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Slower DNA Damage Accumulation in Immune Cells Correlates with Species Life Span

Slower DNA Damage Accumulation in Immune Cells Correlates with Species Life Span

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Today’s open access research is an assessment of DNA damage accumulation in a variety of species, showing the pace of mutational damage correlates with species life span, at least as assessed here in immune cells from blood samples, and using a marker that identifies the response to short telomeres as well as forms of DNA damage. The DNA of the cell nucleus, the genetic blueprint for near all of the proteins produced in a cell, accumulates damage over time due to the normal haphazard chemical reactions that take place constantly inside cells. These mutational changes are largely irrelevant to cellular operation, but some can cause disruption in metabolism, or, worse, make a cell cancerous, by causing certain proteins to be produced in a broken or altered state. Near all mutational damage to DNA is quickly repaired by the highly efficient array of DNA repair mechanisms that a cell is equipped with. But some inevitably slips past.

The way in which mutation leads to cancer is fairly straightforward, but it is less obvious as to how random mutation in single cells can contribute meaningfully to other aspects of aging, such as widespread tissue dysfunction. The present consensus is that the important mutations are those that occur in stem cells and progenitor cells, able to spread widely throughout a tissue via the replication of daughter somatic cells created by those stem cells and progenitor cells. It was also recently suggested that DNA damage, even when repaired, and more or less regardless of what is damaged in DNA, leads to epigenetic changes characteristic of aging, and these epigenetic changes are what causes cell function to decline. In this view, a larger amount of unrepaired DNA damage, the marker usually measured, is indicative of the true cause of harm, which is more frequent DNA repair and thus epigenetic change.

The authors here are primarily focused on DNA damage markers that occur due to critically short telomeres in additional to mutational damage. Average telomere length in tissues, and the fraction of cells with critically short telomeres, is most likely downstream of stem cell function. Telomeres shorten inexorably with each cell division in somatic cells, and cells eventually self-destruct, or become senescent and are destroyed by the immune system. Stem cells use telomerase to maintain long telomeres, and deliver daughter somatic cells with long telomeres into tissues to make up the losses. So telomere length in tissues is a function of how rapidly cells divide and how frequently replacement cells are delivered by the supporting stem cell population – the pace of the latter is well known to decline with age.

Slower rates of accumulation of DNA damage in leukocytes correlate with longer lifespans across several species of birds and mammals


Different species have very different lifespans ranging from less than 1 day for mayflies to more than 400 years for the Greenland shark. However, the exact cause of these differences in longevity are still largely unknown. Our group recently showed that the rate of telomere shortening with age correlates with lifespan in a variety of species from birds to mammals. Species with very fast telomere shortening rates such as mice have very short lifespans, and species with very slow telomere shortening rates such as humans have very long lifespans. It is interesting to note that species that share a similar longevity in spite of being evolutionarily distant like flamingos and elephants, also show a similar rate of telomere shortening, while evolutionarily closer species like mice and elephants, show very different longevities and also have very different rates of telomere shortening.

These findings suggest that longevity can be determined, at least in part, by epigenetic traits, such as the rate of telomere shortening. Furthermore, these findings pose the interesting question of which is the molecular determinant by which higher telomere shortening rates lead to shorter longevities. An obvious answer is that higher rates of telomere shortening will be associated to faster accumulation of critically short/dysfunctional telomeres, which are known to contribute to activation of a persistent DNA damage response stemming from telomeres, which leads to loss of cell viability and aging phenotypes. Thus, species that shorten telomeres at faster rates will reach telomere exhaustion and trigger a persistent DNA damage response earlier than those species that are able to maintain telomeres protected for a longer period of time. A short/dysfunctional telomere is recognized by the cell as an irreparable DNA double strand break (DSB), triggering a persistent DNA damage response which results in phosphorylation of γH2AX, and which eventually leads to cell death and/or senescence. In turn, induction of cellular senescence either owing to critically short telomeres or to other insults is also associated with increased γH2AX levels, involving in some instances the mTOR pathway. Thus, accumulation of cells with DNA damage throughout lifespan should also correlate with species longevity.

