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- Vast Funding is Available for the Later Stages of Development of any Credible Therapy that Addresses a Cause of Aging
- A Mouse Model of Accelerated Mitochondrial Deletion Mutations that Doesn't Exhibit Signs of Accelerated Aging
- Three Recent Papers on the Use of Senolytic Therapies to Address Age-Related Disease
- Mitochondria Touch on All of the Present Methods of Slowing Aging
- A Peptide Based on Amelogenin can Induce Regrowth of Lost Tooth Enamel
- Calorie Restriction Extends Life Span Significantly in Short-Lived Primates
- The Methuselah Foundation Return on Mission Report
- Mitochondrial Mutations and Stem Cell Aging
- MicroRNA-150 is Important in the Contribution of Macrophages to Age-Related Disease
- Correlating Hair Graying and Cardiovascular Disease
- All Current Assessment Methods for Frailty Correlate with Future Mortality
- The SENS Research Foundation on the Ongoing Development of Senolytic Therapies to Treat Neurodegenerative Conditions
- Journalistic Views of Aging and Longevity Have Yet to Reach Maturity
- A Failure to Treat Alzheimer's by Interfering in RAGE-Induced Inflammation
- Precision Vaccination Against LDL Cholesterol Reduces Atherosclerotic Plaque in Mice
Vast Funding is Available for the Later Stages of Development of any Credible Therapy that Addresses a Cause of Aging
Today I'll point out a couple of recent news items that illustrate there is no funding drought for any group that manages to bring a credible approach to addressing one of the causes of aging to the point of human clinical trials. This is the case even when it is generally understood by all involved that the therapies in question are first generation attempts at implementation, subject to all the normal challenges that brings, and in principle not as good as competing forms of technology that are still at an earlier stage in the process of development. The drought lies in the number of groups who can make it to this stage, because there are never enough entrepreneurs, and the issues with fundraising are all further back in the pipeline: it is hard to raise funds for research into most means of rejuvenation, and it is hard to raise funds at the early startup stage, though that second point is rapidly becoming easier with the growth in the number of incubators focused on biotechnology and aging. Look at YC Bio, for example, or Age 1.
(That it takes a ridiculous amount of funding to pass regulatory hurdles on the way to the clinic is an entire and separate topic for discussion. The task of proving that a treatment works and quantifying the risk of using it to a satisfactory level simply doesn't cost more than a small fraction of the amount that the FDA forces it to cost. Everything above that much lower amount is unnecessary waste, the standard corrosion of efficiency produced by the incentives of a large bureaucratic organization, one whose managers are more interested in practice in perpetuating their positions, expanding their powers, and minimizing bad press than in advancing the state of medicine).
The two groups I'll point out today are Unity Biotechnology, working on pharmaceutical means of senescent cell clearance, and Eidos Therapeutics, who are bringing a therapy for transthyretin amyloidosis to the clinic. In the case of Unity Biotechnology, the better technology and earlier stage competitor is represented by Oisin Biotechnologies, who field a programmable cell killing gene therapy that is in principle a considerable improvement over pharmaceuticals. For Eidos Therapeutics, who are putting forward a therapy that would have to be taken continuously to suppress the creation of harmful amyloid, the earlier, better competing approach is typified by the work of Covalent Bioscience, working on a class of therapy that would clear out the amyloid rather than suppressing its creation. Thus treatment would have to be undertaken less often, and would be more helpful for people further along in the process of accumulating amyloid. All this said, there is of course the point that the better therapy at this moment is the one you can take advantage of today, not the one you wish you could take advantage of today.
Unity Biotechnology has pulled in quite the sizable amount of funding in the past year; they start to look more like a finance operation with a sideline in rejuvenation research than a dedicated biotechnology company. That they are now filing for an IPO before announcing any human clinical trial results is, it has to be said, unusually rapid. But if they can raise the funds and put them to good use, good for them - they have declared ambitions to move beyond senolytics to address other mechanisms of aging, which is certainly a good reason to have a sizable pool of funding. Any successful biotechnology company in one of the fields relevant to the SENS view of aging, damage, and rejuvenation could do a great deal to advance all of the others as well, as the cost of early stage progress is small in comparison to the amounts being raised for later clinical development. We'll see how it turns out once the dust has settled.
Unity Biotechnology files for 85M IPO to take anti-aging drugs into phase 1
Unity Biotechnology has filed for an 85 million IPO. Hitting the target would bring the preclinical anti-aging startup's fundraising haul up toward 300 million and set it up to move two assets into the clinic. Unity last tapped private investors last month with a 55 million series C round. But it is already after its next financial hit. This time, Unity wants public investors to buy into its experimental ideas.
The 85 million IPO would secure Unity's financial future into 2020. Over that period, Unity plans to move two drugs into human testing. Lead program UBX0101, an inhibitor of the MDM2-p53 protein interaction, is due to begin testing in osteoarthritic patients in the next couple of months. UBX1967, an inhibitor of certain Bcl-2 apoptosis regulatory proteins, will arrive in the clinic next year. Unity's initial target indications for the drugs - osteoarthritis and an ophthalmologic disease - reflect its strategy for making the daunting task of tackling aging more manageable. The indications enable Unity to start out administering its drugs locally, before expanding into diseases that require systemic treatment if the early trials validate its approach. Systemic administration would open up indications related to the aging of the heart, kidney, and liver.
Whatever the route of administration, Unity will seek to slow or reverse aging by targeting cellular senescence. This process sees cells halt division, leading to the accumulation of senescent cells and secretion of inflammatory factors, proteases, and other proteins. Unity thinks the proteins disturb tissues and trigger senescence in other cells, leading to the emergence of aged or diseased tissues. A lot of questions remain unanswered, though. All biotechs face uncertainties going into the clinic for the first time, but few pocket more than 200 million and then swing for 85 million IPOs before generating human data. With the delivery of that data still on the horizon, the IPO is a test of investors' willingness to put their faith in a management team and founding investor that have delivered in the past - and the appeal of a big idea.
Eidos Therapeutics completes 64M Series B financing
Eidos Therapeutics, Inc., a clinical stage biopharmaceutical company developing a novel oral therapy to treat transthyretin (TTR) amyloidosis (ATTR), today announced a 64.0 million Series B financing. Proceeds from the financing will be used to advance Eidos' small molecule product candidate, AG10, into Phase 2 clinical trials and to continue preparations for Phase 3 clinical trials. AG10 targets ATTR at its source by potently binding and stabilizing TTR tetramers, the destabilization of which underlies the development of ATTR. The Series B financing brings the total capital raised by Eidos to approximately 91.0 million.
"Our clinical data demonstrate that AG10 has a safe, well-tolerated profile and is able to stabilize 100% of plasma TTR at peak concentrations and provide average levels of stabilization greater than 95% at steady-state. Given that increasing levels of stabilization have yielded progressively better clinical results in past trials, our near-complete levels of stabilization suggest that AG10 could be a best-in-class solution. We are targeting ATTR at its source by stabilizing TTR, an approach that is validated by genetics and clinical data."
