Fight Aging! Newsletter, November 25th 2019

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  • The Strategy of mTORC1 Inhibition Fails a Phase III Trial
  • Heat Shock Proteins as a Basis for Tackling Protein Aggregation in Neurodegenerative Diseases
  • Vaccination and Antiviral Therapies Targeting CMV as an Approach to Reducing Immunosenescence
  • Dogs as a Model of Human Aging
  • Libella Gene Therapeutics to Run a Patient Paid Trial of Telomerase Gene Therapy
  • A Role for B Cells in the Chronic Inflammation Generated by Visceral Fat Tissue
  • A Mechanism by which Cellular Senescence Drives Pulmonary Fibrosis
  • Against Senolytics
  • Cellular Senescence May Contribute to Rheumatoid Arthritis in Younger Patients
  • Targeting α-Synuclein in the Gut to Turn Back the Progression of Parkinson’s Disease
  • Greater Physical Fitness Correlates with Lower Risk of Dementia
  • 7-Ketocholesterol as a Contributing Cause of Multiple Age-Related Diseases
  • The Aged Adaptive Immune System is Strange
  • Evidence for Inflammation to Drive Tau Pathology in Alzheimer’s Disease
  • The Dog Aging Project Forges Ahead with a Large Study

The Strategy of mTORC1 Inhibition Fails a Phase III Trial

The worst possible outcome when developing a clinical therapy is not an early failure. It is a late failure, in the final and most expensive phase III clinical trial, in which the therapy interacts with a sizable patient population, and after a great deal of time and funding have been devoted to the program. This result is far more likely for therapies based on mechanisms that have smaller rather than larger effect sizes, and where that smaller effect size varies from individual to individual for reasons that are not well understood – something that describes all too much of the past few decades of efforts to treat age-related disease. Unfortunately this worst case phase III failure just happened to resTORbio’s mTORC1 inhibitor RTB101, in tests of its ability to improve immune function and reduce the burden of infection in later life.

The inhibition of mTOR, and specifically only the mTORC1 protein complex in order to reduce side-effects resulting from inhibition of mTORC2, is one of a range of potential approaches demonstrated in animal models to modestly slow aging via upregulation of cellular stress response mechanisms. It affects some of the same processes as calorie restriction and exercise. Another way of looking at it is that it pushes metabolism into a state that makes it incrementally more resilient to the accumulated damage of aging. However, all such strategies examined to date perform far better in short-lived species than in long-lived species, a situation that may occur at root because calorie restriction evolved to increase the odds of survival through seasonal famine. A season is a long time for a mouse, a short time for a human, and so only the mouse evolves to demonstrate a sizable relative gain in healthspan and life span due to a restricted calorie intake.

Nonetheless, the clinical evidence to date suggested that mTORC1 inhibition would produce enough benefits in human patients to be worth it from the patient perspective: a low cost pill that produces incremental improvement in the experience of late life medical conditions. I don’t think that this outcome is worth it from the point of view of the enormous funding required for development and regulatory approval, however, not when there are far better options on the table, such as senolytic therapies to clear senescent cells and the rest of the SENS rejuvenation research program. The resTORbio team may have made a poor choice of indication to apply their therapy to – though given the promising results to date, I don’t think that could have been known in advance. It may be that incremental gains through mTORC1 inhibition can still be obtained for patients with other age-related conditions, but nonetheless, this present failure should dampen our expectations to some degree for any and all other approaches based on stress response upregulation.

Failure in a late stage trial doesn’t go unnoticed, and nor should it. It sends ripples through the biotech industry, since there are always networks of companies working on conceptually similar approaches to the therapy that failed at the final hurdle. The best outcome of such events would be for investors and entrepreneurs and researchers to gravitate towards better approaches to the treatment of aging – those with larger and more reliable effect sizes, by virtue of actually repairing the underlying damage of aging. Senolytic therapies are a great example of the type. As two decades of relentless fixation on anti-amyloid immunotherapy in the Alzheimer’s industry demonstrates, this can take some time, however. The worst outcome would be for investment in the whole longevity industry to be damaged by failures in its first large trials, because naive investors have little to no insight into the technical and scientific differences between poor strategies and good strategies. This puts greater pressure on the senolytic companies to succeed in their initial trials, as they are up next.

resTORbio Announces That the Phase 3 PROTECTOR 1 Trial of RTB101 in Clinically Symptomatic Respiratory Illness Did Not Meet the Primary Endpoint

resTORbio, Inc., a clinical-stage biopharmaceutical company developing innovative medicines that target the biology of aging to prevent or treat aging-related diseases, today announced that top line data from the PROTECTOR 1 Phase 3 study, evaluating the safety and efficacy of RTB101 in preventing clinically symptomatic respiratory illness (CSRI) in adults age 65 and older, did not meet its primary endpoint, and that it has stopped the development of RTB101 in this indication. RTB101 is an oral, selective, and potent TORC1 inhibitor.

“While we are disappointed in these results, there are extensive preclinical data supporting the potential therapeutic benefit of TORC1 inhibition in multiple aging-related diseases, including Parkinson’s disease, for which we have an active Phase 1b/2a trial of RTB101 alone or in combination with sirolimus. Multiple pre-clinical models have demonstrated that inhibition of TORC1 decreases protein and lipid synthesis, increases lysosomal biogenesis and stimulates the clearance of misfolded protein aggregates, such as toxic synucleins, that cause neuronal toxicity in Parkinson’s disease. We remain committed to exploring the potential benefits of TORC1 inhibition in patients, and we look forward to the data from our Parkinson’s disease trial, which we expect in mid-2020.”

The PROTECTOR 1 Phase 3 trial was a randomized, double-blind, placebo-controlled clinical trial that evaluated the safety and efficacy of RTB101 10mg given once daily for 16 weeks during winter cold and flu season to subjects 65 years of age and older, excluding current smokers and individuals with chronic obstructive pulmonary disease. The primary endpoint of the trial was the reduction in the percentage of subjects with clinically symptomatic respiratory illness, defined as illness associated with a respiratory tract infection, or RTI, based on prespecified diagnostic criteria, with or without laboratory confirmation of a pathogen.

The PROTECTOR 1 trial included 1024 patients who were randomized 1:1 to receive RTB101 or placebo administered once daily for 16 weeks. In an analysis of the primary endpoint, the odds of experiencing a CSRI were 0.44 in the placebo cohort and 0.46 in the RTB101 cohort. The Company plans to conduct detailed analyses of the PROTECTOR 1 study, including additional data on safety and secondary and exploratory endpoints, which are not available at this time, with the goal of gaining insights that may explain the difference in RTB101 activity observed in PROTECTOR 1 as compared to prior Phase 2 studies.