Here, we find that increased global rates of DNA damage, as determined by the DNA damage marker γH2AX which detects occurrence of double stranded DNA breaks in the genome, inversely correlates with species longevity. In particular, we determined here the rates of increase of the DNA damage marker γH2AX in leukocytes of phylogenetically distant species of birds and mammals in parallel and using the same experimental method. Previous studies have also shown a correlation between certain types of DNA damage and aging. Indeed, DNA damage accumulation with aging and telomere shortening may be related processes. Critically short telomeres as the result of cell proliferation throughout life to repair damaged tissues trigger a DNA damage signal specifically at telomeres.

We also measured the percentage of short telomeres of the species in this study, and we found that all of the species showed an increase in the percentage of short telomeres with age. This result is concomitant with the fact that average telomere length shortens with age in many species. Several studies have suggested that the percentage of short telomeres is more indicative of health and senescence than average telomere length. The percentage of short telomeres is an important metric since it is the length of the shortest telomere in a cell that induces a DNA damage response and cell senescence rather than the average telomere length of the telomeres on all of the chromosomes. Here we also noticed a mild trend for species with longer maximum lifespans to have a lower rate of increase of percent short telomeres, thus accumulating short telomeres more slowly with age. We also observed that species with the highest rates of γH2AX increase have the highest rates of increase of percent short telomeres with age. These results make a connection between γH2AX DNA damage, short telomeres, and lifespan. As cells accumulate DNA damage and short telomeres, they will enter into a state of senescence, thus accelerating the aging process and shortening lifespan.

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Topical Rapamycin Evaluated as a Treatment for Skin Aging

Topical Rapamycin Evaluated as a Treatment for Skin Aging

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Given the attention that descends upon any prospect of reversing skin aging, I should probably open by saying that much of the data here for extended low dose topical treatment with rapamycin over eight months, that regarding visible skin aging and collagen production, is no more exciting than that obtained by any number of other approaches, such as topical application of keratinocyte growth factor (KGF). Effect sizes are the only thing that matters, and also the one thing that all too many observers fail to consider. Looking at the paper, I would say that the primary point of interest is the 50% reduction in markers of cellular senescence in skin. Given what is known of rapamycin this seems unlikely to be a senolytic effect, so not destruction of existing senescent cells, but rather a reduction in the number of cells becoming senescent. This in turn suggests that there remains some meaningful level of ongoing natural clearance of lingering senescent cells at older ages.


This study demonstrates a clear impact of rapamycin treatment on both the molecular signature associated with senescence and the clinical signs of aging in the skin. These data support the idea that a reduction in the burden of senescent cells underlies these improvements. The results could reflect a modification of the senescent cells present in the skin or a reduction in the number of senescent cells. Although rapamycin has been shown to reduce pro-inflammatory secretions produced by senescent cells, the fact that p16INK4A is reduced suggests that the absolute number of senescent cells in the epidermis is reduced. This implies that rather than simply modifying senescent cells present in the tissue, rapamycin treatment is either reducing the number of cells entering senescence or increasing the clearance of senescent cells. Based on our studies demonstrating that rapamycin prevents the senescence transition and improves functionality in vitro, we favor the concept that rapamycin reduces entry into senescence, but we cannot rule out an additional role for clearance of senescent cells. Whether the reduction in senescent cells is due to reduced entry or increased clearance, a reduction in the burden of senescent cells would be expected to improve functionality.

Senescent cells produce pro-inflammatory cytokines, matrix metalloproteins, and reduced levels of anti-angiogenic factors, creating a secretory profile known as the Senescence-Associated Secretory Phenotype (SASP). Thus, we anticipate that rapamycin treatment reduces inflammatory cytokines in the skin, although the verification of this change represents a technical challenge due to the fact that such cytokines are present in picomolar amounts. One quantifiable aspect of skin biology that is improved by the rapamycin treatment is the incorporation of collagen VII into the basement membrane, which represents a functional measure of skin quality that is improved upon treatment with rapamycin. Collagen VII is essential for a functional skin barrier, and the levels of collagen VII decrease with age and specifically beneath wrinkles. Although the mechanism whereby rapamycin may increase collagen VII protein levels is not clear at this time, the known effects of rapamycin on autophagy and intracellular trafficking of vesicles may allow for intracellular processing of misfolded collagen and increase proper localization at the cell periphery and basement membrane.