A Mouse Model of Accelerated Mitochondrial Deletion Mutations that Doesn't Exhibit Signs of Accelerated Aging
Few roads in the life sciences are straight and broad, and the way forward to prove and quantify the contribution of mitochondrial DNA damage to aging is turning out to be particularly winding. The open access paper noted below is the latest in a series of attempts to engineer mice that generate specific forms of mitochondrial mutation at an accelerated rate. The hope here is that this sort of study will, even if carried out for other reasons, help to clarify contradictory results obtained from prior lineages of mitochondrial mutator mice, but I'm not sure that any such goal has been achieved in this case. When compared with the theory of what is expected to happen as the result of a greater number of mitochondrial mutations, the results here are more of an additional puzzle than an answer to outstanding questions.
There is a herd of mitochondria in every cell, replicating like bacteria, and each carrying their own small circular genome - mitochondrial DNA. One important view of mitochondrial DNA mutation in aging is summarized in the SENS research proposals. In short, deletion mutations eliminate important mitochondrial genes, and an affected mitochondrion malfunctions in a way that causes it to either replicate more efficiently or resist cellular quality control mechanisms more effectively than its undamaged peers. The cell is overtaken by the descendants of this broken mitochondria, and as a consequence enters a dysfunctional state that exports harmful reactive molecules into the environment, contributing to the aging process.
In this view, point mutations are not thought to be anywhere near as important - but they are much more common. Indeed, some thought has to go into explaining how deletion mutations can be significant in aging given their rarity. In the course of investigating these questions, mice have been engineered to have abnormally high levels of mitochondrial mutations. There are mice with enormous numbers of point mutations in mitochondria that exhibit no signs of accelerated aging, and there are the later mitochondrial mutator mice with both greatly increased point mutations and deletions that do exhibit accelerated aging. A reasonable conclusion on this basis is that the deletions are the important factor.
Now, however, we have this new lineage of mice exhibiting extra deletions and no point mutations, but that also show no signs of accelerated aging. At this point, I think we're forced to concede that the implementation details matter greatly, and every one of these studies and models is going to have to be picked over with a fine comb in order to figure out what to try next. It is perhaps time to give up on building a model of accelerated aging, and put time and effort into engineering a mouse with fewer mitochondrial mutations to see if more can be learned by trying to slow aging.
On this front, it isn't clear that the SENS program of allotopic expression has progressed far enough to make an attempt to gain data in mice. There are thirteen mitochondrial genes to protect, and only protecting the three that can so far be protected might not be enough of a difference to obtain reliable data for outcomes on aging. Mitochondrial damage is only one of seven classes of damage that cause aging, and what is the effect size of a quarter of a seventh? How comfortably would anyone feel trying to find an adjustment in aging rate of a few percentage points in mice? Smaller effects are very hard to reliably identify in animal studies, in which 10% effect sizes typically come and go at random and should really be treated as noise. Up to a certain point, it is more cost effective to put resources towards protecting more mitochondrial genes.
Mice lacking the mitochondrial exonuclease MGME1 accumulate mtDNA deletions without developing progeria
Mutations in nuclear genes can cause mitochondrial DNA (mtDNA) instability resulting in mtDNA depletion or accumulation of deletions and/or point mutations, ultimately leading to impaired oxidative phosphorylation (OXPHOS). The vast majority of mutations causing human mtDNA instability map to genes encoding proteins involved in mtDNA replication. Extensive in vitro work has led to significant progress in our understanding of the biochemical processes underlying mtDNA maintenance disorders, but animal models are nevertheless essential to understand the wide range of phenotypes and secondary metabolic consequences of mtDNA instability in different tissues.
To gain further insight into diseases of defective mtDNA replication, we created a knockout mouse model for the recently described disease gene encoding MGME1 (also known as Ddk1). Loss-of-function mutations in MGME1 were reported to cause a severe multisystem mitochondrial disorder in humans with depletion and rearrangements of mtDNA. Loss of MGME1 expression, either in siRNA treated cells or in patient fibroblasts, leads to an accumulation of 7S DNA, which is the single-stranded DNA species formed by premature replication termination at the end of the control region of mtDNA, thus suggesting a role for MGME1 in repressing formation or increasing turnover of these molecules.
We have studied the in vivo mtDNA replication phenotypes associated with MGME1 deficiency in various mouse tissues of knockout mice. Although MGME1 is not essential for embryonic development, its loss leads to accumulation of multiple deletions and depletion of mtDNA in a range of different mouse tissues.
A hallmark of MGME1 deficiency in patient fibroblasts and mice is an 11 kb linear mtDNA fragment spanning the entire major arc of the mtDNA, which has been previously described in mtDNA mutator mice and flies. Numerous studies suggest that mtDNA mutations and deletions contribute to the ageing phenotypes in experimental animals and in humans. Indeed, mtDNA mutator mice develop progressive premature ageing syndrome phenotypes. In addition to the presence of the above mentioned 11 kb subgenomic mtDNA species, the mtDNA mutator mice also accumulate an increased number of point mutations, that most likely drive the ageing phenotype. Consistent with this hypothesis, Mgme1-/- mice do not accumulate point mutations and do not display a progeroid phenotype. In line with this finding, mtDNA subgenomic fragments have not been detected in tissues from aging mammals further indicating that this lesion on its own does not induce ageing.
Three Recent Papers on the Use of Senolytic Therapies to Address Age-Related Disease
Today, a few papers on cellular senescence and the application of therapies to remove senescent cells. Senescent cells are one of the root causes of aging. Over the past five years, once the research community finally started to make progress on ways to selectively destroy senescent cells, the presence of these cells has been directly implicated in a wide range of age related diseases. They cause fibrosis. They produce calcification in blood vessels. They help to upset the balance of bone maintenance to generate osteoporosis. They are at the root of localized inflammatory conditions such as osteoarthritis. They harm lung function. And so on and so forth through a long list of issues. All of this progress in knowledge and methods of therapy could have happened ten or twenty years earlier, in a different world, in which the leadership of the aging research community didn't engage in decades of hostility towards anyone who wanted to treat aging as a medical condition. The evidence was there.
Countless cells become senescent in the body day in and day out. It is the end state of somatic cells that reach the Hayflick limit on replication, quickly followed by programmed cell death or destruction by the immune system. Cells also become senescent in response to injury, a toxic cellular environment, or DNA damage likely to lead to cancer. Again, a quick destruction is their fate. A very tiny fraction of senescent cells evade this fate to linger indefinitely, however. These lingering cells secrete a potent mix of molecules that triggers chronic inflammation, damages the surrounding tissue structures, and changes the behavior of nearby cells for the worse. The harm grows as the number of senescent cells grows.
Fortunately, work on senolytic therapies capable of selectively destroying senescent cells has moved out of the laboratory and into a number of startup companies. Numerous different pharmaceuticals trigger senescent cells to self-destruct by interfering in mechanisms that are only of great importance in the senescent state, and Unity Biotechnology is moving ahead with several of those. Oisin Biotechnologies is pioneering a programmable gene therapy that can destroy cells based on their internal biochemistry. SIWA Therapeutics is working on an immunotherapy approach to the problem of senescent cells. There will be others in the years ahead - there is plenty of room in a market in which every adult over the age of 40 is a potential customer. Effective senolytic therapies would likely be undertaken once every few years at most, to keep the number of senescent cells too low to cause serious issues, thus taming this contribution to degenerative aging. That advance in clinical medicine is just a few years away now.