Heat Shock Proteins as a Basis for Tackling Protein Aggregation in Neurodegenerative Diseases

Neurodegenerative conditions are largely characterized by the aggregation of a few altered proteins that are prone to forming solid deposits in and around neurons. Tissues, such as the brain, made up of long-lived cells, such as neurons, are particularly vulnerable to this sort of dysfunction, as they cannot dilute harmful protein aggregates by cell division, and dysfunctional cells are not readily destroyed and replaced. Cells must rely upon internal quality control mechanisms such as the presence of chaperone proteins responsible for chasing down misfolded or otherwise problematic proteins, and ensuring they are refolded correctly or recycled via autophagy.

The quality control mechanisms of chaperone mediated autophagy are known to be important in aging. Increased autophagic activity is associated with many of the means of modestly slowing aging demonstrated in laboratory animals in past decades. Autophagy declines with age, and this is thought to be important in the development of neurodegenerative conditions precisely because neurons are heavily reliant on quality control to maintain function. Researchers are interested in finding ways to build therapies for age-related conditions based on upregulation of autophagic activity, and, as noted in today’s open access paper, the class of chaperone proteins called heat shock proteins are one prominent area of investigation.

Small Heat Shock Proteins, Big Impact on Protein Aggregation in Neurodegenerative Disease

Maintenance of cellular protein homeostasis (proteostasis) is crucial for cell function and survival. Neurons are particularly sensitive to dysregulated proteostasis as evidenced by the accumulation and aggregation of amyloidogenic proteins, which are a hallmark of neurodegenerative disease. Cellular molecular chaperone systems modulate proteostasis, and, therefore, are primed to influence aberrant protein-induced neurotoxicity and disease progression. Molecular chaperones have a wide range of functions from facilitating proper nascent folding and refolding to degradation or sequestration of misfolded substrates.

ATP-dependent chaperones, like the 70 kDa heat shock protein (Hsp70) and the 90 kDa heat shock protein (Hsp90), facilitate refolding, degradation, or sequestration of these misfolded proteins. Small heat shock proteins (sHsps) that lack an ATPase domain and are between 12 and 43 kDa are a class of molecular chaperones that typically associate early with misfolded proteins. These interactions hold proteins in a reversible state that helps facilitate refolding or degradation by other chaperones and co-factors.

Potential therapeutic strategies that aim to modulate endogenous sHsp expression or phosphorylation generally suffer from a lack of specificity for the sHsp family, let alone for discrete sHsps. Heat stress-responsive sHsps can be activated by drugs that generate a challenge to proteostasis, which includes proteasome inhibitors (e.g. Bortezomib), Hsp90 inhibitors (e.g. 17-AAG), and oxidative stress inducers (e.g. terrecyclic acid). However, these treatments also induce expression of other molecular chaperone families (e.g. Hsp70 and Hsp40) and are not specific for sHsp activation. Efforts to identify Hsp co-inducers, substances that potentiate stress responses without inducing a primary stress response on their own, may offer improved selectivity.

Small molecules that interact with sHsps may be a promising strategy for therapeutics, but the nature of this family of chaperones makes drugability difficult. There are no known small molecule ligands to use as a scaffold to start from. The dynamic nature of these proteins taunt the idea of engineering a high affinity binding drug; indeed, these promiscuous proteins likely have many client binding sites with a variety of conformations.

The diversity of sHsps from different organisms, from bacteria to humans, provides a rich set of proteins to explore for aggregation prevention activity. For example, a sHsp from a parasite was shown to be a potent inhibitor of amyloid-β fibrillation and reduced associated toxicity in a neuroblastoma cell model. Specific mutant or engineered sHsp variants, with altered oligomeric structure or client interactions, may prove to have increased chaperone activity towards amyloidogenic proteins. Small peptides derived from human HspB4 and HspB5 sequences, termed mini-chaperones, display chaperone-like activity. One of these constructs reduced cellular toxicity of amyloid-β.

Vaccination and Antiviral Therapies Targeting CMV as an Approach to Reducing Immunosenescence

Today’s open access paper discusses possible approaches to the treatment of immunosenescence, the age-related decline in effectiveness of the immune system. Unfortunately it is largely a tour of compensatory treatments, ways to force the cells of the immune system into greater or more useful activity without addressing any of the underlying causes of immunosenescence. Many of these methodologies have serious side-effects, are disruptive of normal immune function and overall health, and cannot be applied for the long term. Checkpoint inhibition, or the delivery of recombinant IL-7, for example, both of which are used as short term interventions to treat cancer.

The path to actually fixing the aged immune system by addressing causes is quite different. It would involve restoring the thymus from atrophy in order to restore a more youthful pace of production of T cells. Replacing the hematopoietic stem cell population to ensure that the right balance of immune cells are produced in the bone marrow. Reversing the degeneration of lymph nodes, where immune cells coordinate. Clearing out the populations of worn, malfunctioning, and misconfigured immune cells in tissues and bloodstream. This is a lot of work, but it is an oversight to omit these active lines of research and development from any review of ways to treat immunosenescence.

The one approach outlined at length in this open access paper that does address a plausible cause of immunosenescence is vaccination against cytomegalovirus (CMV). Near everyone is silently infected by late life, and the adaptive immune system becomes ever more devoted to trying and failing to clear this persistent viral infection. Ever more T cells are specialized to CMV, leaving ever fewer available for other tasks. As the supply of new T cells diminishes with age, this overspecialization becomes a serious issue, contributing greatly to the decline in immune function.

The authors here make the point that all of the necessary knowledge and technology already exists to put together a viable, widely used vaccine for CMV, but the will to do so is absent. We live in a world in which HPV vaccination became a reality, however, and CMV is arguably far worse when it comes to costs and suffering. Perhaps, at some point in the years ahead, the slow machineries of regulation will come to the point at which people are regularly vaccinated against CMV in order to reduce the impact of aging on immune function. I think it likely that selective destruction of CMV-specialized immune cells is more likely to emerge as a branch of therapy before that happens, however.

Immunosenescence and Its Hallmarks: How to Oppose Aging Strategically? A Review of Potential Options for Therapeutic Intervention

Until a few decades ago, a very small fraction of the population would reach 80 years of age. Now this is a frequent event, with the average life expectancy for a newborn to have risen to 80 years in most Western European countries. However, the increase in lifespan does not coincide with increase in healthspan. The link between aging and disease is in part a reflection of the functional changes in the immune system of older people. Different factors contribute to the development of age-related immune dysfunction, but the epilog of an aged immune system is an increased propensity toward a reduced resistance to infection, poorer responses to vaccination, and the development of age-related diseases.

The analysis of the contributing factors to this profound immune remodeling has revealed a complex network of alterations that influence both innate and adaptive arms of the immune system. The diversity of cells, molecules and pathways involved in this remodeling, and their ability to influence each other, including the intra- and inter-individual variability of the immune response, make it hard to identify interventions that can be predicted to improve or, at least, to maintain the immune function in older adults. Within the past few years, numerous studies of the underlying mechanisms of age-related immune decline have laid the groundwork for the identification of targeted approaches, focusing on interventions able to target the hallmarks of immunosenescence.