A notable aspect of this study is the use of such a low dose of rapamycin (10 μM, or 0.001%) for topical application. Topical treatment with higher concentrations (0.1-1%) has been employed for the treatment of tuberous sclerosis complex (TSC) in adults and children and has shown efficacy. We chose to use rapamycin at a ten-fold lower dose because the concentrations used in TSC patients are intended to inhibit cell growth, while our aim was to improve cell function while maintaining proliferative potential and preventing senescence. The positive impact of our treatment regimen suggests that age-related therapy with rapamycin may be feasible at doses far below those associated with side effects; however, this possibility will require careful evaluation in each specific clinical setting.

Link: https://doi.org/10.1007/s11357-019-00113-y

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In Search of Genes that Were Lost in Longer-Lived Mammals

In Search of Genes that Were Lost in Longer-Lived Mammals

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Researchers here describe an interesting approach to improving the understanding of how differences in species longevity arise from differences in the operation of cellular metabolism. They report on a search for genes in short-lived mammals, mice in this case, that have been lost in long-lived mammals such as our species. Finding such genes can then lead to an investigation of specific aspects of cell and tissue function relevant to life span. As is often the case in this field, the work is of scientific interest, but not really all that relevant to near future efforts to produce rejuvenation. A complete understanding of how exactly aging progresses in detail and which mechanisms are more or less important would be helpful, but it is by no means necessary. The research and development community can forge ahead to repair the known causes of aging without a full understanding of aging – indeed, this is already progressing quite well in the matter of stem cells and senescent cells.


The genetic propensity of certain species for longevity and anti-aging is a challenging problem in vertebrate biology. Of particular interest are the genes that influence life expectancy differences among species. These genes are expected to be the real longevity genes of interest and should explain the wide differences in the rate of aging among diverse species and why similarly sized rodents or primates sometimes have anomalous life expectancies – such as naked mole-rats or humans.

No such genes have been unequivocally identified. We performed a computer-aided analysis of data relevant to lifespan and made a bioinformatic search for the genes, the loss of which might modulate lifespan. This search is based on the general idea that such genes are lost in a predefined set of species but are present in another predefined set of species. Examples of such pairs of sets include long-lived vs short-lived, homeothermic vs poikilothermic, among others. Species are included in one of two sets depending on the property of interest, such as longevity or homeothermy. A bioinformatics method and software relevant to the idea are universal towards these sets and the property that defines them.

Here, the proposed method was applied to study the longevity of Euarchontoglires species. It largely predicted genes that are highly expressed in the testis, epididymis, uterus, mammary glands, and the vomeronasal and other reproduction-related organs. In conclusion, the developed method and its software allowed us to identify a short list of presumably lost genes associated with a long lifespan in Euarchontoglires. The predicted lost genes largely demonstrate specific expressions in reproductive organs, which agrees with Williams’ hypothesis concerning the reallocation of the physiological resources of the body between self-maintenance and reproduction (transition from r-strategy to К-strategy in the species evolution). The loss of some predicted vomeronasal and olfactory receptor genes in human and naked mole-rat conforms to their specific anatomical features. We suggest that the loss of certain genes in evolution is one of the essential determinants of lifespan. Overall, it is a likely driving force for many aspects of species evolution in vertebrates.