Strategies targeting cellular senescence
Cellular senescence is a physiological phenomenon that has both beneficial and detrimental consequences. Senescence limits tumorigenesis and tissue damage throughout the lifetime. However, at the late stages of life, senescent cells increasingly accumulate in tissues and might also contribute to the development of various age-related pathologies. Recent studies have revealed the molecular pathways that preserve the viability of senescent cells and the ones regulating their immune surveillance. These studies provide essential initial insights for the development of novel therapeutic strategies for targeting senescent cells. At the same time they stress the need to understand the limitations of the existing strategies, their efficacy and safety, and the possible deleterious consequences of senescent cell elimination. Here we discuss the existing strategies for targeting senescent cells and upcoming challenges in translating these strategies into safe and efficient therapies. Successful translation of these strategies could have implications for treating a variety of diseases at old age and could potentially reshape our view of health management during aging.
Senescent cells: a therapeutic target for cardiovascular disease
Cellular senescence, a major tumor-suppressive cell fate, has emerged from humble beginnings as an in vitro phenomenon into recognition as a fundamental mechanism of aging. In the process, senescent cells have attracted attention as a therapeutic target for age-related diseases, including cardiovascular disease (CVD), the leading cause of morbidity and mortality in the elderly. Given the aging global population and the inadequacy of current medical management, attenuating the health care burden of CVD would be transformative to clinical practice. Here, we review the evidence that cellular senescence drives CVD in a bimodal fashion by both priming the aged cardiovascular system for disease and driving established disease forward. Hence, the growing field of senotherapy (neutralizing senescent cells for therapeutic benefit) is poised to contribute to both prevention and treatment of CVD.
Senescent cells and osteoarthritis: a painful connection
Senescent cells (SnCs) are associated with age-related pathologies. Osteoarthritis is a chronic disease characterized by pain, loss of cartilage, and joint inflammation, and its incidence increases with age. For years, the presence of SnCs in cartilage isolated from patients undergoing total knee artificial implants has been noted, but these cells' relevance to disease was unclear. In this review, we summarize current knowledge of SnCs in the multiple tissues that constitute the articular joint. New evidence for the causative role of SnCs in the development of posttraumatic and age-related arthritis is reviewed along with the therapeutic benefit of SnC clearance. As part of their senescence-associated secretory phenotype, SnCs secrete cytokines that impact the immune system and its response to joint tissue trauma. We present concepts of the immune response to tissue trauma as well as the interactions with SnCs and the local tissue environment. Finally, we discuss therapeutic implications of targeting SnCs in treating osteoarthritis.
Mitochondria Touch on All of the Present Methods of Slowing Aging
Read on the topic aging research and one will soon enough arrive at a consideration of mitochondria, their function and dysfunction. They are everywhere in the literature. These organelles are responsible for processing nutrients into chemical energy stores, and also play a role in a variety of important mechanisms in cell growth and cell death. They mediate many beneficial cellular responses to stress via generation of reactive oxygen species in greater or less amounts. Further, they are a primary target for the cellular maintenance processes of autophagy, as when mitochondria malfunction they can cause serious harm to a cell and its surroundings. That portfolio of functions and concerns is connected to all of the present methods of metabolic alteration shown to modestly slow aging in laboratory animals.
Most of these methods utilize the induction of stress response mechanisms, particular those involved in calorie restriction, the reduction of nutrient intake, which overlap with responses to exercise, to heat, to toxins, and to lack of oxygen. Altered mitochondrial function appears frequently as a central mediating mechanism. Calorie restriction itself appears to depend on increased levels of autophagy - and as soon as autophagy is involved one has to consider the reduction in mitochondrial breakage and dysfunction that results from more active mitochondrial quality control. It is even possible to tie mitochondria to the more recent efforts that depart from metabolic manipulation in order to produce rejuvenation through targeted destruction of senescent cells. Since senescent cells are primed to self-destruct, and since that process of self-destruction is mediated by mitochondria, the various pharmaceutical senolytic drug candidates target mitochondrial molecular machinery in order to force the issue.
How much of degenerative aging is mediated by mitochondria? Mitochondrial composition correlates well with species life span, suggesting importance, but that doesn't necessarily bear any relationship to the degree of harm done in any given species by the age-related failure of mitochondrial function, by the damage that accumulates in mitochondrial DNA. The only sure way to find out is to repair the damage, restore mitochondrial function, and watch what happens in a mouse study. Unfortunately, the research community is not yet capable of achieving that goal, though inroads have been made on the SENS approach of allotopic expression - copying mitochondrial DNA into the cell nucleus to prevent damage to mitochondrial genes from depriving mitochondria of necessary proteins.
Targeting Mitochondria to Counteract Age-Related Cellular Dysfunction
In a rapidly aging society, new treatment options for age-related disorders and diseases will be increasingly important. Consequently, in recent decades, research has focused heavily on the processes of aging to reveal potential targets for prolonging health and lifespan. Consistent with this, interventions such as caloric restriction (CR) or exercise, as well as pharmacological strategies have been well established to improve health and to slow down aging.
As adenosine triphosphate (ATP)-producing power plants of the cell, mitochondria are in a unique position to influence an organism's aging process. Recent reports suggest that mitochondrial function is linked to age-associated biphasic alterations in metabolic activity, including an increase and afterwards progressive decrease in mitochondrial function. In addition, the byproducts of mitochondrial respiration, reactive oxygen species (ROS), are key determinants in the initiation of cellular senescence when present in high concentrations. Moreover, changes in mitochondrial dynamics in fusion and fission, as well as alterations in the mitochondrial membrane potential have been reported to cause cellular dysfunctions during senescence. Consequently, it seems reasonable that life-prolonging interventions, such as CR or exercise, as well as various drugs, target mitochondria.
Notably, impaired mitochondrial functions are reported to cause accelerated aging that affects primarily organs with high levels of energy demand, such as the brain, the heart, the skeletal muscle, as well as liver and kidney. The critical role of mitochondria in these organs becomes clinically visible in the case of mitochondrial diseases that frequently affect organs with high energy demand. The link between mitochondrial dysfunction and age-related diseases is well-established for Alzheimer's disease, myocardial infarction, and sarcopenia.
The process of aging evokes various alterations in mitochondrial Ca2+ handling, mitochondrial respiration, mitochondrial structure, as well as in the mitochondrial genome, which are mutually interrelated to each other. Results from cell culture and animal experiments suggest enhanced mitochondrial activity in middle age, but a decline in old age. Initially, increased activity of mitochondria might compensate for the decreased mitochondrial efficiency that occurs during aging. However, this enhanced mitochondrial activity might harm the cell long-term, for instance, by increased ROS production, and might even further promote age-related cellular dysfunction. It is of major importance to further investigate the molecular processes behind the role of mitochondria in aging, as well as their potential to serve as targets for therapeutic interventions.