Taking into account the role of HCMV in the decrease of naïve T cells and increase of memory T cells, the reduction of the latent/lytic viral load, by vaccination and/or antiviral drugs, should be beneficial to diminish HCMV-associated immunosenescence. As a result of 40 years of work, there are many candidate HCMV vaccines. Therefore, we know the antigens needed in a HCMV vaccine, and that vaccination can be protective. To reach the goal of an effective HCMV vaccine, now we need a concentrated effort to combine the important antigens and to generate durable responses that will protect for a significant period.

Further, Letermovir is an antiviral agent that inhibits HCMV replication by binding to components of the terminase complex. In patients undergoing hematopoietic stem cell transplantation, Letermovir daily prophylaxis is effective in preventing clinically significant HCMV infection when used through day 100 after transplantation, with only mild toxic effects and with lower all-cause mortality than placebo. However, there is no suggestion yet for the use of antiviral therapy as a strategy for prophylactic mitigation of immunosenescence.

Dogs as a Model of Human Aging

Dogs are an interesting species when it comes to the study of aging. Firstly they are much closer to human metabolism and cellular biochemistry than mice, and secondly selective breeding has generated lineages with a very wide range of sizes and life spans. Thirdly, they occupy a good compromise position in the range of life spans, study cost, and similarity to humans. Mice live short lives, so studies are rapid and comparatively cheap, but there are sizable, important differences between mouse and human biochemistry. Humans live so long that most studies of aging are simply out of the question. Even in non-human primates that live half or less as long as we do, a study of aging and calorie restriction has lasted for decades, and few organizations can or will commit to that sort of effort.

Interest has picked up in recent years in the dog as a model of aging, to be used in the development of therapies to slow or reverse progression of aging. This is illustrated by the activities of the Dog Aging Project, for example, which seeks to obtain data on mTOR inhibitor therapies via their use in companion animals. Given this increased interest, researchers have started to catalog the holes in present knowledge. Even though dogs are very well studied, there is plenty to room to improve the understanding of how the mechanisms of aging progress and are influenced by genetics in this species.

Genetic Pathways of Aging and Their Relevance in the Dog as a Natural Model of Human Aging

Several genes have been shown to affect the body size variability of dogs, which is unmatched by any other mammalian species. Importantly, dogs also show marked differences in their expected lifespan in connection with body mass. On average, giant sized breeds (above 50 kg) have an expected lifespan of 6-8 years, while small sized breeds (below 10 kg) can live up to 14-16 years. This wide range of expected lifespans, together with other aspects, has made dogs promising as model organisms for aging research. Despite the huge progress in understanding the genetic basis of morphological variability of dogs, still very little is known about the functional relevance of canine homologs of conserved longevity genes. Currently, this may stand as an obstacle in the way of effectively utilizing dogs as aging models. As dogs can provide unique insights into many aspects of human aging, the current lack of detailed information about the canine genetic pathways of aging should be overcome by future research approaches. In this review, we provide an overview of the evolutionary conserved biological mechanisms that contribute to aging, following the Hallmarks of Aging classification, and we summarize current knowledge about these pathways in dogs.

Genomic Instability

The DNA repair machinery involves divergent pathways, each aimed to correct certain forms of DNA damage. These protective mechanisms have been in the focus of cancer and aging research for a long time. Polymorphisms in several genes of the DNA damage response machinery have been linked to longevity in humans. Intriguingly, no canine progeria syndrome, resulting from DNA repair deficiency, has been documented in the scientific literature. On the other hand, several studies that investigated various forms of canine cancer revealed alterations in the DNA repair machinery, which corresponded to findings in human cancers. While these findings clearly promote the dog as a natural model of human cancers, it is still unclear how exactly variations in DNA repair capacity contribute to the expected lifespan of dogs.

Telomere Attrition

Telomere shortening is a characteristic only of somatic cells, while in germ line cells, telomere sequences are constantly restored by telomerase enzymes. The limited proliferative potential of somatic cells may seem disadvantageous for an individual, yet it may increase fitness by limiting the growth of malignant cells. Contrary to mice, dogs were reported to have low or no telomerase expression in normal somatic tissues, a pattern similar to that in humans. Tumors in dogs often showed high levels of telomerase expression, similarly to human malignancies. Although very little is known about the molecular mechanisms that regulate telomere maintenance and cell cycle arrest in dogs, such findings indicate that dogs may also share basic telomere biology with humans. Importantly, telomere length was shown to be variable across different dog breeds and was in correlation with expected lifespan. Also, telomere length in individual dogs was found to decrease with age, similarly as described in humans.

Epigenetic Alterations

Although age associated changes in chromatin structure and DNA methylation patterns have been reported in several model animals, there can be major differences between species. For example, epigenetic regulation in C. elegans seems to be limited to chromatin remodeling by histone modifications, limiting its utilization as a model to study epigenetic changes in aging. In dogs, an increasing body of evidence has suggested epigenetic regulation is behind species and breed-specific traits. Importantly, a recent study demonstrated that changes in methylation status in DNA regions, which were homologous to regions with known age-sensitive methylation patterns in humans, were in strong correlation with chronological age in dogs and wolves. This finding supported the applicability of the dog as a model of age-related epigenetic changes, while it also provided a molecular approach to determine the biological age of individual canines.

Disruption of Proteostasis

Chaperone proteins play an important role in the post-translational maturation of nascent proteins by facilitating their folding. They also function as protectors of mature proteins under various stressful conditions, by helping to maintain their natural conformation and by preventing aggregation. In dogs, the few studies that investigated chaperone proteins in relation to aging reported similar age-related changes as in humans. For example, blood levels of the Hsp70 chaperone were shown to decrease with age in dogs, similarly to what had been previously reported in humans.

Deregulation of Nutrient Sensing

Cellular metabolism, protein synthesis, and autophagy are strictly regulated by various signaling pathways. Most of these have evolved to synchronize cell growth and metabolism with nutrient availability; hence, they are often referred to as nutrient sensing pathways. Many of them converge on the target of rapamycin (TOR) kinase. Importantly, the function of mTOR can be efficiently inhibited by rapamycin, which is an already approved immunosuppressant in human medicine, and therefore has been proposed as a promising anti-aging compound to be used in humans. However, it was reported to cause severe side effects in medical dosages. Therefore, optimal dosages, which do not cause undesirable syndromes, yet still exert longevity promoting effects should be carefully determined in preclinical studies. Actually, pharmaceutical studies have already been initiated to investigate the effects of rapamycin on the lifespan of dogs.

Mitochondrial Dysfunction

Nutrient sensing pathways converge on the regulation of mitochondrial activity, as these organelles are the main sources of energy (in the form of adenosine triphosphate, ATP) in eukaryotic cells under normal circumstances, when enough oxygen is present. The availability of nutrients determines the rate of mitochondrial respiration, which, however, generates not only ATP but also chemical by-products, including reactive oxygen species. The oxidative burden created by mitochondria may be especially high in neurons, which solely depend on aerobic mitochondrial respiration as energy source. The role of mitochondrial dysfunction and increased oxidative burden in neural aging has been investigated in dogs. In general, dog brains were shown to accumulate oxidative damage with age. Several mitochondrial diseases are known in dogs, which have human homologs, such as the sensory ataxic neuropathy found in Golden Retriever dogs or the familial dilated cardiomyopathy in Doberman Pinschers. As several promising anti-aging drugs are likely to be tested in dogs in preclinical studies, looking into their effects on mitochondrial function and testing their possible interactions with mitochondrial genotypes can be highly relevant for humans.

