimate is unlikely to emerge any time soon, but the much less rigorous process of theorizing and modeling suggests 5% as a reasonable ballpark. Anything much larger than that would appear as a strong statistical signal in many historical data sets that are known to show no such signs.

It is worth bearing in mind that when we seek to build therapies to treat aging as a medical condition, to bring it under control, the ideal goal is to postpone it, not slow it. A therapy that can postpone aging is a therapy that can be reused later to postpone aging some more. A therapy that only slows aging has no such option: it has a flat maximum benefit to life span. Postponing aging, provided it works well enough and doesn't let any aspect of aging leak though to accumulate, has an unlimited upside in terms of the years of healthy life it can add. This is one of the reasons why I'm very focused on repair of damage after the SENS model as the path ahead for the treatment of aging. Repair of the forms of cell and tissue damage that cause aging can in principle produce rejuvenation and indefinite postponement of aging, provided it can be made comprehensive enough. In comparison, work aimed at modestly slowing aging by developing drugs to beneficially alter metabolic state, meaning slowing the pace at which damage accumulates rather than repairing existing damage, has no such upside and will be of very limited utility to people who are already old and damaged.

Measuring aging rates of mice subjected to caloric restriction and genetic disruption of growth hormone signaling

Extensive experiments have demonstrated that caloric restriction and genetic disruption of growth hormone signaling can profoundly counteract aging in mice. Caloric restriction - or dietary restriction - is an environmental intervention, whereby the usual ad libitum dietary intake is limited to an intake of 30-40% less. Mice subjected to caloric restriction can live up to 60% longer, suffer less often and at higher ages from age-associated disorders, and exhibit less molecular stress and damage. Disruption of growth hormone signaling is a genetic intervention, whereby the production of growth hormone-releasing hormone, growth hormone, or the receptor of growth hormone is impaired, so that the effects of growth hormone are annulled. Mice with disrupted growth hormone signaling can live up to 70% longer, suffer less often and at higher ages from age-associated disorders, have youthful metabolic characteristics such as a higher insulin sensitivity, and have an enhanced resistance against molecular-genetic stress and damage.

However, since age-dependent survival and life expectancy do not reveal at which ages and to what extent the risk of death increases, they conceal the effects on aging. Age-dependent mortality rates are generally fitted to the Gompertz model, after which they increase linearly with age on a logarithmic scale. The linear increase of such a modeled mortality rate is classically interpreted as an aging rate. However, the use of the Gompertz model constrains mortality rates to increase linearly on a logarithmic scale, which may not correspond with the increases in the crude age-dependent mortality rates, especially in relatively small populations. Therefore, alternative methods are needed to accurately examine the effects of interventions such as caloric restriction and genetic disruption of growth hormone signaling on age-dependent mortality rates.

According to the classical method, these interventions negligibly and non-consistently affected the aging rates. By contrast, according to the alternative method studied here, the aging rates of mice subjected to caloric restriction or disruption of growth hormone signaling increased at higher ages and to higher levels as compared with mice not subjected to these interventions. A key question in research on aging is whether increases in life expectancy reflect a postponement or a slowing of aging. The answer to this question is pivotal to gain insight in the mechanisms of aging, to identify interventions that modulate these mechanisms, and to predict the effects of such interventions on aging. However, with respect to caloric restriction and disruption of growth hormone signaling, a clear answer to this question is lacking. While caloric restriction has long been assumed to slow aging, it is debated whether it postpones aging instead. Likewise, some presume that genetic disruption of growth hormone signaling slows aging, whereas others pose that it rather postpones aging.

Our method interprets these interventions to affect the aging rates in an age-dependent manner: aging was slowed at lower ages, postponed until higher ages, but quickened at higher ages. Such a pattern resembles a compression of aging, whereby aging is postponed as well as intensified, reflected by a risk of death that increases sharply at a high age. A compression of aging also becomes apparent from the life expectancies of the mice: these interventions bring about an increase in median life expectancy that is two to four times larger than the increase in maximal life expectancy, indicating a sharper increase in the risk of death at a higher age. This effect was shared by caloric restriction and genetic disruption of growth hormone signaling. This conclusion warrants a reevaluation of previous studies on the effects of these interventions on murine aging with the use of the alternative method.