A Peptide Based on Amelogenin can Induce Regrowth of Lost Tooth Enamel
Teeth are subject to many problems, most of which are caused by bacteria. Unfortunately, the state of medical technology when it comes to control of harmful bacteria in the mouth lags far behind the policing of bacterial populations in other scenarios and locations. It is fairly well understood how bacteria cause gum disease and cavities, meaning which species are responsible and which mechanisms are important, but so far no lasting strategy for removing unwanted oral bacteria or blocking their activities has made it out of the laboratory and into the clinic. Getting rid of bacteria in the mouth is easy, but ensuring that only certain specific types are removed, and keeping them removed past a few hours or days, has turned out to be far more challenging.
Nonetheless, some promising avenues have emerged, even though they remain somewhere in the process of development. This is the case for methods of regrowth of tooth enamel; I recall discussing a few specific approaches more than a decade ago, and yet here we are, still reliant upon drills and fillings. Some groups have pursued cell and tissue engineering approaches to growing enamel. Back in 2010, a group demonstrated regeneration of cavities in mice by delivering a peptide known to encourage bone formation, and that worked on enamel as well. That attempt was conceptually similar to far more recent research noted here, in which a different peptide is used to spur enamel deposition.
Peptide-based biogenic dental product may cure cavities
Researchers have designed a product that uses proteins to rebuild tooth enamel and treat dental cavities. This can - in theory - rebuild teeth and cure cavities without today's costly and uncomfortable treatments. "Remineralization guided by peptides is a healthy alternative to current dental health care. Peptide-enabled formulations will be simple and would be implemented in over-the-counter or clinical products."
Bacteria metabolize sugar and other fermentable carbohydrates in oral environments and acid, as a by-product, will demineralize the dental enamel. Although tooth decay is relatively harmless in its earliest stages, once the cavity progresses through the tooth's enamel, serious health concerns arise. Good oral hygiene remains the best prevention. Taking inspiration from the body's own natural tooth-forming proteins, researchers came up with a way to repair the tooth enamel. They accomplished this by capturing the essence of amelogenin - a protein crucial to forming the hard crown enamel - to design amelogenin-derived peptides that biomineralize and are the key active ingredient in the new technology.
"These peptides are proven to bind onto tooth surfaces and recruit calcium and phosphate ions." The peptide-enabled technology allows the deposition of 10 to 50 micrometers of new enamel on the teeth after each use. Once fully developed, the technology can be used in toothpaste, gels, solutions and composites as a safe alternative to existing dental procedures and treatments. The technology would enable people to rebuild and strengthen tooth enamel on a daily basis as part of a preventive dental care routine.
Biomimetic Tooth Repair: Amelogenin-Derived Peptide Enables in Vitro Remineralization of Human Enamel
White spot lesions (WSL) and incipient caries on enamel surfaces are the earliest clinical outcomes for demineralization and caries. If left untreated, the caries can progress and may cause complex restorative procedures or even tooth extraction which destroys soft and hard tissue architecture as a consequence of connective tissue and bone loss. Current clinical practices are insufficient in treating dental caries.
A long-standing practical challenge associated with demineralization related to dental diseases is incorporating a functional mineral microlayer which is fully integrated into the molecular structure of the tooth in repairing damaged enamel. This study demonstrates that small peptide domains derived from native protein amelogenin can be utilized to construct a mineral layer on damaged human enamel in vitro. Six groups were prepared to carry out remineralization on artificially created lesions on enamel: (1) no treatment, (2) Ca2+ and PO43- only, (3) 1100 ppm fluoride (F), (4) 20 000 ppm F, (5) 1100 ppm F and peptide, and (6) peptide alone. While the 1100 ppm F sample (indicative of common F content of toothpaste for homecare) did not deliver F to the thinly deposited mineral layer, high F test sample (indicative of clinical varnish treatment) formed mainly CaF2 nanoparticles on the surface.
Fluoride, however, was deposited in the presence of the peptide, which also formed a thin mineral layer which was partially crystallized as fluorapatite. Among the test groups, only the peptide-alone sample resulted in remineralization of fairly thick (10 μm) dense mineralized layer containing HAp mineral, resembling the structure of the healthy enamel. The newly formed mineralized layer exhibited integration with the underlying enamel as evident by cross-sectional imaging. The peptide-guided remineralization approach sets the foundation for future development of biomimetic products and treatments for dental health care.
Calorie Restriction Extends Life Span Significantly in Short-Lived Primates
The practice of calorie restriction slows aging to a degree that scales with species life span. Short lived species exhibit a sizable gain in maximum life span, while long-lived species do not. In this paper, researchers report on a study of calorie restriction in grey mouse lemurs, one of our more distant and short-lived primate cousins. The effects are about as dramatic as those observed in mice, and the study is interesting on that point: lab mice normally reach 50% mortality due to aging after 2-3 years while the lemurs used here reach that point at 6-7 years, so one might have expected the lemurs to exhibit much smaller gains in life span as a result of calorie restriction. Nonetheless, by the end of the study, the longest surviving non-calorie-restricted lemurs had been dead for a year, while more than a third of the calorie restricted animals were still alive. Calorie restriction extended the 50% mortality age from 6-7 years to 9-10 years in this species, quite similar to the relative size of results in mice.
Caloric restriction, i.e., reducing calorie availability by ~20-50%, is one of the rare known strategies that can extend lifespan. In short-lived species such as rodents, caloric restriction can increase maximal lifespan up to 50% while improving general health and decreasing aging-associated diseases. Beneficial effects of caloric restriction on age-related diseases have also been reported for long-lived species, including rhesus monkeys.
Here we examine the effects of caloric restriction on the health and lifespan of the grey mouse lemur Microcebus murinus, a small lemurid primate with a median survival in captivity of 5.7 years for males and maximum lifespan of 12 years. Mouse lemurs are widely used models for human ageing. They display age-related alterations of their sensorial system, motor functions, biological rhythms, and immune and endocrine systems. In this species, aging leads to increased prevalence of diseases such as neoplasia or sarcopenia and glucoregulatory function alterations that also increase with aging in humans. Finally, their cerebral aging profile is similar to that of humans.
Because of their reduced lifespan (as compared to rhesus macaque), cohorts of calorie-restricted lemurs can be easily created to evaluate mechanisms leading to caloric restriction-related changes. Here we provide the first complete set of caloric restriction-related survival data for a non-human primate in association with a longitudinal follow-up of age-associated alterations in cognition and brain volumes.
In 2006, 34 captive adult male mouse lemurs (age 3.2 ± 0.1 years) were randomly assigned to either a control diet or a chronic 30% caloric restriction diet. Compared to control animals, caloric restriction extended lifespan by 50% (from 6.4 to 9.6 years, median survival), reduced aging-associated diseases and preserved loss of brain white matter in several brain regions. However, caloric restriction accelerated loss of grey matter throughout much of the cerebrum. Cognitive and behavioural performances were, however, not modulated by caloric restriction. Thus chronic moderate caloric restriction can extend lifespan and enhance health of a primate, but it affects brain grey matter integrity without affecting cognitive performances.