Link: https://doi.org/10.1186/s13040-019-0208-x

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Notes on the 1st Alcor New York Science Symposium

Notes on the 1st Alcor New York Science Symposium

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This past weekend, I was in New York City for a meeting organized by Alcor New York, a cryonics community group that is presently seeking to set up a more robust Biostasis Society of New York complete with well-organized standby capacity to help people achieve a successful cryopreservation at the end of life. Setting aside technical issues, the greatest challenge in cryopreservation is the fact the euthanasia, and thus the ability to arrange time of death, remains largely illegal. Hence there must be expensive standby operations, suboptimal deaths that cause significant damage to the brain, and a scramble to ensure rapid cooldown and preservation when death does occur. Since there are only two reputable cryonics providers in the US, local organizations capable of coordinating standby and transport are essential.

A number of folk in the cryonics community can be found in and around New York of late; Aschwin de Wolf and Chana Phaedra of Advanced Neural Biosciences, for example. In the introduction to the meeting, it was noted that early cryonics of the 60s and 70s started as much in New York as in California – there was a Cryonics Society of New York, and restoring that entity seems a worthy goal. There were a few noteworthy visitors from elsewhere, such as one of the Nectome folk, and a representative of the European Biostasis Foundation in Switzerland – this is not CryoSuisse, interestingly enough, but a distinct initiative with some overlapping members.

The talks at the meeting were divided between discussions of progress towards slowing aging or attaining rejuvenation, and discussions of cryonics itself. In general, cryonicists have a strong interest in not dying if all possible, and thus most are quite interested in what is going on in the newly formed longevity industry. The weight given to cryonics is tempered by expectations as to how soon rejuvenation therapies will arrive, and how effective they will be over time.

Joao de Magelhaes presented remotely from the UK, and gave his view on where things stand in working towards therapies to treat aging and thereby slow or reverse age-related degeneration and mortality. He is fairly conservative and pessimistic; he doesn’t think that there will be enough progress in our lifetimes to achieve actuarial escape velocity, but he does think that we will see a slowing of aging in our later lives. Therefore cryonics is very important, and it is particularly important to achieve for cryonics the same that has already been achieved for work on the treatment of aging – to move it from a small, comparatively poorly regarded fringe concern to a field with notable technical successes and greater financial support. In this, there is little substitute for the hard work of bootstrapping, advocacy, research in resource constrained environment, and so forth. On the cryonics side of the house, de Magelhaes is involved in setting up the UK Cryonics and Cryopreservation Research Network to spur more academic research into relevant technologies.

Ben Best spoke about NAD+ upregulation and senolytics; he works at the Life Extension Foundation, and the principals there have recently started to heavily promote these approaches to treating aging. To the extent that they work, this is an example of what will happen to the “anti-aging” industry of fraud and hope and supplements that do little good: many of the people involved are motivated to do something about aging, and thus the good should chase out the bad, given time and therapies that actually work. Ben Best has experimented with these approaches to therapy, as one of the physicians connected with the LEF is willing to prescribe the senolytic dasatinib and NAD+ infusions, but committed the cardinal sin of not assessing metrics before and after. This is sadly prevalent in the self-experimentation community. If you don’t measure, nothing happened. Still, there is evidence for both NAD+ upregulation and senolytics to be beneficial in older people, and sooner or later ever more physicians will become comfortable enough with the evidene to prescribe these therapies the many who might benefit.

Mike Perry gave a fascinating talk on the early history of cryonics, starting in the mid-1960s. It is eye-opening just how much information can be lost even at a distance of a mere fifty to sixty years. For example, James Bedford was the second preserved individual; the first may have been a woman called Sarah Gilbert, but this is uncertain. Of the fifteen people cryopreserved from 1966 to 1973, only Bedford remains. All of the others were lost to the haphazard, unprofessional nature of the early initiatives. Perry exhibited a short film made in 1968 by members of the New York Cryonics Society, showing the process of cryopreservation in one of the dewars of the time. It is quite the artifact of its era.

Chana Phaedra gave a presentation on paths towards optimization of cryopreservation. The success of cryopreservation depends upon delivery of cryoprotectant to the brain, efficiently and rapidly. At present, even in the best of circumstances the perfusion of cryoprotectant isn’t optimal. This is challenging on a number of fronts: the skull is in the way; you can’t just push fluid through tissue at high pressures; the blood-brain barrier blocks all cryoprotectants to some degree. The present conclusion based on work at Advanced Neural Biosciences is that the low-hanging fruit here is finding ways to bypass or open the blood-brain barrier. That may mean new cryoprotectants, or some chemical way of disrupting the blood-brain barrier rapidly and selectively. Other options to improve the situation: faster perfusion, less ischemia, and better assays that can be used in animal studies or on preserved human brains to reliably establish the quality of the preservation.