Cellular Senescence

A marked elevation of senescent cell numbers was reported in old mice, although not in all tissues. Importantly, this accumulation process can result from both the increased generation of senescent cells and a decreased activity of macrophages that are able to eliminate aged or apoptotic cells from tissues. Little is known about the accumulation of senescent cells in canine tissues, although this phenomenon is also likely to show fundamental similarities with other mammalian species. As there is a growing interest toward pharmacological approaches to deplete senescent cells in tissues by specific apoptosis inducing agents (senolytic drugs), dogs may eventually be involved in testing these types of anti-aging interventions.

Stem Cell Exhaustion

Tissue renewal depends on the abundance and replicative capacity of tissue-specific stem cells. Hematopoietic stem cells (HSCs) were reported to have reduced replicative capacity in both aged mice and humans, mainly because of accumulating DNA damage. This reduction can explain the old age anemia of elderly people. Importantly, similar forms of age-associated changes in blood parameters, including anemia, were reported in dogs. Besides pharmacological interventions, stem cell therapy has also been suggested as a possible anti-aging intervention, with highlighted promises to treat certain forms of neurodegeneration. In this regard, stem cell therapy trials conducted on dogs affected by forms of neurodegeneration could represent a crucial step before progressing to human trials. In the case of the Golden Retriever model for Duchenne muscular dystrophy, successful stem cell-based interventions had actually preceded human clinical trials

Altered Intercellular Communication

In addition to hormones and metabolites, extracellular vesicles released by cells into the blood, called exosomes and ectosomes, have emerged as important transducers of various cellular signals. Consequently, exosomes may also modulate aging and neurodegeneration. Exosome research in dogs have been limited until recently. However, blood miRNA levels – which were hypothesized to be mainly found in exosomes – were reported to correlate with disease phenotypes in canine Duchenne muscular dystrophy. Similarly, miRNA content in circulating exosomes was shown to correlate with progression of secondary heart failure in cases of myxomatous mitral valve disease in dogs. Altogether, investigations about the connections between exosome content and aging or age-related pathologies in dogs may lead to the identification of diagnostic markers with potential translational prospects into human studies.

Libella Gene Therapeutics to Run a Patient Paid Trial of Telomerase Gene Therapy

After Bioviva Science, Libella Gene Therapeutics is the second company to take a run at commercializing telomerase gene therapy treatments for human use. Telomerase is the enzyme responsible for lengthening telomeres, repeated DNA sequences at the ends of chromosomes, though it may have other roles. Telomeres are a part of the mechanism that limits the number of times that a somatic cell can replicate. Telomeres shorten with each cell division, and when too short they trigger programmed cell death or cellular senescence followed by destruction by the immune system. Ordinary somatic cells in humans do not express telomerase; it is only present in stem cells, which can replicate indefinitely to supply tissues with new somatic cells with long telomeres. This split between a small privileged stem cell population and the vast majority of restricted somatic cells is how higher forms of animal life keep cancer risk low enough for evolutionary success. Obviously not low enough for comfort, but evolution was never about individual happiness.

Telomerase gene therapies have been demonstrated to extend life span and reduce cancer risk in mice. The former outcome is likely largely due to increased stem cell activity, while the latter outcome is somewhat counterintuitive: if damaged cells are pushed into more activity and replication that they would not normally have undertaken, won’t this raise the risk of cancerous mutations arising? It may be that improvements in immune function act to more than offset this risk – a primary task of the immune system is to destroy potentially cancerous cells before they have the chance to form a tumor. There is still some concern, in that mice have very different telomere and telomerase dynamics in comparison to humans. Will the balance of risk and improved function be the same in our species? The way we will find out is via brave volunteers trying the therapies, most likely, rather than any of the other, much slower options.

Neither Bioviva nor Libella took the standard regulatory path forward, opting for some combination of regulatory arbitrage and medical tourism to bring their therapies to patients. This sort of effort, carried out responsibly, is, I think, necessary and must spread if the present excesses of the FDA are to be reined in. The FDA sees its role as reducing risk to zero, at any and all cost, including the cost of slowing medical development to a crawl. Analyses have long shown that the cost in lives of this regulatory burden of slowed development far outweighs the benefits – but absent therapies are invisible and arouse no media outrage. Bureaucracies inevitably optimize to minimize visible problems. The only way to combat this issue effectively, given that working to change the system from within, and political advocacy to change the system from the outside, have been ongoing energetically for the past few decades, a time over which the financial burden imposed by the FDA has more than doubled, is to prove out a viable, responsible, cost-effective path to market outside the FDA system of regulation.

Libella Gene Therapeutics recently announced a patient paid trial to be held outside the US. Patient paid trials are unfairly excoriated by the research and regulatory establishment. As I have remarked upon in the past, they are an entirely legitimate approach to obtaining data. The chief objection is the lack of a control group in most such trials – but if we are only interested in large, reliable effect sizes, then the control group is the rest of the patient population, and that works just fine. In general, good therapies for aging, those that target relevant mechanisms in ways that will truly move the needle on life span, will indeed have large and reliable effects.

A second objection, more valid, is the sort of marketing that tends to accompany these trials. That is very much in evidence here, sadly. Libella should rein that in; in the long term it only harms the very necessary development of reliable, well-defined pathways for regulatory arbitrage. Telomerase gene therapies are not a cure for aging. They are a compensatory or enhancement therapy that addresses one of the downstream consequences of aging, while having little to no effect on a wide range of other important issues, such as accumulation of persistent metabolic waste in long-lived cells. No amount of telomerase will enable the body to break down harmful compounds that it cannot break down even in youth. Further, no-one has yet demonstrated that you can reverse, say, even an epigenetic clock measure by 20 years in humans using telomerase gene therapy. Even if you could, one can’t say that this corresponds to 20 years of rejuvenation, given how little is known of what exactly these clocks measure. These sorts of claims are just aggravating. I understand the need for marketing, but one can carry out good marketing without having to resort to this sort of thing.

The Libella Gene Therapeutics trial will likely make waves because of the cost, at 1 million per patient. This is, however, a systemically administered gene therapy using AAV as the vector, stacked with one of the new biotechnologies that can reduce the ability of neutralizing antibodies to destroy the viral particles. If Libella is manufacturing to one of the usual Good Manufacturing Practice (GMP) standards, it is likely that the overwhelming majority of that 1 million cost is the cost of manufacture. AAV, while the most popular vector in the gene therapy development community, remains enormously expensive to manufacture. For a point of comparison, there is a systemically administered viral gene therapy for an inherited disease that is used in newborns, where it requires a 100,000 square foot facility 40 days to produce one dose. That costs more than 2 million. Everyone in the industry agrees that this situation must change and will change, that there will be disruptive advances in cost and efficiency, just as happened for monoclonal antibodies – but it hasn’t happened yet.