The Methuselah Foundation Return on Mission Report
The Methuselah Foundation has hard at work on the matter of aging for more than fifteen years. It is where SENS rejuvenation research first moved from idea to reality, prior to spinning off into the SENS Research Foundation. Over the years, the Methuselah Foundation principals and volunteers have been involved in many of the activities that have helped to transform the aging research community since the turn of the century, setting into motion the projects that will lead to clinical therapies that can turn back aging. In this Return on Mission report (PDF), written for all of us who have supported the Methuselah Foundation over the years, the progress achieved to date is reviewed.
Methuselah Foundation is a biomedical charity co-founded by David Gobel and Dr. Aubrey de Grey. Our mission is to make 90 the new 50 by 2030. We chose that mission because it's falsifiable - it keeps us committed to "return on mission." Having a falsifiable mission keeps us focused. It drives a mindset based in urgency and action. We never want to become the type of charity that exists for existing's sake! Our approach is to put the mission first and money second. We look for high-leverage interventions that spur concrete progress in the short term, and synergistic ripple effects over time. We have built a record of spotting and betting early on people and projects that, with our significant incubation and strategic services, go on to realize remarkable results.
When we began in 2001, it was widely considered both immoral and a fool's errand to work on extending healthy human life. For scientists, it was academically dangerous to even discuss the possibility. Seventeen years later, Methuselah Foundation, its partners and donors have played an unmistakable role in transforming the scientific and cultural outlook. We've had the honor to serve as the first charity to catalyze the movement to address aging. That is almost solely thanks to those of you who've stepped up as the bold few committed to extending healthy life, even in the face of that aim being derided by the press and scientific establishment over the last decade. Our Return on Mission report is an eye-opening look at how far our community has traveled - when progress was never inevitable. It doesn't seem unreasonable to think the last 15 years embody how even a small group can move society. If you've contributed to this progress, thank you!
It has always been the fervent desire of the Methuselah Foundation to find itself with nothing left to accomplish. Over the years, we have been focused on seeking the point of greatest leverage to prevent or reverse the damage associated with aging. We treat aging the way a Medieval diamond cutter would face the challenge of cleaving one of the most valuable and hardest substances known to man. In an era where tools were primitive, the gem cutter would carefully examine the internal crystalline structure, as well as the faults in the diamond. After careful and methodical analysis, the gem cutter would strike the diamond with a cleaver, which would result in the large diamond breaking into predictable and useful smaller pieces, ready for polishing and setting in jewelry.
Aging has been, not just an engineering problem, but a cultural one. One of our "first strikes at the diamond" was aimed not just at scientific progress, but also at publicly celebrating advances in the field. This was the Methuselah Mouse Prize, designed to reward scientific advances and simultaneously overcome the reluctance of the biogerontology community to deliberately explore extending healthy human lifespan. As a social engineering effort, the prize has been spectacularly successful. Efforts to engineer life extension have gone from practically zero worth of investment when we began, to well over a billion in investment.
When we started, the very idea of working on increasing the human lifespan would result in career suicide. Now, the worldwide community is publicly focused on extending lifespan and reversing aging. Due to these early successes, more and more investors are giving attention and funding to our space. In anticipation of this sea change, the Methuselah Foundation created the Methuselah Fund to help curate and direct investments into projects and startups that will move the needle in the near future as we prosecute our mission to extend healthy human lifespan. None of this would have happened without the incredible support of our donors over the years.
Mitochondrial Mutations and Stem Cell Aging
This open access review paper looks over current thinking on the role of mutations in mitochondrial DNA in the decline of stem cell activity in aging. Every cell contains a swarm of mitochondria, the evolved descendants of symbiotic bacteria now responsible for generating chemical energy store molecules. Each contains a small amount of mitochondrial DNA, the last remnant of the original bacterial genome that hasn't either been lost over time or moved to the cell nucleus. Mutational damage in this DNA can produce significant cellular dysfunction, and unfortunately it is a good deal less robust and protected than the DNA of the cell nucleus. It is also right next to energetic chemical processes that produce reactive molecules as a byproduct, and it replicates more frequently than nuclear DNA, all of which suggests a greater rate of damage and error. In long-lived and important stem cell populations, this process is probably important.
Ageing is a process where tissue gradually loses homeostasis and regeneration. This process is systemic and closely associated to age-related changes in somatic stem cells. These cells renew themselves and differentiate into tissue-specific daughter cells for tissue maintenance and regeneration. The age-related alterations in somatic stem cell properties include failure to generate functional progenies, depletion of the stem cell pool, and cancerous transformation. These changes largely affect mitotic tissue, such as blood, intestine, and skin, where the stem cells actively produce progenies to maintain the high turnover of the tissue. However, they also contribute to ageing post-mitotic tissue, such as brain and muscle, though stem cells in these tissues are considered quiescent under normal physiological conditions and activated in response to damage for repairing the tissue.
Mitochondria synthesize ATP via oxidative phosphorylation (OXPHOS) through five multi-subunit complexes. Mitochondria contain their own DNA (mtDNA), which encodes key subunits of these complexes. Replication of the mitochondrial genome is independent of the cell cycle. In addition, mtDNA is susceptible to damage due to lack of histone protection and proximity to oxidative stress. Due to these reasons, compared with the nuclear DNA, mtDNA is more prone to mutations. Multiple copies of mtDNA reside in a cell. Mutations of mtDNA usually occur as a proportion of the total copies and once they reach a threshold, mitochondria will display respiratory chain deficiency, a consequence of which is potentially excessive production of reactive oxygen species (ROS).
Ageing is accompanied by a reduction of mitochondrial function, resulting in respiratory chain defects which are thought to be associated with the accumulation of somatic mtDNA mutations. The age-related change in mitochondria may in turn accelerate the ageing process. Although the significance of mtDNA mutations in various parenchymal cells in normal ageing and age-related degenerative diseases has been broadly studied, the findings might not be able to be extrapolated to stem cells, as they are distinct from somatic cells in terms of biological and metabolic characteristics.
Somatic mtDNA mutations accumulating in stem cell populations in normal humans have a tissue-specific ability to expand clonally during ageing. The premature ageing mtDNA-mutator mouse model gives insight into how acquired mtDNA mutations affect the function of the stem cells and progenitors in both the mitotic and post-mitotic tissue, as well as the potential mechanisms by which age-related mtDNA mutagenesis affects stem cell homeostasis. Recently, studies have reported that stem cells might actively regulate their identity by manipulating the quality control of the mitochondria, for example, by removing the dysfunctional mitochondria or by unevenly segregating young and aged mitochondria. The quality control system might lose its function during ageing, leading to the absence of selective pressures on the somatic mtDNA mutations, which in turn accelerates ageing.
MicroRNA-150 is Important in the Contribution of Macrophages to Age-Related Disease
Researchers here provide evidence for microRNA-150 to be a part of the regulatory machinery that determines whether macrophage behavior is inflammatory and damaging, or regenerative and helpful. This is part of a most interesting line of research that examines the various polarizations of macrophages, a polarization being a class of behavior and activity, and their contribution to age-related disease. As aging progresses, an ever large fraction of the macrophage population in many tissues becomes inflammatory and aggressive, hindering regeneration, or promotes unhelpful functions in tissue, such as excessive growth of blood vessels. The exact chain of cause and effect that lies between the known root causes of aging and macrophage dysfunction is yet to be determined, but researchers are making progress in mapping mechanisms that might be used to force macrophages to be less damaging in older individuals.