Aschwin de Wolf discussed the prospects for revival of patients who were frozen rather than vitrified, in part or in whole. The present wisdom is that straight freezing – which can and does occur in sections of the brain given a suboptimal perfusion of cryoprotectant – is highly destructive and causes large amounts of ice crystal formation. Can people with this sort of damage be repaired? De Wolf argued that the best approach, conceptually, is some form of low-temperature repair, via nanomachinery capable of operating in a preserved tissue at liquid nitrogen temperatures. The more interesting part of the discussion was a presentation of straight frozen and then thawed brain tissue that doesn’t appear to have anywhere near as much damage as we might expect. The state of the tissue is worse than the same case for vitrification, but perhaps not as much worse as thought. More work is needed to assess this conjecture, however.

Since one of the presenters was ill, I filled in and gave an impromptu talk on self-experimentation: how to do it responsibly and effectively. We might consider four classes of self-experimentation at increasing levels of sophistication. Class 1: the sort of thing that everyone does with dieting for weight loss or eating foods and supplements for benefits. Class 2: compounds that are easy to obtain, easy to use, have great human safety data, and that may have effects on aging, such as metformin (a poor idea, I think) or senolytics (a better prospect). Class 3: treatments that are logistically challenging, and that may need a personal lab. Few people would be able to safety inject themselves with myostatin antibodies, for example. Get that wrong, and you die. But it is technically plausible, and helpful in terms of spurring muscle growth, given the evidence. Class 4: treatments that require a company or other significant effort to create. Liz Parrish’s efforts with Bioviva , in order to self-experiment with telomerase gene therapy, for example. Or cryonics, for that matter. In near all cases, from dieting to quite sophisticated efforts, people tend self-experiment poorly. They do not do the one fundamental thing, which is to measure the effects.

Researchers in the fields of neurobiology and cryobiology gave a couple of technical presentations. One was an interesting outline of methods that could be used to evaluate the quality of brain preservation protocols, not limited to cryonics. It essentially boils down to examining labelled dendritic spines in neural tissue, which can be done before and after an experimental preservation to see how well the fine structures survived. It is even in principle possible to do this in a brain, rather than just in sections of brain tissue. The second presentation was on the use of computer modelling and machine learning to optimize cryopreservation procedures. There are many variables that can be tweaked, from cooldown trajectory to type and mix of cryoprotectants. Modelling could be used to find optimal parts of this large state space more effectively than other forms of experimentation.

The European Biostasis Foundation (EBF) representative outlined their efforts to build a professional cryonics provider in Switzerland, which would be the first in Europe if they are successful. I liked a lot of what he had to say, particularly that customer focus and scalability are the weak points of the present cryonics industry, given its non-profit roots. Thus one of the initial projects is to ramp up the professionalization of signup and standby. They are launching a brand called Tomorrow, which streamlines the process of signing up for cryopreservation, making it an entirely online process that runs more smoothly and requires less work on the part of the individual. They are also looking into how to make a for-profit cryonics organization viable through the path of long-term asset management, meaning partnership with life insurance companies. As you may know, most cryopreservations are funded by life insurance policies, making it quite cost-effective, particularly if started at a younger age. Middlemen in the the life insurance industry are a well established business model, and so this might be a path towards for-profit cryonics. Beyond these early stage efforts, EBF supports research efforts to improve the quality and reliability of cryopreservation, and is planning a storage facility, but this will be contingent on success in the initial for-profit path, opening the door to capital investment.