Breakthrough Gene Therapy Clinical Trial is the World’s First That Aims to Reverse 20 Years of Aging in Humans

Libella Gene Therapeutics, LLC (“Libella”) announces an institutional review board (IRB)-approved pay-to-play clinical trial in Colombia (South America) using gene therapy that aims to treat and ultimately cure aging. This could lead to Libella offering the world’s only treatment to cure and reverse aging by 20 years. Under Libella’s pay-to-play model, trial participants will be enrolled in their country of origin after paying 1 million. Participants will travel to Colombia to sign their informed consent and to receive the Libella gene therapy under a strictly controlled hospital environment.

Bill Andrews, Ph.D., Libella’s Chief Scientific Officer, has developed an AAV gene therapy that aims to lengthen telomeres. The AAV gene therapy delivery system has been demonstrated as safe with minimal adverse reactions in about 200 clinical trials. Dr. Andrews led the research at Geron Corporation over 20 years ago that initially discovered human telomerase and was part of the team that led the initial experiments related to telomerase induction and cancer.

Telomerase gene therapy in mice delays aging and increases longevity. Libella’s clinical trial involves a new gene-therapy using a proprietary AAV Reverse (hTERT) Transcriptase enzyme and aims to lengthen telomeres. Libella believes that lengthening telomeres is the key to treating and possibly curing aging. On why they decided to conduct its project outside the United States, Libella’s President, Dr. Jeff Mathis, said, “Traditional clinical trials in the U.S. can take years and millions, or even billions, in funding. The research and techniques that have been proven to work are ready now. We believe we have the scientist, the technology, the physicians, and the lab partners that are necessary to get this trial done faster and at a lower cost in Colombia.”

A Role for B Cells in the Chronic Inflammation Generated by Visceral Fat Tissue

Much of the long-term harm caused by excess visceral fat tissue is due to raised levels of chronic inflammation, the inappropriate over-activation of the immune system characteristic of both obesity and aging. Chronic inflammation accelerates the progression of near all of the common age-related conditions. There are numerous mechanisms via which fat tissue rouses an immune response: cellular debris that triggers immune cells into action; generation of excessive numbers of senescent cells; inappropriate signaling from fat cells that mimics the response to infection; infiltration of inflammatory macrophages into fat tissue; and so forth. Researchers here investigate some of the details of the way in which the immune system interacts with visceral fat, focusing on a role for B cells in spurring the inflammation that results.

Previous work found that as people age, their body’s ability to generate energy by burning belly fat is reduced. Consequently, fat that surrounds the internal organs increases in the elderly. Researchers had found that the immune cells necessary to the fat-burning process, called macrophages, were still active but their overall numbers declined as belly fat increased with aging. This latest study found that something else is happening as well. Adipose B cells in belly fat unexpectedly proliferated as animals aged, contributing to increased inflammation and metabolic decline. “These adipose B cells are a unique source of inflammation. Normally the B cells produce antibodies, and defend against infection. But with aging, the increased adipose B cells become dysfunctional, contributing to metabolic disease.”

When they are working correctly, some B cells expand as needed to protect the body from infection, and then contract to baseline. But with aging, they don’t contract in belly fat. This predisposes to diabetes and metabolic dysfunction like inability to burn fat. Researchers theorizes that this ongoing expansion may be due to increased human life expectancy – a pushing of the body’s cells beyond their evolutionary limits. Researchers discovered that adipose B cells expand by receiving signals from nearby macrophages. Relatedly, they found that by reducing the macrophage signal and by removing adipose B cells, they could reverse the expansion process, and protect against age-induced decline in metabolic health.

A Mechanism by which Cellular Senescence Drives Pulmonary Fibrosis

The lingering senescent cells that accumulate with age are an important contributing cause of degenerative aging. If nothing else, their secretions generate a significant fraction of the chronic inflammation of aging, disrupting tissue function and immune function. Chronic inflammation is in turn well known to accelerate all of the most common age-related conditions. Fibrosis is a consequence of dysfunctional tissue maintenance and regeneration, in which scar-like deposits form, degrading tissue function. There is good evidence for fibrotic diseases, such as those of the lung, kidney, and heart, to be driven in large part by the presence of senescent cells. This is good news for patients, as while there is little that can be done to treat these conditions in the practice of medicine at the present time, senolytic therapies to clear senescent cells may well help to turn back fibrosis.

Accumulation of senescent cells is associated with the progression of pulmonary fibrosis but mechanisms accounting for this linkage are not well understood. To explore this issue, we investigated whether a class of biologically active profibrotic lipids, the leukotrienes (LT), is part of the senescence-associated secretory phenotype. The analysis of conditioned medium (CM) lipid extracts and gene expression of LT biosynthesis enzymes revealed that senescent cells secreted LT regardless of the origin of the cells or the modality of senescence induction.

The synthesis of LT was biphasic and followed by anti-fibrotic prostaglandin (PG) secretion. The LT-rich CM of senescent lung fibroblasts induced pro-fibrotic signaling in naïve fibroblasts, which were abrogated by inhibitors of ALOX5, the principal enzyme in LT biosynthesis. The bleomycin-induced expression of genes encoding LT and PG synthases, level of cysteinyl leukotriene in the bronchoalveolar lavage, and overall fibrosis were reduced upon senescent cells removal either in a genetic mouse model or after senolytic treatment. Quantification of ALOX5+cells in lung explants obtained from idiopathic pulmonary fibrosis (IPF) patients indicated that half of these cells were also senescent (p16Ink4a+). Unlike human fibroblasts from unused donor lungs made senescent by irradiation, senescent IPF fibroblasts secreted LTs but failed to synthesize PGs.

This study demonstrates for the first time that senescent cells secrete functional LTs, significantly contributing to the LTs pool known to cause or exacerbate idiopathic pulmonary fibrosis.

Against Senolytics

There is no consensus in science that is so strong as to have no heretics. So here we have an interview with a naysayer on the matter of senolytic treatments, who argues that the loss of senescent cells in aged tissues will cause more harm to long-term health than the damage they will do by remaining. To be clear, I think this to be a ridiculous argument given the present evidence. To make it one has to declare the existing results showing extension of healthy life span in mice to be something other than credible data, which just isn’t the case. Further, it seems shaky on theoretical grounds to suggest that removal of something like 1% of cells will put onerous stress on the remaining 99%, particularly given that the 1% were contributing to declining stem cell activity via inflammatory signaling. All told, it is hard to take seriously the idea that loss of senescent cells can possibly produce greater degrees of dysfunction in tissue than is caused by the inflammatory signaling of senescent cells.

Your new review on senolytics suggests that senolytics may cause more harm than good. Can you summarize your objections and concerns?