Macrophages are critical effector cells of the innate immune system. Multiple groups, including our own, have reported that macrophages from aged mice demonstrate a functional drift compared with those isolated from young mice. For example, aged macrophages exhibit epigenomic changes, leading to reduced autophagic capacity, and are defective in their ability to fight viral infections due to reduced phagocytic activity. Moreover, aged macrophages are skewed toward a proangiogenic gene and cytokine expression profile, which leads to dysregulated inflammation and the inability to inhibit pathological angiogenesis. Aged macrophages also exhibit impaired cholesterol efflux due to decreased Abca1 expression, leading to intracellular cholesterol accumulation and pathologic vascular proliferation. Age-associated macrophage dysfunction has been proposed to contribute to the pathogenesis of numerous diseases of aging, including age-related macular degeneration (AMD) and atherosclerosis. In addition, age-associated changes in microglia, the major resident immune cell in the retina with similar phagocytic functions, may also promote AMD.
AMD is a leading cause of blindness in industrialized nations and displays a complex disease course characterized, initially, by accumulation of cholesterol-rich deposits known as drusen underneath the retina. Though drusen themselves do not typically cause vision loss, they are risk factors for progression to one of 2 forms of advanced AMD: advanced neovascular (wet) AMD, characterized by pathologic subretinal angiogenesis, or advanced dry AMD, characterized by geographic atrophy secondary to loss of retinal neurons and underlying cells. Both forms of advanced AMD can cause debilitating blindness, though wet AMD causes a significant portion of the vision loss associated with AMD.
There is support for the idea that impaired cholesterol homeostasis contributes to AMD pathogenesis. Impaired cholesterol homeostasis also contributes to the pathogenesis of atherosclerosis. Atherosclerotic plaque formation begins when circulating monocytes adhere to the vascular endothelium, migrate to the sub-endothelial space, and activate into macrophages that take up lipids and become foam cells. Past studies have demonstrated that the activation/polarization state of macrophages is important for predicting plaque phenotype and stability. For example, in patients with hypercholesterolemia, macrophages polarize to a more proinflammatory state, which could predispose to plaque formation. Remarkably, atherosclerotic plaques and drusen have similar lipid compositions, unifying the pathogenic pathways underlying these diseases. Based on these similarities, some have proposed that it may be possible to repurpose statins, lipid-lowering drugs used to treat atherosclerosis, for treating AMD.
Despite these advances in our understanding of the phenotype of aged macrophages and how such changes contribute to age-associated diseases, the molecular mechanisms by which macrophages drift toward the disease-promoting phenotype remain elusive. Given the immense spectrum of these changes in aged macrophages, we hypothesized that microRNAs (miRs) may regulate the transcriptome of macrophages and, thereby, the transition of macrophages to a disease-promoting phenotype. The ability of miRs to target multiple genes makes them strong candidates as molecular regulators.
In this study, we sought to identify one or more miRs that regulate the disease-promoting programmatic changes in macrophages that are associated with AMD. Our results demonstrate that miR-150 is highly upregulated both in disease-promoting murine macrophages and in human peripheral blood mononuclear cells (PBMCs) from AMD patients. Moreover, we show that miR-150 regulates macrophage-mediated inflammation and pathologic angiogenesis, suggesting that it regulates the transition of macrophages from a healthy profile to the AMD-promoting phenotype. Ultimately, these findings provide insight into the mechanisms underlying the pathological programmatic changes in aged macrophages and may lead to the identification of novel therapeutic targets and candidate biomarkers.
Correlating Hair Graying and Cardiovascular Disease
Whenever one looks at correlations discovered between manifestations of aging, it is worth bearing in mind that it is easy to find these correlations, but hard to show that they are in any way meaningful. Aging is caused by a few comparatively simple processes of damage accumulation that spread out into a vast, complicated, branching tree of interacting secondary and later consequences. Aging is complicated because our biology is very complicated, not because its causes are especially complicated. This spreading out from common roots means that many parts of aging proceed at fairly similar rates in any given individual. That can be true even if those correlated portions of aging have little connection to one another aside from that same root cause, all the way down beneath many layers of cause and effect.
Aging is a complex process that affects all of us. All organs undergo a series of age related changes, in which the vascular system is prominent. Hair graying is one of the natural aging processes. Although it is generally not a medical problem, it greatly concerns many people for aesthetic reasons. Because of the strong association between aging and hair graying, many researchers have been concerned that hair graying, especially when occurs prematurely, is a predictor of some severe systemic disease and several studies evaluated the association of premature hair graying (PHG) with osteopenia or coronary artery disease (CAD).
Atherosclerosis and graying of hair share a similar mechanism includes impaired DNA repair, oxidant stress, androgens, inflammatory processes, and senescence of functioning cells, and the incidence of both conditions increases with age. Accordingly, this study was conducted to determine the prevalence and degree of hair graying among a cohort of males with suspected CAD who underwent computed tomography coronary angiography (CTCA) and whether it is an independent marker for CAD.
This study recruited 545 adult male patients who underwent a CTCA for suspicion of CAD. Extent of grayness was assessed with two observers using hair whitening score (HWS), defined according to percentage of gray/white hairs. Patients were divided into different subgroups according to the percentage of gray/white hairs and to the absence or presence of CAD.
We found that patients who had atherosclerotic CAD were older in age and among all cardiovascular risk factors, hypertension, diabetes, and dyslipidemia were more prevalent, and that high HWS was associated with increased risk of CAD independent of chronological age and other established cardiovascular risk factors. The results of our study not only confirm an association between hypertension, diabetes, smoking, and hair graying but also shows that coronary calcification detected by CTCA was significantly higher in patient with high HWS.
All Current Assessment Methods for Frailty Correlate with Future Mortality
Researchers here report on the effectiveness of methods used by researchers and clinicians to assess degree of frailty in older patients. They find that all methods correlate with future mortality, but there are variances in the details of how they correlate to the risk of suffering specific age-related conditions. An optimist might take this to mean that any future rejuvenation therapy with sizable, reliable effects could be correctly categorized as a real rejuvenation therapy by applying the existing systems of testing and assessment. New biomarkers of aging would help, but they are not necessarily required. We'll find out whether or not this is the case over the next five to ten years as senolytic therapies work their way into widespread use, and the large assessment studies begin.
Frailty is common in elderly people with cardiovascular disease and goes along with elevated mortality. However, no consensus exists on the definition of frailty. Many scores have been developed to assess frailty and to make predictions on disease and mortality, but there is no gold standard. Researchers examined the predictive ability of 35 frailty scores for cardiovascular disease, cancer and all-cause mortality using data from the English Longitudinal Study of Ageing. The analysis reveals that all frailty scores are associated with future mortality, and that some are linked to cardiovascular disease but none to cancer. The study underscores that the comparative evaluation of strength of associations between health outcomes in elderly people provides a solid evidence base for researchers and health professionals.