Passive immunotherapy involves the delivery of an agent, such as a monoclonal antibody, that spurs the immune system to attack specific targets. This response lasts for as long as the agents are consistently delivered as a therapy, and most are short-lived molecules, meaning that passive immunotherapies are easily halted. This is thus an attractive approach in fields such as cancer treatment and amyloid clearance where there is still a fair degree of uncertainty in the differences between animal models and human patients, and trials that accidentally cause harm are rare but not unheard of. The ability to stop a treatment immediately if results are unexpected is very helpful for all involved.

In recent years researchers have been making progress in the development of useful amyloid antibodies capable of instructing the immune system to clear the amyloid β that is associated with Alzheimer's disease. To take a broader point of view, this is an important class of technology for the near future of rejuvenation therapies after the SENS model. Success against amyloid β using antibodies and passive immunization would mean that success against other forms of extracellular aggregate that contribute to the aging process is also plausible via this methodology. I think that at this point success is just a matter of time, of finding good enough antibodies or related agents, a process that unfortunately isn't turning out to be as rapid or as cheap as anyone would like it to be. In that light it is good that this line of development is attached to a comparatively well-funded field of medical research.

The first paper linked below is a great example of the way in which today's biotechnology is already catching up with the science fiction of a few decades past. Here we have living cells converted into drug manufactories, encapsulated in an implant that secretes the drug at a slow pace, and the whole set in motion to clear some proportion of unwanted metabolic waste so as to slow the pace at which dementia develops - to slow one aspect of aging by consistently removing some fraction of the damage that causes it. All of that engineering is actually the fairly reliable part of the equation, for all that it tends to sound more interesting and impressive than the biochemistry involved in producing antibodies. The challenge in this field is to find a means of control over immune activities that is much, much more effective at clearing unwanted amyloids and other forms of harmful extracellular waste than the present crop of antibodies.

A subcutaneous cellular implant for passive immunization against amyloid-β reduces brain amyloid and tau pathologies

Passive immunization against misfolded toxic proteins is a promising approach to treat neurodegenerative disorders. For effective immunotherapy against Alzheimer's disease, recent clinical data indicate that monoclonal antibodies directed against the amyloid-β peptide should be administered before the onset of symptoms associated with irreversible brain damage. It is therefore critical to develop technologies for continuous antibody delivery applicable to disease prevention. Here, we addressed this question using a bioactive cellular implant to deliver recombinant anti-amyloid-β antibodies in the subcutaneous tissue. An encapsulating device permeable to macromolecules supports the long-term survival of myogenic cells over more than 10 months in immunocompetent allogeneic recipients. The encapsulated cells are genetically engineered to secrete high levels of anti-amyloid-β antibodies. Peripheral implantation leads to continuous antibody delivery to reach plasma levels that exceed 50 µg/ml.

In a proof-of-concept study, we show that the recombinant antibodies produced by this system penetrate the brain and bind amyloid plaques in two mouse models of Alzheimer's pathology. When encapsulated cells are implanted before the onset of amyloid plaque deposition in TauPS2APP mice, chronic exposure to anti-amyloid-β antibodies dramatically reduces amyloid-β40 and amyloid-β42 levels in the brain, decreases amyloid plaque burden, and most notably, prevents phospho-tau pathology in the hippocampus. These results support the use of encapsulated cell implants for passive immunotherapy against the misfolded proteins, which accumulate in Alzheimer's disease and other neurodegenerative disorders.

Passive immunotherapy targeting amyloid-β reduces cerebral amyloid angiopathy and improves vascular reactivity

Prominent cerebral amyloid angiopathy is often observed in the brains of elderly individuals and is almost universally found in patients with Alzheimer's disease. Cerebral amyloid angiopathy is characterized by accumulation of the shorter amyloid-β isoforms (predominantly amyloid-β40) in the walls of leptomeningeal and cortical arterioles and is likely a contributory factor to vascular dysfunction leading to stroke and dementia in the elderly.