Unfortunately I had to leave before the final keynote by Robin Hanson, but it was an interesting event. The cryonics community needs to grow and find success: we live in a strange world, in which there is an alternative to oblivion and the grave, but it is poorly capitalized, poorly supported, and rarely used. Cryonics, as happened for the treatment of aging as a medical condition, must find its way to success and growth. I think that this will be achieved in part by the slow process of building technologies that work, such as reversible vitrification of donor organs, carried out in research communities that presently have little funding for rapid progress, and in part by efforts such as those of the EBF, the process of discovery in business models and persuasion.

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To What Degree Does Loss of Skeletal Muscle with Age Contribute to Immunosenescence?

To What Degree Does Loss of Skeletal Muscle with Age Contribute to Immunosenescence?

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Sarcopenia, the progressive loss of muscle mass and strength, is characteristic of aging. A perhaps surprisingly large fraction of the losses can be averted by strength training, but there are nonetheless inexorable processes of aging that, until therapies exist to repair this damage, will cause decline in muscle tissue over time even for those who maintain their fitness as best as possible. Researchers here consider the evidence for skeletal muscle tissue to do more than just move us around, but also to be an active participant in many aspects of metabolism. The focus in this open access paper is on the immune system: to what degree does sarcopenia contribute to the loss of immune function that also occurs with age?


In the last two decades, the perception of skeletal muscle as a pure locomotors unit has shifted. Muscle is increasingly recognized as an organ with immune regulatory properties. As such, skeletal muscle cells modulate immune function by signalling through different soluble factors, cell surface molecules, or cell-to-cell interactions. Although our knowledge of the muscle-immune system interplay has advanced considerably, the impact of age is relatively unknown. Sarcopenia may severely disturb this interaction, providing a potential explanation for the observed clinical outcomes of sarcopenic patients

Muscle is increasingly recognized as an endocrine organ producing and releasing cytokines and other peptides, which exert autocrine, paracrine, and endocrine activity on numerous tissues. Consequently, these soluble factors are commonly termed myokines. Proteomic profiling has been applied to the secretome of skeletal muscle and identified more than 300 potential myokines. Myokines such as IL-6, IL-7, IL-15, or LIF have been shown to modulate the immune system. Remarkably, serum concentrations of myokines such as IL-7 and IL-15 are inversely correlated with age, suggesting a link between skeletal muscle and age-dependent loss of immune system function.

As humans age, the immune system undergoes drastic changes. The umbrella term immune senescence is used to encompass these changes. Moreover, ageing is associated with increased serum levels of pro-inflammatory molecules. Skeletal muscle exhibits immune regulatory properties and that chronic, low-grade inflammation may induce muscle wasting. The concept of skeletal muscle as a regulator of immune function is relatively new and adds a new layer of complexity to the muscle-immune system link. Consequently, the muscle-immune system connection might be bidirectional: chronic, low-grade inflammation induces muscle catabolism via pleiotropic mechanisms mediated by the inflammatory secretome. Concurrently, homeostasis of skeletal muscle is, in part, responsible for healthy immune function. However, when dysregulated, insufficient myokine signalling, alteration of membrane bound factors towards a pro-inflammatory profile and impaired regenerative capacities of immune cells might result in disruption of immune system function.

We propose that biological aging may disturb the equilibrium of muscle-immune system homeostasis with skeletal muscle acting as a potential central link between sarcopenia and immune senescence. Healthy muscle function is gradually lost in an aging biological system due to physical inactivity, metabolic changes and the accumulation of chronic, low-grade inflammation. In turn, impaired muscle function curtails skeletal muscle cell signalling needed for immune regulation and maintenance, culminating in a vicious cycle in which immune and muscle system dysfunction sustain each other.

Link: https://doi.org/10.1016/j.ebiom.2019.10.034

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Upregulation of Autophagy Improves Vascular Function in an Animal Model of Type 2 Diabetes

Upregulation of Autophagy Improves Vascular Function in an Animal Model of Type 2 Diabetes

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Autophagy is the name given to a collection of cellular maintenance processes that recycle damaged structures, unwanted protein, and other metabolic waste. Many forms of stress, such as heat, lack of nutrients, and so forth spur greater autophagy, and this is thought to be a large part of why mild, temporary stress can produce lasting benefits to health – a process known as hormesis. Cell function is improved, and thus tissue function is improved. Many of the methods shown to modestly slow aging in laboratory species involve increased autophagy, and at least some, such as the practice of calorie restriction, have been shown to depend on functional autophagy for their benefits.