Here is the argument: 1) theoretically, senolytics should make things worse and 2) the available data support this theoretical concern. To use an analogy, imagine that you have a factory in which 10 of the 100 factory workers are feeling overworked and tired. Furthermore, their complaints are disrupting the other workers. You have two possible interventions. You can: (a) Fire the 10 workers, thereby removing the complainers. The result is that the remaining 90 workers are now overworked, and they, too, begin to complain. You end up with 30 workers who are now complaining and disrupting your factory. This is the senolytic approach. (b) Improve the health and conditions of the 10 workers who are overworked and complaining. You now have 100 workers who are doing an excellent job. This is the telomerase therapy approach.

In the first case, your factory has a problem and you make it worse. In the second case, your factory has a problem and you solve the problem. This figure from my new paper illustrates the same point in terms of nine cells subjected to senolytics, with the result being temporary short-term improvement followed by decline and a worse situation than we started with.

This does not take into account the idea of replacing that pool of “workers” by bringing in fresh stem cells.

You have to keep a few points in mind. 1) Will the stem cells populate as desired? 2) If you do get a stem cell population, that requires cell division, which shortens telomeres, which accelerates cell senescence, and once again you have accelerated pathology. 3) Why would you bother recruiting stem cells when you can much more easily reset cell senescence in the resident cells of the tissue? 4) The long-term data (what there is of it) supports the failure of senolytics. Again: remember where those “new cells” come from: you are accelerating senescence in the stem cell pool. The only way to “replace them with healthy working cells” is to simply and effectively reset gene expression, taking senescing cells and turning them into functionally young cells.

It seems that we can only speculate on these issues, as these long-term follow-ups have not yet been done. However, senolytics have been shown to increase median lifespan and healthspan in murine models.

I don’t see any credible data that supports the contention that “senolytics have been shown to increase median lifespan and healthspan in murine models”.

Cellular Senescence May Contribute to Rheumatoid Arthritis in Younger Patients

Senescent cells are a cause of aging, and much of the present focus in the study of cellular senescence is thus on targeting and destroying these unwanted cells in order to treat aging. However, a comparatively recent and intriguing finding is that at least some autoimmune diseases, such as type 1 diabetes, involve cellular senescence. The question at present is whether or not this true for all forms of autoimmunity.

An autoimmune condition must have a trigger, something that prompts the immune system to attack healthy tissues, and it is possible that many different triggers converge on the generation of senescent cells, with their ability to rouse the immune system to action via inflammatory secretions. Here, researchers provide evidence for cellular senescence to be involved in rheumatoid arthritis, but only in younger patients. Rheumatoid arthritis is one of the less well understood autoimmune conditions: it remains unclear as to why it occurs. It may well turn out to be several similar conditions with quite different causes, given the wide variety of patient experiences.

Tissue accumulation of senescent cells has been identified as a deleterious factor that promotes inflammation and tissue damage in different human diseases and animal models of aging related diseases. Regarding joint diseases, evidence of this concept has been only provided in human and experimental osteoarthritis (OA), with the main focus on chondrocytes and cartilage damage. Human cartilage and chondrocyte cultures from OA patients have shown increased number of senescent cells that contribute to cartilage degradation by increased IL-1, IL-6, and MMP-3 expression.

The expression of the senescence marker p16INK4a (p16) was analyzed by immunohistochemistry in rheumatoid arthritis (RA), osteoarthritis (OA), and normal synovial tissues from variably aged donors. The proportion of p16(+) senescent cells in normal synovial tissues from older donors was higher than from younger ones. Although older RA and OA synovial tissues showed proportions of senescent cells similar to older normal synovial tissues, senescence was increased in younger RA synovial tissues compared to age-matched normal synovial tissues. The percentage of senescent SA-β-gal(+) synovial fibroblasts after 14 days in culture positively correlated with donor’s age.

Accumulation of senescent cells in synovial tissues increases in normal aging and prematurely in RA patients. Senescence of cultured synovial fibroblasts is accelerated upon exposure to TNFα or oxidative stress and may contribute to the pathogenesis of synovitis by increasing the production of pro-inflammatory mediators.

Targeting α-Synuclein in the Gut to Turn Back the Progression of Parkinson’s Disease

Like most neurodegenerative conditions, Parkinson’s disease is driven in large part by the pathological aggregation of misfolded proteins, in this case α-synuclein. These solid deposits of protein spread from cell to cell, and are accompanied by a surrounding halo of harmful biochemical interactions. There is evidence for the protein aggregation of Parkinson’s disease to start in the gut and then spread to the brain. You might look at a recent paper that discusses whether or not we should consider Parkinson’s to be two diseases with a similar outcome, one in which the α-synuclein aggregation originates in the gut, and the other in which it originates in the brain. In the research noted here, scientists are following the gut origin hypothesis and targeting α-synuclein there in order to slow or reverse the progression of Parkinson’s disease.

Aggregates of the protein alpha-synuclein arising in the gut may play a key role in the development of Parkinson’s disease (PD). Investigators are testing the hypothesis that by targeting the enteric nervous system with a compound that can inhibit the intracellular aggregation of alpha-synuclein, they can restore enteric functioning in the short term, and possibly slow the progressive deterioration of the central nervous system in the long term. “The concept is that aggregates of the protein alpha-synuclein, thought to play a key role in the disease, arise within the enteric nervous system (ENS) and travel up the peripheral nerves to the central nervous system (CNS) where they ultimately cause inflammation and destruction of parts of the brain. Targeting the formation of alpha-synuclein aggregates in the ENS may therefore slow the progression of the disease.”

Alpha-synuclein is one of the defensive proteins produced by enteric nerves when they encounter infections. In children with acute bacterial gastrointestinal (GI) infections, for example, intestinal nerves produce alpha-synuclein. In children who have undergone intestinal transplants and who are prone to GI infections, investigators have shown that enteric neurons start making alpha-synuclein at the time of acute viral infections, and this outlasts the infection by many months, protecting nerve cells for prolonged periods of time. Within a nerve cell, alpha-synuclein could envelop invading viruses and disrupt their replication. It could also attach itself to small vesicles containing neurotransmitters and be released from the nerve cell hitching a ride with them. Once on the outside, it can attract protective immune cells from surrounding tissues.

To determine whether targeting alpha-synuclein within enteric neurons might help patients with PD, researchers are currently conducting clinical trials with a compound called ENT-01, a synthetic derivative of squalamine, a compound originally isolated from dogfish bile. It displaces alpha-synuclein from nerve cell membranes and restores the normal electrical activity of enteric neurons. Investigators completed a 50-patient Phase 2a study (RASMET) in patients with PD in 2018, which corrected constipation, a common symptom of PD, in more than 80% of participants, with the dose titrated up for each patient until a response was obtained. “The RASMET study demonstrated that the ENS is not irreversibly damaged in patients with PD. We believe that this is the first demonstration of the reversal of a neurodegenerative process in humans.” Possible benefits were also observed in motor and non-motor symptoms such as hallucinations, depression, and cognitive function. A 110-patient double-blind, placebo-controlled Phase 2b trial (KARMET) evaluating the effect of oral ENT-01 tablets on constipation and neurologic symptoms is currently being conducted.