We used transgenic mice with prominent cerebral amyloid angiopathy to investigate the ability of ponezumab, an anti-amyloid-β40 selective antibody, to attenuate amyloid-β accrual in cerebral vessels and to acutely restore vascular reactivity. Chronic administration of ponezumab to transgenic mice led to a significant reduction in amyloid and amyloid-β accumulation both in leptomeningeal and brain vessels. We hypothesized that the reduction in vascular amyloid-β40 after ponezumab administration may reflect the ability of ponezumab to mobilize an interstitial fluid pool of amyloid-β40 in brain. Acutely, ponezumab triggered a significant and transient increase in interstitial fluid amyloid-β40 levels in old plaque-bearing transgenic mice but not in young animals. We also measured a beneficial effect on vascular reactivity following acute administration of ponezumab, even in vessels where there was a severe cerebral amyloid angiopathy burden. Taken together, the beneficial effects ponezumab administration has on reducing the rate of cerebral amyloid angiopathy deposition and restoring cerebral vascular health favours a mechanism that involves rapid removal and/or neutralization of amyloid-β species that may otherwise be detrimental to normal vessel function.


Monday, March 7, 2016

Researchers are working on a method of targeting stellate cells in the liver to prevent them from causing fibrosis when overactivated in response to infections, autoimmunity, and other causes of liver disease:

Liver fibrosis and its more severe form, cirrhosis, are caused by scar tissue that forms in the liver. The progressive stiffening of the liver, a hallmark of the disorders, occurs when a type of liver cell known as the hepatic stellate cell is "activated" and overproduces the stringy network of proteins called the extracellular matrix that binds cells together. Being able to turn cirrhosis around, especially in its late stages, would be a great boon, because liver fibrosis and cirrhosis can be asymptomatic for decades. Many patients only seek treatment when their disease becomes very advanced, at which point liver transplant is their only option.

Scientists have known for more than a decade that a protein called tumor necrosis factor-related apoptosis-inducing ligand - TRAIL, for short - can specifically kill activated hepatic stellate cells that overproduce the extracellular matrix, sparing healthy cells in the liver. However, TRAIL has thus far proven unsuccessful for clinical use because in animal studies, enzymes in the bloodstream quickly degrade it before it has time to work. Seeking a way to extend TRAIL's half-life, or the time that it remains intact in the bloodstream, researchers coated TRAIL with polyethylene glycol (PEG), a synthetic polymer. Initial experiments showed that this "PEGylated" TRAIL had a half-life of between eight and nine hours in monkeys, compared to less than 30 minutes for the unmodified protein. When the scientists intravenously dosed rats that had liver fibrosis with the modified TRAIL for 10 days, the animals' activated hepatic stellate cells died off. By fighting these bad cells, signs of fibrosis began to diminish. Further investigation showed that multiple genes associated with fibrosis had reduced activity, and the proteins produced by these genes faded away.

Findings were similar in rats with advanced cirrhosis. Additionally, when the researchers examined the rodents' liver tissue under a microscope, they found that animals treated with PEGylated TRAIL had fewer deposits of collagen and other extracellular matrix proteins, offering some evidence that the disease had actually been reversed. The research team hopes to develop PEGylated TRAIL for clinical trials in human patients in the next two years. Some preliminary data suggest that the modified protein could also treat other fibrotic diseases as well, such as pancreatic or lung fibrosis, which also have no effective treatment.

Monday, March 7, 2016

Specialized components of the immune system present in the brain, such as microglia, are integral to many of the processes involved in or degraded by neurodegenerative conditions. For example, microglia may be a primary cause of the chronic inflammation found in older brain tissue, and which contributes to the pathology of a range of conditions, including Alzheimer's disease. The study noted here focuses on a different aspect of the role of microglia, a way in which they participate in the normal operation of the brain in conjunction with neurons: the researchers involved show that microglia play a necessary role in altering the connections between neurons. This will no doubt be of interest to the field of aging research, as the plasticity of neural connections diminishes with age, and it will be interesting and potentially useful to know the degree to which this is a problem of neurons versus a problem of the immune system.

A new study shows that cells normally associated with protecting the brain from infection and injury also play an important role in rewiring the connections between nerve cells. While this discovery sheds new light on the mechanics of neuroplasticity, it could also help explain diseases like dementia, which may arise when this process breaks down and connections between brain cells are not formed or removed correctly. "We have long considered the reorganization of the brain's network of connections as solely the domain of neurons. These findings show that a precisely choreographed interaction between multiple cells types is necessary to carry out the formation and destruction of connections that allow proper signaling in the brain."