In this study, the scientists analysed frailty scores identified by a systematic literature review on their ability to predict mortality, cardiovascular disease, and cancer. Data was used from 5,294 adults aged 60 years or more and followed up over a period of seven years within the English Longitudinal Study of Ageing. The researchers observed that all frailty scores were associated with all-cause mortality, some were also associated with the incidence of cardiovascular disease, but none were associated with cancer events. In models adjusted for demographic and clinical information, 33 out of 35 frailty scores showed significant added predictive performance for all-cause mortality. Certain scores outperform others with regard to all-cause mortality and cardiovascular health outcomes in later life. The authors specify that multidimensional frailty scores may have a more stable association with mortality and incidence of cardiovascular disorders.
The SENS Research Foundation on the Ongoing Development of Senolytic Therapies to Treat Neurodegenerative Conditions
Senescent cells are a significant cause of age-related disease. Now that the research community is earnestly developing ways to remove senescent cells, and trying them out in animal studies, every few months there is a new announcement of one or another definitive connection between the accumulation of senescent cells and a specific medical condition. The SENS vision for the development of rejuvenation therapies assembled the existing evidence and strongly advocated for senescent cell clearance around the turn of the century, ten long years prior to the point at which the rest of the research community finally got on board. In a better world, most of the impressive progress today towards the effective treatment of many age-related diseases by clearance of senescent cells would have happened certainly ten and perhaps twenty years ago. There is no compelling technical reason for it to have waited until now; the delay is near all cultural, a consequence of the attitudes of the research community during the decades in which its members actively discouraged work on slowing or reversing the aging process.
It was a bit of a mystery to the scientists investigating the phenomenon: a brain disease driven by the death of specialized neurons was strongly linked to exposure to a particular pesticide. Why, then, didn't exposing those same neurons directly to that same pesticide seem to affect them? Parkinson's disease (PD) is a neurodegenerative disease of aging, whose most obvious symptoms involve the loss of fine motion control. This is the result of the loss of specialized cells in an area of the brain called the substantia nigra pars compacta (SNc) that specialize in producing the chemical signal-molecule dopamine. Once a critical number of these dopaminergic SNc neurons are lost, the unbalanced firing of those neurons begins to manifest itself in the main motion-related symptoms of the disease.
In all but a few people with rare mutations, degenerative aging processes (such as the accumulation of mitochondrial mutations in SNc neurons) are primarily responsible for the disease. But lifestyle and environmental factors also damage these neurons. A striking example of this is MPP+, a well-established neurotoxin that specifically attacks the SNc dopaminergic neurons. For a long time, scientists have focused on paraquat, a neurotoxic pesticide subject to restricted use. Paraquat was originally restricted because it can cause lung damage when workers are exposed to high levels of it in the air, but scientists studying it also noted that it has a strong structural resemblance to MPP+. And sure enough, under some conditions it can cause a Parkinson's-like syndrome in laboratory animals, and a strong and consistent relationship has been found between on-farm exposure to paraquat in farm workers and risk of PD.
Yet, puzzlingly, paraquat doesn't seem to be particularly toxic to dopaminergic neurons when tested directly; much of the rodent data that seems to show such an effect is ambiguous or unlikely to reflect paraquat exposures actually present in the brain. So what might be going on? As it turned out, the scientists were looking in the wrong place. Paraquat, it turns out, doesn't directly kill dopaminergic neurons. Instead, it acts by deranging the cells that are supposed to support and nourish them. Meanwhile, the same thing goes wrong in the aging brain, culminating in Parkinson's and other degenerative syndromes. The lesson here isn't just "avoid exposure to dangerous pesticides." The same study that revealed this surprising indirect mechanism of paraquat's neurotoxicity also showed how much of the harm can be blocked, and in doing so revealed a new tool in our toolbox for taking the "normal" Parkinson's disease of aging out of our futures forever.
Astrocytes are a kind of support cell for the neurons in the brain. They provide a source of nutrients, maintain the equilibrium in the fluids that surround the neurons, participate in neural repair, and take up and release brain messenger-molecules. Scientists discovered several years ago, however, that rising numbers of astrocytes in the aging brain become senescent. Senescent cells lose their normal function in the tissue, cease dividing, and begin secreting a deadly mix of inflammatory and tissue-degrading factors collectively known as the senescence-associated secretory phenotype (SASP) that damages and deranges local tissues.
It was no surprise, then, when scientists found that the burden of astrocytes with tell-tale signs of senescence rises with age in the brain and even faster in those with Alzheimer's disease. Could it also be part of the explanation for the effect of paraquat? And what are the therapeutic implications of such findings in aging people not exposed to this neurotoxin? When the researchers examined the brains of PD patients, they found more cells exhibiting signs of senescence than in people without the disease - and especially astrocytes.
How might one prove that the newly-discovered induction of senescence in astrocytes was responsible for the damage, and not some other direct or indirect effect? The "damage-repair" heuristic of SENS suggested eliminating the senescent cells themselves, and seeing if that was enough to block the downstream mayhem. Research have in fact found that eliminating senescent astrocytes confers benefits to mice with a model of PD that mimics the fundamental processes that drive Parkinson's in aging people. In recent years, researchers have developed so-called "senolytic" drugs that wipe out senescent cells in aging mice and mouse models of age-related disease, exploiting the high dependence of these cells on specific biochemical survival pathways. The benefits of senescent cell clearance to the health and longevity of aging mice have turned out to be more dramatic and sweeping than anyone ever expected.
Journalistic Views of Aging and Longevity Have Yet to Reach Maturity
While journalistic treatment of serious rejuvenation research has improved greatly over the past decade, the mainstream media remains decidedly childish at times. Much of the profession of journalism works hard at producing the appearance of educated folk paid to play the fool, writing for an imagined audience of inattentive, ignorant peers, while ensuring that their education slips through the mask just enough to be seen. It degrades the author and insults the world at large. Everyone in this picture is better than they are portrayed, capable of introspection and self-determination. I noted the article here because it veers from the histrionic to the sensible, covering in one outing a fair portion of the existing journalistic spectrum of quality and common sense regarding aging and age-related disease. It predictably asks whether or not we should work to make progress in medical science, thereby producing far longer healthy life spans - the manticore of journalistic balance in place of actual thought on the matter.
Advances in anti-aging medicine suggest that even serious life extension may be within reach. Millions in funding have poured into longevity research ranging from the radical (head transplants, cancer-killing nanobots) to the slightly more recognizable (repurposing diabetes medications to kill off senescent cells, drugs to mimic genes that have quadrupled the lives of worms). The hotly debated question among longevity experts, in fact, is not whether we'll celebrate significantly more birthdays but how many more.
Saving a life and extending a life are part of the same continuum. When we save a life, with defibrillators or bypass surgery or by pulling someone who's drowning out of a lake, we move the time of death. "We all believe in postponing deaths. We all want our own deaths postponed and we invest vast amounts as individuals and societies in methodologies for achieving that. To withdraw from that is to say that postponing death is not a good thing."