Greater Physical Fitness Correlates with Lower Risk of Dementia

It is well established that exercise and physical fitness correlate well with reduced incidence of all of the common age-related diseases, and reduced mortality risk. It is hard to establish causation from the contents of human epidemiological databases, but the analogous animal studies convincingly demonstrate that exercise improves health. There is no reason to expect humans to be all that different in this matter. Here, researchers show that, much as expected, greater fitness correlates with reduced risk of dementia. Of note, patients that improved their fitness over the years of later life exhibited reduced disease risk and improved life expectancy.

Cardiorespiratory fitness is associated with risk of dementia, but whether temporal changes in cardiorespiratory fitness influence the risk of dementia incidence and mortality is still unknown. We aimed to study whether change in estimated cardiorespiratory fitness over time is associated with change in risk of incident dementia, dementia-related mortality, time of onset dementia, and longevity after diagnosis in healthy men and women at baseline. We linked data from the prospective Nord-Trøndelag Health Study (HUNT) with dementia data from the Health and Memory Study and cause of death registries (n=30,375). Included participants were apparently healthy individuals for whom data were available on estimated cardiorespiratory fitness and important confounding factors.

Cardiorespiratory fitness was estimated on two occasions 10 years apart, during HUNT1 (1984-86) and HUNT2 (1995-97). HUNT2 was used as the baseline for follow-up. Participants were classified into two sex-specific estimated cardiorespiratory fitness groups according to their age (10-year categories): unfit (least fit 20% of participants) and fit (most fit 80% of participants). To assess the association between change in estimated cardiorespiratory fitness and dementia, we used four categories of change: unfit at both HUNT1 and HUNT2, unfit at HUNT1 and fit at HUNT2, fit at HUNT1 and unfit at HUNT2, fit at both HUNT1 and HUNT2. Using Cox proportional hazard analyses, we estimated adjusted hazard ratios (AHR) for dementia incidence and mortality related to temporal changes in estimated cardiorespiratory fitness.

During a median follow-up of 19.6 years for mortality, and 7.6 years for incidence, there were 814 dementia-related deaths, and 320 incident dementia cases. Compared with participants who were unfit at both assessments, participants who sustained high estimated cardiorespiratory fitness had a reduced risk of incident dementia (AHR 0.60) and a reduced risk of dementia mortality (AHR 0.56). Participants who had an increased estimated cardiorespiratory fitness over time had a reduced risk of incident dementia (adjusted hazard ratio 0.52) and dementia mortality (adjusted hazard ratio 0.72) when compared with those who remained unfit at both assessments. Each metabolic equivalent of task increase in estimated cardiorespiratory fitness was associated with a risk reduction of incident dementia (AHR 0.84) and dementia mortality (AHR 0.90). Participants who increased their estimated cardiorespiratory fitness over time gained 2.2 dementia-free years, and 2.7 years of life when compared with those who remained unfit at both assessments.

7-Ketocholesterol as a Contributing Cause of Multiple Age-Related Diseases

One noteworthy difference between the biochemistry of young and old individuals is a greater presence of oxidative molecules, resulting from dysfunctional cells, inflammatory processes, and other issues. As a consequence, there are also many more oxidized molecules, changed from their original structure and now either broken or actively harmful. Cells clear out this sort of oxidative damage constantly, and are quite efficient at this sort of maintenance until levels of oxidization become high, but they nonetheless struggle with some particularly toxic or resilient oxidized molecules, even in smaller amounts. A good example of the type is 7-ketocholesterol, a form of oxidized cholesterol. It is primarily understood as an important contributing cause of atherosclerosis via its detrimental effects on the macrophages responsible for clearing lipids from blood vessel walls, but there is evidence for it to contribute to other age-related conditions as well.

Cholesterols exist both inside and outside of the cell, as they are important components of all cellular membranes, but these and other nonpolar substances are transported in the plasma via lipoprotein particles. Low density lipoprotein (LDL) is the principle carrier of cholesterol to peripheral tissue. All of the components of LDL are susceptible to oxidation to produce an oxidized form of LDL (OxLDL). OxLDL has been linked to a variety of pathologies. Oxidation of the cholesterol in LDL produces several oxidation products including 7-ketocholesterol (7KC), which is the most abundant oxysterol present in OxLDL. We believe that it is important to distinguish between the effects of OxLDL and that of unsequestered 7KC, as many studies fail to account for this important difference in how 7KC interacts with the cell.

OxLDL is not the only source of 7KC within the body. 7KC can be produced endogenously by a series of oxidation or, much less commonly, enzymatic reactions. It can also be ingested directly in food, however the liver is well equipped to process and rid the body of exogenous toxins, so 7KC is not acutely poisonous to ingest. However, endogenously produced, unsequestered 7KC can wreak havoc inside of most cells. Unesterified 7KC can be found within membranes of organelles where it disrupts fluidity and signaling pathways, causing cellular damage via multiple stress-response pathways. These stress-response pathways induce a vicious cycle by increasing the population of reactive oxygen species, which in turn increases the oxidation of cholesterol and production of 7KC. Particularly in people with already-compromised cholesterol pathways, 7KC buildup can be overwhelming and cause significant damage to membranes, pathways, and overall cell function.

7KC is the most abundant oxysterol in both oxLDL particles and atherosclerotic plaques, indicating the significant role 7KC plays in the progression of atherosclerosis. 7KC has been shown to induce macrophage reprogramming, foam cell formation, and oxiapoptophagy in a multitude of cell types. In atherosclerotic plaques, this results in the deposition of calcium-laden apoptotic bodies, leading to subsequent calcification of the blood vessel.

It has been shown that oxysterols are likely a cause of altered brain cholesterol metabolism which is an integral part of Alzheimer’s disease, Parkinson’s disease, and other aspects of neurological aging. It is not yet fully understood whether 7KC can cross the blood-brain barrier, but 7KC is highly toxic to neuronal cells and should certainly form spontaneously inside of them with age. Additionally, 7KC is implicated in macular degeneration as it is a major component of the drusen within the retina. 7KC can also damage the liver by disrupting membrane rafts and fenestrations. Lastly, 7KC is also characterized in congenital disorders such as sickle cell, Niemann Pick, and other lysosomal storage disorders. Ambiguous links between many of these diseases, particularly atherosclerosis and neurodegeneration, further implicates 7KC as an unexplored target in many diseases.

We propose that 7KC could be an effective therapeutic target due to its implication in a wide variety of diseases. Although the abundance of 7KC has not yet been strongly correlated to aging or the severity of different pathologies, there is clear evidence to show its destructiveness in biological systems. As more studies are conducted on toxic oxysterols in aging and disease, we hope that more will become known about 7KC abundance in different cells and tissues. This would increase the potential of 7KC as a therapeutic target for various diseases, especially those specifically associated with aging. Considering nonenzymatic oxysterol accumulation, particularly 7KC, as an integral factor in disease progression could change the way we identify and treat these diseases, offering new and possibly broadly effective therapeutics.