The study is another example of a dramatic shift in scientists' understanding of the role that the immune system, specifically cells called microglia, plays in maintaining brain function. Microglia have been long understood to be the sentinels of the central nervous system, patrolling the brain and spinal cord and springing into action to stamp out infections or gobble up dead cell tissue. However, scientists are now beginning to appreciate that, in addition to serving as the brain's first line of defense, these cells also have a nurturing side, particularly as it relates to the connections between neurons. The formation and removal of the physical connections between neurons is a critical part of maintaining a healthy brain and the process of creating new pathways and networks among brain cells enables us to absorb, learn, and memorize new information.

While this constant reorganization of neural networks - called neuroplasticity - has been well understood for some time, the basic mechanisms by which connections between brain cells are made and broken has eluded scientists. Performing experiments in mice, the researchers employed a well-established model of measuring neuroplasticity by observing how cells reorganize their connections when visual information received by the brain is reduced from two eyes to one. The researchers found that in the mice's brains microglia responded rapidly to changes in neuronal activity as the brain adapted to processing information from only one eye. They observed that the microglia targeted the synaptic cleft - the business end of the connection that transmits signals between neurons. The microglia "pulled up" the appropriate connections, physically disconnecting one neuron from another, while leaving other important connections intact. "These findings demonstrate that microglia are a dynamic and integral component of the complex machinery that allows neurons to reorganize their connections in the healthy mature brain. While more work needs to be done to fully understand this process, this study may help us understand how genetics or disruption of the immune system contributes to neurological disorders."

Tuesday, March 8, 2016

Neurogenesis, the creation of new neurons in the brain, slows with age. This is most likely an important contributing factor in the age-related loss of neural plasticity, the ability of the central nervous system to change, adapt, and to a limited degree repair itself. Here researchers show that they can increase the pace of neurogenesis in old mice by raising the level of fibroblast growth factor (FGF) signaling:

The mechanisms regulating hippocampal neurogenesis remain poorly understood. Particularly unclear is the extent to which age-related declines in hippocampal neurogenesis are due to an innate decrease in precursor cell performance or to changes in the environment of these cells. Several extracellular signaling factors that regulate hippocampal neurogenesis have been identified. However, the role of one important family, FGFs, remains uncertain. Although a body of literature suggests that FGFs can promote the proliferation of cultured adult hippocampal precursor cells, their requirement for adult hippocampal neurogenesis in vivo and the cell types within the neurogenic lineage that might depend on FGFs remain unclear.

Here, specifically targeting adult neural precursor cells, we conditionally express an activated form of an FGF receptor or delete the FGF receptors that are expressed in these cells. We find that FGF receptors are required for neural stem-cell maintenance and that an activated receptor expressed in all precursors can increase the number of neurons produced. Moreover, in older mice, an activated FGF receptor can rescue the age-related decline in neurogenesis to a level found in young adults. These results suggest that the decrease in neurogenesis with age is not simply due to fewer stem cells, but also to declining signals in their niche. Thus, enhancing FGF signaling in precursors can be used to reverse age-related declines in hippocampal neurogenesis.

Tuesday, March 8, 2016

Researchers have developed a means of reversing periodontitis, inflammation of the gums, in an animal model. This is of interest in the context of aging as periodontitis is widespread in the population, and inflammation in the gums doesn't remain isolated: it spreads to contribute to the progression of much more dangerous conditions such as atherosclerosis. A clinical therapy that eliminates periodontitis entirely would be a very positive advance.

Periodontitis, a gum disease present in nearly half of all adults in the United States, involves inflammation, bleeding and bone loss. In its severe form, it is associated with systemic inflammatory conditions such as atherosclerosis and rheumatoid arthritis. Few treatment options exist beyond dental scaling and root planing, done in an attempt to reduce plaque and inflammation. Now, however, researchers have employed an inhibitor of a protein called C3, a component of the body's complement system, which is involved in immunity and inflammatory responses. Delivering this inhibitor, Cp40, to the periodontal tissue just once a week reversed naturally occurring chronic periodontitis inflammation in a preclinical model. "Even after one treatment, you could see a big difference in inflammation. After six weeks, we saw reversals in inflammation, both clinically and by looking at cellular and molecular measures of osteoclast formation and inflammatory cytokines. The results were so clean, so impressive. The next step is to pursue Phase 1 trials in humans."