For all but our most recent history, death was a common, ever-present possibility. Life expectancy has increased in the West mainly because fewer children are dying before that fifth birthday, mostly thanks to improved nutrition, sanitation, and vaccines. But modern medicine has also helped the "bottom to drop out later and later" - past 50, past 80, past 100. In Canada, for the first time in history, there are now more over-65s than under 15s, and the biggest boom is in the centenarians, whose numbers grew by 41 per cent from 2011 to 2016.
Still, when we do die we tend to follow a predictable period of decline. By age 85, half of us will have three or more major chronic diseases. Our lungs start to give out, our reflexes slow, our vision dims. But Aubrey de Grey hopes to pull us out of that dive. Reach age 40, say, and then go in for a series of "rejuvenation" tune-ups that return us to the biological fitness (inside and out) of a a 20- or 30-year-old. Repeat a few decades later. And again, and again - until we achieve what de Grey calls "longevity escape velocity," renewal at a pace faster than aging. SENS-funded researchers, some of them leaders in their field, are working towards a panel of rejuvenation therapies to repair or eliminate seven different kinds of biological "junk" that accumulates as we age - cell loss, mutations in chromosomes, death-resistant cells, and so on - so that we are able to get seriously old without falling apart.
A Failure to Treat Alzheimer's by Interfering in RAGE-Induced Inflammation
Alzheimer's disease certainly has an inflammatory component to it, as do other neurodegenerative conditions. The immune system of the brain runs awry in characteristic ways. Evidence exists to suggest that short-lived advanced glycation end products (AGEs) of the sort found in individuals with metabolic syndrome and type 2 diabetes are a significant source of inflammation. They act via the receptor for AGEs, RAGE. This, I should note, is entirely unrelated to the detrimental effects of persistent, long-lived AGEs on tissue structure. Short-lived AGEs are more of a lifestyle issue, in that everyone has them to some degree, but they are strongly associated with diet, obesity, and the metabolic diseases of obesity.
In any case, some effort has gone into building ways to interfere in RAGE-induced inflammation, and one of them made it as far as clinical trials for Alzheimer's disease. Unfortunately it joins the sizable and growing pyre of failed trials for this condition - and by the look of it was running largely on hope for much of its lifetime, one of many things wrong with the present system of trials and its dominant focus on marginal effects. It is possible that reducing inflammation simply isn't enough on its own, given everything else that is going on in the Alzheimer's brain, or that RAGE is not an important source of inflammation in comparison to others in Alzheimer's patients, or the effects did not translate well from animal studies.
Yesterday, vTv Therapeutics announced the termination of both parts of its STEADFAST clinical study, which had been testing the small molecule azeliragon in patients with probable Alzheimer's. According to data from the Phase 3 clinical trial, patients who took the drug for 18 months performed no better than those on placebo in tests of cognition and function. Though only a fraction of patients in Part B, which is identical in design, have completed 12 months on the drug, the company has terminated that trial.
Azeliragon blocks the receptor for advanced glycation end products (RAGE), which can cause inflammation in the brain. Because microglia and astrocytes upregulate expression of RAGE in AD, and because evidence suggested RAGE binds and mediates Aβ toxicity, researchers reasoned that blocking the receptor would be beneficial. TransTech Pharma discovered azeliragon, a.k.a. TTP 488, and licensed it to Pfizer, which, together with the National Institute on Aging, sponsored an 18-month trial of the antagonist back in 2007. Run by the Alzheimer's Disease Cooperative Study, it tested daily doses of 5 mg and 20 mg given after six-day ramp-ups of 15 mg and 60 mg, respectively, in patients with mild to moderate AD. Trials of both dosing regimens were halted early for lack of efficacy.
Latching onto hints of a benefit in patients with mild AD, TransTech Pharma, which would become vTv, received fast-track approval from the Food and Drug Administration to test the drug in patients with probable AD and a brain MRI consistent with that diagnosis. No other markers were used for inclusion criteria. The STEADFAST study was slated to recruit 800 participants randomized to either 5 mg/day azeliragon or placebo.
Precision Vaccination Against LDL Cholesterol Reduces Atherosclerotic Plaque in Mice
Vaccination technology has advanced to the point at which tiny fragments of a protein can be used to direct the adaptive immune system to attack very specific targets. In this case, the target is LDL cholesterol. Reducing the amount of LDL cholesterol in the bloodstream is a proven strategy to slow the onset and progression of atherosclerosis. In this condition, damaged lipids carried in the bloodstream irritate cells in the blood vessel wall, leading to a runaway process of inflammation and cell death that generates fatty plaques. These eventually lead to rupture or blockage of blood vessels that is severe enough to result in death. A global reduction in blood lipids - in cholesterol in the bloodstream - reduces the input of damaged lipids to this process.
In recent years the research community has broadened its efforts in this direction, moving beyond pharmaceuticals such as statins in order to find more efficient means of long-term reduction in blood lipids. Examples other than the vaccination approach noted here include PCSK9 gene therapies, or similar efforts that target other genes noted to significantly reduce cholesterol levels without side-effect in mammals. Diversity in research for any particular therapeutic goal is usually a good sign for future progress.
Researchers report successful vaccination of atherosclerotic mice with a small chunk of protein snipped out of "bad cholesterol." Vaccination reduced plaque levels in test mice, and other experiments with human blood samples identified the class of T cells likely responsible for positive outcomes. The results suggest that a comparable strategy could form the basis of a human vaccine. "We knew atherosclerosis had an inflammatory component but until recently didn't have a way to counteract that. We now find that our vaccination actually decreases plaque burden by expanding a class of protective T cells that curb inflammation."
So-called "bad cholesterol" is actually an amalgam of the lipid cholesterol carried on Low Density Lipoprotein, or "LDL". To create the new vaccine, the team engineered a short stretch (or peptide) of the core LDL protein. They then undertook a type of molecular fishing expedition, using a version of the peptide mounted on a scaffold called a tetramer as bait, to identify what immune cells became active in its presence. To do that, the researchers obtained human blood from two groups - women with plaque accumulation in their carotid arteries versus women without plaque formation - and screened those samples for immune cells that latched onto the peptide. In both groups, the peptide bound to subset of CD4+ T cells known as T regulatory cells (or "Tregs"). But the percentage of Tregs from atherosclerotic subjects was much smaller, and other types of T cells were much more common than in healthy donors, suggesting that the Tregs may undergo some kind of molecular switch that hampers their effectiveness once cardiovascular disease progresses.
Beyond addressing a major health concern, this paper exemplifies next-generation vaccinology. "We are now engineering vaccines to be more specific. Once we can manipulate the immune response with a single peptide or epitope, we will be able to create more highly targeted vaccines with fewer non-specific responses." These results is evidence that this goal is feasible against atherosclerosis, but more work is needed to create a vaccine appropriate for human use. A preventative, not just a treatment like statins, is needed to block plaque deposition, because atherosclerosis can go undiagnosed. "Men in their 50's with apparently normal cholesterol may be at risk, and seemingly healthy people occasionally suffer fatal heart attacks. Only then their docs realize they had atherosclerotic disease." A widely available vaccine that prevented plaque formation would make that scenario a thing of the past.