The Aged Adaptive Immune System is Strange

The adaptive immune system of an older person is a very different beast in comparison to that of the younger self. It has lost the supply of new T cells due to atrophy of the thymus, and the remaining population of T cells becomes ever more damaged, misconfigured, strange, and different. The immune system as a whole is complex enough to still be hiding many unexplored details, even in this era of biotechnology. Here, researchers outline a novel discovery in the immune function of supercentenarians. It seems that at very advanced ages, some T cells start to undertake radical shifts in function in order to compensate somewhat for the growing lack of capacity. It remains to be seen whether or not this only occurs to a significant degree in a minority of the population, and is thus a feature of supercentenarians because it increases the odds of survival.

Supercentenarians, people who have reached 110 years of age, are a great model of healthy aging. Their characteristics of delayed onset of age-related diseases and compression of morbidity imply that their immune system remains functional. Here we performed single-cell transcriptome analysis of 61,202 peripheral blood mononuclear cells (PBMCs), derived from 7 supercentenarians and 5 younger controls. We identified a marked increase of cytotoxic CD4 T cells as a signature of supercentenarians. This characteristic is very unique to supercentenarians, because generally CD4 T cells have helper, but not cytotoxic, functions under physiological conditions. Furthermore, single-cell T cell receptor sequencing of two supercentenarians revealed that cytotoxic CD4 T cells had accumulated through massive clonal expansion, with the most frequent clonotypes accounting for 15-35% of the entire CD4 T cell population.

The cytotoxic CD4 T cells exhibited substantial heterogeneity in their degree of cytotoxicity as well as a nearly identical transcriptome to that of cytotoxic CD8 T cells. This indicates that cytotoxic CD4 T cells utilize the transcriptional program of the CD8 lineage while retaining CD4 expression. Indeed, cytotoxic CD4 T cells extracted from supercentenarians produced IFN-γ and TNF-α upon ex vivo stimulation. Our study reveals that supercentenarians have unique characteristics in their circulating lymphocytes, which may represent an essential adaptation to achieve exceptional longevity by sustaining immune responses to infections and diseases.

Evidence for Inflammation to Drive Tau Pathology in Alzheimer’s Disease

Researchers here provide evidence for the aggregation of altered forms of tau protein in the aging brain, and the resulting death of neurons, to be driven by chronic inflammation. This is good news if true, given recent work carried out in animal models of tauopathy, in which clearance of inflammatory, senescent glial cells in the brain was achieved via the use of senolytic drugs. The result was a marked reduction in both inflammation and tau pathology. To the degree that senescent cells in the brain prove to be the major cause of the chronic inflammation of aging and neurodegenerative conditions, it may well turn out that senolytic drugs will do a great deal for Alzheimer’s patients. Since the senolytic drug dasatinib is off-patent, crosses the blood brain barrier, and is well tested for human use, trials could in principle begin just as soon as a sponsoring organization emerges and chooses to start.

Tau proteins usually stabilize a neuron’s cytoskeleton. However, in Alzheimer’s disease, frontotemporal dementia (FTD), and other tauopathies these proteins are chemically altered, they detach from the cytoskeleton and stick together. As a consequence, the cell’s mechanical stability is compromised to such an extent that it dies off. In essence, tau pathology gives neurons the deathblow. The current study provides new insights into why tau proteins are transformed. As it turns out, inflammatory processes triggered by the brain’s immune system are a driving force.

A particular protein complex, the NLRP3 inflammasome, plays a central role for these processes. It is a molecular switch that can trigger the release of inflammatory substances. For the current study, the researchers examined tissue samples from the brains of deceased FTD patients, cultured brain cells, and mice that exhibited hallmarks of Alzheimer’s and FTD. In particular, the researchers discovered that the inflammasome influences enzymes that induce a hyperphosphorylation of tau proteins. This chemical change ultimately causes them to separate from the scaffold of neurons and clump together. “It appears that inflammatory processes mediated by the inflammasome are of central importance for most, if not all, neurodegenerative diseases with tau pathology.”

This especially applies to Alzheimer’s disease. Here another molecule comes into play: amyloid beta (Aβ). In Alzheimer’s, this protein also accumulates in the brain. In contrast to tau proteins, this does not happen within the neurons but between them. In addition, deposition of Aβ starts in early phases of the disease, while aggregation of tau proteins occurs later. The results of the current study support the amyloid cascade hypothesis for the development of Alzheimer’s. According to this hypothesis, deposits of Aβ ultimately lead to the development of tau pathology and thus to cell death. The study shows that the inflammasome is the decisive and hitherto missing link in this chain of events, because it bridges the development from Aβ pathology to tau pathology. Thus, deposits of Aβ activate the inflammasome. As a result, formation of further deposits of Aβ is promoted. On the other hand, chemical changes occur to the tau proteins resulting into their aggregation.

The Dog Aging Project Forges Ahead with a Large Study

As noted here by the Life Extension Advocacy Foundation, the Dog Aging Project researchers are moving ahead with a large study of companion animals. While much of the study is observational, a sizable cohort will be treated with the mTOR inhibitor rapamycin. Dogs are much closer to humans than mice, so it will be interesting to see what results. Given what is known of the way in which stress response upregulation behaves in different species, we would expect to see similar effects on cellular biochemistry – such as upregulation of autophagy – but smaller relative gains in life span in dogs versus mice. Short-lived species have a much greater plasticity of life span in response to environmental circumstances than longer-lived species, something that probably has its roots in adaptation to seasonal famine. A mouse must extend its reproductive life span by a larger proportion than a dog or a human in order to pass through a famine and carry on its lineage on the other side.

The Dog Aging Project has kicked into high gear and is recruiting 10,000 of our furry friends in what will be the largest dog aging study in history. The researchers hope that the study will also reveal more about human aging and longevity. The National Institute on Aging is funding the 23 million project, which will see a vast amount of data being collected during the five years that the project will run for. The research team will be collecting data such as vet records, DNA samples, gut microbiome samples, and information on diet and exercise.

The study chose to use dogs as they share many things with us humans, including living in the same environment and similar biology, and they even develop many age-related diseases that we do. The dogs in the study will continue to live at home and enjoy their usual daily lives, and the study will include dogs of all ages, sizes, and breeds, including mutts. To be part of the study, owners will have to complete periodic surveys, take their dogs to a vet once a year for examination, and possibly have to make extra visits for additional tests. A panel of animal welfare advisors will be involved in the study to ensure that the participants are treated well. The data from the study will be made available publicly, which is great news for open science and knowledge sharing.

Five hundred lucky pooches will also be given rapamycin, which appears to slow down aging according to various mouse studies; the hope is those results will translate to the dogs in this study. Rapamycin is an immune system suppressant and is currently used in humans to prevent organ rejection during transplants. However, in smaller doses in mouse studies, it has been shown to increase lifespan. A pilot safety study in dogs found no serious side effects.

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