This study builds on earlier work which identified C3 as a promising target for treating periodontal disease. C3, or the third component of the complement system, is a key part of signaling cascades that trigger inflammation and activate the innate immune system. Their previous research, which used an inducible model of periodontal disease, found that Cp40 could reduce signs of the disease. To get closer to a natural scenario, however, the current work was conducted on animals that naturally had developed chronic periodontitis. Initially the research team tried administering Cp40 three times a week, but after seeing significant reductions in inflammation, they tried giving it only once a week to a different group and saw the same good results. This study delivered the drug via a local injection to avoid any potential systemic effects from inhibiting a component of the immune system. There were no adverse effects reported. "Some people have been concerned that blocking complement would lead to more infections but that is not the case here. We're stopping the inflammation in the gums and thereby killing the bacteria that need inflammatory tissue breakdown proteins to survive."

Wednesday, March 9, 2016

In recent years, tissue engineers have made great progress in 3-D printing very small sections of a wide variety of functional tissue types. Printing tissue masses that include the intricate blood vessel networks needed to support larger volumes remains a challenge, however. Progress on this front has been slow, as illustrated by the fact that this reported research is a step forward in terms of size and complexity:

Researchers have invented a method for 3D bioprinting thick vascularized tissue constructs composed of human stem cells, extracellular matrix, and circulatory channels lined with endothelial blood vessel cells. The resulting network of vasculature contained within these deep tissues enables fluids, nutrients and cell growth factors to be controllably perfused uniformly throughout the tissue. To date, scaling up human tissues built of a variety of cell types has been limited by a lack of robust methods for embedding life-sustaining vascular networks. Building on earlier work, researchers have now increased the tissue thickness threshold by nearly tenfold, setting the stage for future advances in tissue engineering and repair.

In the study, the team showed that their 3D bioprinted tissues could sustain and function as living tissue architectures for upwards of six weeks. They demonstrated the 3D printing of one centimeter-thick tissue containing human bone marrow stem cells surrounded by connective tissue. By pumping bone growth factors through the supporting vasculature lined with the same endothelial cells found in our blood vessels, the team induced cell development toward bone cells over the course of one month. The novel 3D bioprinting method uses a customizable, printed silicone mold to house and plumb the printed tissue structure. Inside this mold, a grid of vascular channels is printed first, over which ink containing living stem cells is then printed. The inks are self-supporting and strong enough to hold shape as the structure's size increases with each layer of deposition. At intersections meeting within the foundational vascular grid, vertical vascular pillars are printed, which interconnect a pervasive network of microvessels throughout all dimensions of the stem cell-laden tissue. After printing, a liquid composed of fibroblasts and extracellular matrix fills in the open regions around the 3D printed tissue, cross linking the entire structure. The resulting soft tissue structure is replete with blood vessels, and via a single inlet and outlet on opposite ends of the chip, can be immediately perfused with nutrients to ensure survival of the cells.

Wednesday, March 9, 2016

Researchers have demonstrated that introducing a gel scaffold material of the type used in tissue engineering into living tissues can improve the ability to regenerate at some forms of injury and compensate for some forms of age-related degeneration. Here they test this approach on peripheral artery disease, in which narrowing of major blood vessels due to atherosclerosis means insufficient oxygen and nutrients are delivered to tissues. This causes a wide range of dysfunction, leading eventually to critical limb ischemia and amputation or worse. Spurring tissue regrowth and remodeling via the introduction of scaffolding material doesn't address the underlying causes of the condition, the harmful processes that generate fatty deposits inside blood vessel walls that narrow them, but it can partially compensate by spurring adaptation and increased blood vessel size:

Bioengineers and physicians have developed a potential new therapy for critical limb ischemia, a condition that causes extremely poor circulation in the limbs. The therapy consists of injecting in the affected area a gel derived from the natural scaffolding, or extracellular matrix, in skeletal muscle tissue. The team tested the procedure in a rat model of the disease and found that it promotes muscle remodeling and improves blood flow.