Rather than applying stress to generate autophagy, development programs focus on the use of small molecule drugs to influence the gene networks that regulate stress responses – such as targeting mTOR through rapamycin and analogous mTOR inhibitors. The research results here are an example of the type, showing that forcing a greater pace of autophagy helps to resist some of the metabolic consequences of type 2 diabetes – though of course this compares unfavorably with low calorie diets and consequent reduction in excess visceral fat tissue, the cause of the condition, as an approach to therapy in this specific case.


Vascular dysfunction is a major complication in type 2 diabetes (T2D). It has been suggested dysregulation of autophagy is associated with various cardiovascular diseases. However, the relationship between autophagy and vascular dysfunction in T2D remains unclear. Thus, we examined whether reduced autophagy is involved in vascular dysfunction and stimulation of autophagy could improve vascular function in diabetes.

Ten to 12-week old male type 2 diabetic (db-/db-) mice and their control (db-/db+) mice were treated with rapamycin or trehalose. Mesenteric arteries (MAs) were mounted in the arteriography and diameter was measured. Western blot analysis and immunofluorescence staining were assessed. Myogenic response (MR) was significantly increased, whereas endothelium-dependent relaxation (EDR) was significantly attenuated in the MAs of diabetic mice. These results were associated with increased expressions of LC3II, p62, and beclin-1 in diabetic mice.

Treatment of autophagy stimulators significantly reduced the potentiation of MR and improved EDR in the diabetic mice. Furthermore, autophagy stimulation normalized expressions of LC3II, p62, and beclin-1 in the diabetic mice. In addition, phosphorylation level of eNOS was decreased in diabetic mice, which was restored by rapamycin and trehalose. In conclusion, T2D impairs vascular function by dysregulated autophagy. Therefore, autophagy could be a potential target for overcoming diabetic microvascular complications.

Link: https://doi.org/10.1113/EP087737

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Fight Aging! Newsletter, November 25th 2019

Fight Aging! Newsletter, November 25th 2019

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Fight Aging! publishes news and commentary relevant to the goal of ending all age-related disease, to be achieved by bringing the mechanisms of aging under the control of modern medicine. This weekly newsletter is sent to thousands of interested subscribers. To subscribe or unsubscribe from the newsletter,
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Contents

  • 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

https://www.fightaging.org/archives/2019/11/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

https://www.fightaging.org/archives/2019/11/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

https://www.fightaging.org/archives/2019/11/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

https://www.fightaging.org/archives/2019/11/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

https://www.fightaging.org/archives/2019/11/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

https://www.fightaging.org/archives/2019/11/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

https://www.fightaging.org/archives/2019/11/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

https://www.fightaging.org/archives/2019/11/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

https://www.fightaging.org/archives/2019/11/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

https://www.fightaging.org/archives/2019/11/targeting-%ce%b1-synuclein-in-the-gut-to-turn-back-the-progression-of-parkinsons-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

https://www.fightaging.org/archives/2019/11/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

https://www.fightaging.org/archives/2019/11/7-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

https://www.fightaging.org/archives/2019/11/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

https://www.fightaging.org/archives/2019/11/evidence-for-inflammation-to-drive-tau-pathology-in-alzheimers-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

https://www.fightaging.org/archives/2019/11/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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The Dog Aging Project Forges Ahead with a Large Study

The Dog Aging Project Forges Ahead with a Large Study

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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.

Link: https://www.leafscience.org/the-dog-aging-project-is-enrolling-10000-pets-in-new-study/

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

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

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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.

Link: https://www.dzne.de/en/news/public-relations/press-releases/press/inflammatory-processes-drive-progression-of-alzheimers-and-other-brain-diseases/

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

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

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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, of dollars. 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.”

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