Researchers had already shown that injection of a gel derived from cardiac muscle tissue extracted from pigs could help repair the heart after a heart attack. The tissue is stripped of cells, leaving behind a scaffold of the extracellular matrix from cardiac muscle, which acts a regenerative environment where cells can grow again. Using this same concept, the team now are turning their attention to peripheral artery disease and critical limb ischemia. They developed a material that was derived from the skeletal muscle of pigs to treat damaged skeletal muscle in these patients. Researchers injected the gel into the affected area in a rat model of the disease seven days post-surgery and monitored blood flow in the rats' limbs up to 35 days after injection. Researchers found that the hydrogel increased the diameter of the rats' larger blood vessels, called arterioles. The increased diameter led to improved blood flow in the limbs. By day 35, the size and structure of muscle fibers in the rats treated with the hydrogel was comparable to that in healthy rats.

The gel, which forms a fibrous scaffold upon injection, also attracted muscle stem cells to the affected area. Gene expression analysis showed that inflammatory response and cell death decreased while blood vessel and muscle development pathways increased in rats injected with the gel. Next steps include looking at other disease models in animals and refining preclinical safety protocols and quality control for manufacturing.

Thursday, March 10, 2016

Researchers are making progress in the tissue engineering of components of the eye, an area of development that is less hindered by the challenge of producing blood vessel networks than is the case for most other tissue types:

Discs made of multiple types of eye tissue have been grown from human stem cells - and that tissue has been used to restore sight in rabbits. The work suggests that induced pluripotent stem (iPS) cells - stem cells generated from adult cells - could one day be harnessed to provide replacement corneal or lens tissue for human eyes. The discs also could be used to study how eye tissue and congenital eye diseases develop. A second, unrelated paper describes a surgical procedure that activates the body's own stem cells to regenerate a clear, functioning lens in the eyes of babies born with cataracts.

In the first study, a team cultivated human iPS cells to produce discs that contained several types of eye tissue. The cells grew in distinct regions so that researchers could extract and purify specific types, including those found in the cornea, retina and lens. The team was able to remove cells from one region of a disc to grow sheets of corneal epithelium that the researchers then successfully transplanted into rabbits with defective corneas. Previous studies have generated retinal or corneal tissue using iPS cells, but none has produced such different types of eye cell in a single experiment. Cells made from the recipient's own cells using the disc method could one day supply tissue to repair damaged eyes without the threat of rejection by the immune system. But much remains to be done before any such therapy could be tested in humans.

By contrast, the cataract paper could have an almost immediate impact on treatment. The technique described does not involve culturing cells outside the body or transplanting material that would require regulatory approval. "This is just a change in a surgical procedure. They are not putting in an artificial lens: they are just letting the lens regrow." The research was inspired by a typical side effect of implanting artificial lenses to treat cataracts: the new lenses often become cloudy as the recipient's own cells grow over them. A team decided to find out whether this regrowth signalled that the body is capable of regenerating an entire lens. The scientists began a series of animal studies to assess whether lens epithelial stem/progenitor cells (LECs) that exist naturally in a fully formed mammalian eye can produce a new lens. Encouraged by the results, the team developed a surgical technique and tested it in rabbits, macaque monkeys and, finally, 12 human infants.

In the new method, surgeons slice a 1.5-millimetre opening in the side of the lens capsule to remove the diseased lens, prompting the eye's LECs to grow a new one. In initial tests, this approach produced a much lower rate of complications - 17% - than the 92% seen after typical cataract surgery. And the lenses generated did not grow opaque as artificial lenses tend to do. The first infant treated using the method underwent surgery two years ago and still has good vision.

Thursday, March 10, 2016

In this open access review paper, researchers discuss the associations and possible contribution of advanced glycation end-product (AGE) accumulation to the age-related decline in motor function, though given that they focus on short-lived forms of AGE and omit mention of glucosepane, I suspect that the relevance of their conclusions is limited. The differences between types of AGE are important, and they can't all be lumped together based on the study of just one type. In particular the contribution to aging from AGEs that cross-link versus AGEs that promote inflammation is quite distinct.

Where do AGEs come from? They are a class of waste produced by the normal operation of cellular metabolism, and which can also arrive in the diet. They accumulate in tissues with advancing age. There are various types of AGE, but the important ones are the long-lasting varieties based on glucosepane that the body cannot effectively break down. They form cross-links in the extracellular matrix, degrading tissue function by altering its structural properties, as is the case in age-related loss of elasticity in skin and blood vessels. Other classes of AGEs - such as N(6)-carboxymethyllysine (CML) - are probably involved in different ways in the progression of age-related disease and especially in metabolic dysfunctions such as type 2 diabetes, as they can increase chronic inflammation through their interactions with cells. These types are better studied than glucosepane, but they can be broken down and cleared by our biochemistry, their levels are quite dynamic over short time frames, and it isn't completely clear as to the degree to which their accumulation is secondary to other forms of age-related dysfunction, or even to diet and lifestyle choices.To tackle the inexorable increase in glucosepane cross-links, however, it is definitely the case that a viable strategy is the development of therapies to clear these damaging and unwanted molecules.

Diminishing motor function is commonly observed in the elderly population and is associated with a wide range of adverse health consequences. Advanced Glycation End products (AGE's) may contribute to age-related decline in the function of cells and tissues in normal ageing. Although the negative effect of AGE's on the biomechanical properties of musculoskeletal tissues and the central nervous system have been previously described, the evidence regarding the effect on motor function is fragmented, and a systematic review on this topic is lacking. Therefore, a systematic review was conducted from a total of eight studies describing AGE's related to physical functioning, physical performance, and musculoskeletal outcome which reveals a positive association between high AGE's levels and declined walking abilities, inferior activities of daily living (ADL), decreased muscle properties (strength, power and mass) and increased physical frailty.

The available literature on musculoskeletal outcomes support the hypothesis that high AGEs levels are associated with a decline in muscle function. However, the correlations and calculated effect sizes indicate only a moderate relationship. It is known that AGEs can affect muscle function through a variety of pathways. In fact, AGEs can alter the biomechanical properties of muscle tissue, increasing stiffness and reducing elasticity through cross-linking and upregulated inflammation by RAGE binding and endothelial dysfunction in the intra-muscular microcirculation. This is also consistent with studies on sarcopenia in which decreased muscle mass and strength is explained by an overall increase in inflammatory burden. Examining the studies in this review that report decline in walking abilities, it is suggested by the authors that this decline is also attributed to the effects of AGEs on muscle tissue, thereby impairing muscle function. It has been considered that impaired muscle function - through AGEs-induced muscle damage - can contribute to decline in walking abilities and ADL and can also contribute to physical frailty.

It is important to realise that, in this review, decline in motor function was primarily associated with elevated CML levels. Association with circulating CML was determined in four studies, and a relation with tissue CML was found in one study. One study reported an association with Pentosidine and two other studies with non-specified skin tissue fluorescent AGEs. It is suggested that fluorescent and non-fluorescent AGE's such as CML behave similarly and fluorescence may be employed as a marker for the total skin tissue AGEs pool. Although CML is a dominant AGE in blood circulation and correlates with other AGEs, it is possible that the association between AGE's and motor function outcome could be different if crosslinking AGEs such as Pentosidine were assessed.

The vast majority of participants included in this review were elderly people older than 64 years. Interestingly, in two studies, the participants were middle-aged between 37 and 56 years. This indicates that the negative effect of AGEs on motor function already begins during midlife and, as AGE levels increase with ageing, could be an important factor in age related decline in motor function. A high AGE level, as a biomarker, therefore, could predict a decline in motor function later in life. This could also imply that preventive interventions should start as soon as possible as part of healthy ageing. In accordance with the results of this review, it would be interesting to investigate whether motor function can be improved by reducing AGE levels. Intensive glycaemic control may be a method to decrease AGEs formation. CML levels correlate to dietary consumption, therefore, dietary intake is a possible factor that can be influenced.

Friday, March 11, 2016

In this short editorial, researchers summarize their exploration of a possible causative link between age-related mitochondrial dysfunction and the observed changes in cancer risk over the course of later life. This is interesting, given the assembly of evidence outlined below, but still fairly speculative at this stage:

Aging is associated with increased manifestation of many diseases. In particular, the chances of cancer increase exponentially starting from middle age. At the same time, there is a convincing evidence that in the case of certain tissues/organs the increase of cancer incidence is followed by a plateau or even a decrease of reported cases. As a rule, the decrease starts at the age above 80 years. What could be the reason for such a decline? Possibly, only a small proportion of human population is susceptible to the certain types of cancer and most of such people die at the age of 80 or younger. If so, the age group above 80 will be depleted for people prone to the cancers. Alternatively, several biological explanations for such a decrease were suggested: for instance, age-dependent decrease of angiogenesis can suppress tumor growth.

We propose that mitochondrial dysfunction is also responsible for the age-dependent changes of cancer incidences. First, mitochondrial oxidative capacity and ATP production decrease with age. The reasons for the mitochondrial dysfunction are the mutations of mitochondrial DNA (mtDNA) and a continuous expansion of mtDNAs with large deletions. Second, in aged mammals the clonal expansion is likely to be a primary source of abnormal mtDNAs rather than de novo mutations. How could mitochondria dysfunction interfere with cancer incidence and progression? On one hand, mild mitochondrial dysfunctions can be carcinogenic due to increased mitochondrial reactive oxygen species-mediated inflammation or due to inhibition of apoptosis. On the other hand, the severe ones can inhibit the proliferation of cancerous cells. It has been shown that the cells lacking mtDNA have lower tumorogenic potential compared to the ones with the mild mutations or even with intact mtDNA. This is surprising, because for their energy needs cancer cells tend to rely on glycolysis instead of oxidative phosphorylation. Our study with model eukaryotic cells - baker's yeast - provides an explanation: we found that the loss of mtDNA activates a signaling cascade that tightens the S-phase arrest of the cells caused by inactivation of telomerase. Importantly, this effect was not due to alterations in ATP supply. We speculate that such mitochondria-dependent signaling pathways play a significant role in the regulation of cell cycle progression in higher eukaryotes.

If so, it provides an explanation for the age-dependency of cancer incidences. During the development and aging of multicellular organisms various mutations appear in mtDNAs. Some of them have severe tumorogenic capacity and eventually lead to cancerous transformation of the host cells. We speculate that, with age, the severe mutations (i.e. common deletions of mtDNA) expand and prevail over the mild ones, strengthening the S-phase arrest and thus decreasing cancer incidences. Interestingly, this hypothesis explains why, during evolution, mtDNA of some higher eukaryotes (including humans) did not get rid of the repeat regions which are prone to recombination leading to the common deletions. In other words, the intrinsic instability of mtDNA may serve as a cancer-prevention mechanism.

Friday, March 11, 2016

Here I'll point out recently published results for a cystathionine beta-synthase inhibitor drug candidate. The researchers involved have demonstrated that in rats it greatly reduces cell death in brain tissue following stroke:

Most strokes occur when a disruption of blood flow prevents oxygen and glucose from reaching brain tissue, ultimately killing neurons and other cells. The team found that its molecule, known as 6S, reduced the death of brain tissue by as much as 66 percent when administered to the cerebrum of a rat that had recently suffered a stroke. It also appeared to reduce the inflammation that typically accompanies stroke. "The fact that this inhibitor remained effective when given as post-stroke treatment is encouraging, as this is the norm in the treatment of acute stroke."

The inhibitor works by binding to cystathionine beta-synthase, or CBS - an enzyme that normally helps regulate cellular function but can also trigger production of toxic levels of hydrogen sulfide in the brain. Though hydrogen sulfide is an important signaling molecule at normal concentrations, stroke patients exhibit elevated concentrations believed to initiate the brain damage they often suffer. Researchers modeled their inhibitor on a naturally occurring molecule produced by the CBS enzyme, tailoring the molecule's structure to improve its performance. By swapping out functional groups of atoms known as amines with hydrazines, the team ultimately increased the inhibitor's binding time from less than a second to hours. "We wanted a compound that would bind well, specifically to this enzyme. But we also wanted one that could be synthesized easily. Those are two very different considerations." The team achieved the latter goal, in part, by plucking out the molecule's carbon-sulfur bond and replacing it with a double bond. Slicing that double bond gave the researchers two identical halves of the molecule.

Because the 6S inhibitor has demonstrated its effects in cell cultures and the brain tissue of rats, it represents just an initial step toward developing a stroke-treating drug for humans. However, the proof-of-principle experiments effectively illustrate the concept's promise. The researchers expressed optimism that the synthesis method detailed in the study could streamline the more general production of enzyme-targeting inhibitors. "We started out with a very fundamental-science perspective on understanding the chemistry of this whole class of vitamin B6-dependent enzymes. We're in a good place now, because that science has allowed us to make these inhibitors and many others. We're now working on several enzymes that may represent important targets for translation of the basic inhibitor chemistry into truly therapeutic goals."


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