Fight Aging! Newsletter, October 28th 2019

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  • Help the SENS MitoMouse Rejuvenation Research Project Hit Its Crowdfunding Stretch Goals
  • Aubrey de Grey on the TAME Metformin Trial
  • A Mouse Lineage with Very Long Telomeres Exhibits Longer Life Span
  • Depletion of Microglia Greatly Reduces Tau Pathology in Mouse Models of Alzheimer's Disease
  • The Resurrection of Aducanumab Doesn't Change the Picture for Amyloid-β Clearance in Alzheimer's Disease
  • The Role of Adipogenic Progenitor Cells in Muscle Stem Cell Aging
  • TET2 Regulates the Neuroinflammatory Response in Microglia
  • Cardiac Glycosides, a Category that Includes Several Approved Drugs, are Found to be Senolytic
  • Treating Periodontitis Reduces Inflammatory Markers and Blood Pressure in Hypertensive Patients
  • Processing Epidemiological Data to Show that Obesity and High Blood Pressure Cause Shorter Life Spans
  • REST Regulates Neural Activity and Influences Life Span
  • Libella Gene Thereapeutics Moving Ahead with a Small Phase 1 Trial of Telomerase Gene Therapy
  • Significant Differences in Memory Formation are Observed in Young Mice versus Old Mice
  • Deoxydihydroceramide is Required for Much of the Cell Death Following Hypoxia
  • Investigating the Mechanisms by which Klotho Increases Autophagy

Help the SENS MitoMouse Rejuvenation Research Project Hit Its Crowdfunding Stretch Goals

The latest crowdfunded research project undertaken by the SENS Research Foundation involves using the genetically engineered maximally modifiable mouse lineage in order to demonstrate the ability to copy a version of the ATP8 mitochondrial gene into the cell nucleus, a process known as allotopic expression, and thus prevent mutational damage to this gene from degrading mitochondrial function. This is a modest step on the road towards bringing this class of genetic engineering project to the point of readiness for commercial development, when a biotech startup company could be created to carry it forward.

In just a few weeks of crowdfunding, the project has already hit the initial funding goal of 50,000. There are still stretch goals to reach, however - so if you want to see more work on preventing the mitochondrial contribution to aging, then join in and help.

Mitochondria are the power plants of the cell, every cell containing a herd of these organelles, descendants of ancient symbiotic bacteria. They bear a remnant of the original bacterial DNA, and that is where the problems start. This DNA encodes thirteen proteins vital to the operation of mitochondria. Unfortunately, this genome is poorly protected, poorly repaired, and vulnerable to the oxidative molecules generated by mitochondria as a side-effect of their duties in the cell. Some forms of damage, such as major deletions, can cause mitochondria to become both dysfunctional and more competitive, in replication and resistance to quality control mechanisms, than their undamaged peers. The cell is quickly taken over by broken mitochondria, and becomes broken itself, exporting oxidative molecules into the surrounding tissue. This contributes to the aging process.

If, however, copies of these mitochondrial genes are placed into the cell nucleus, then DNA damage in the mitochondria will not affect their function. The necessary proteins will still be manufactured, delivered, and used. This has been demonstrated for the ND4 gene in recent years, that development program conducted by Gensight Biologics, and the SENS Research Foundation team have achieved allotopic expression of ATP6 and ATP8 in cell studies. More and faster progress is needed, however, to move this work into animal models, and then towards human studies.

The MitoMouse Project Smashes its Initial Fundraising Goal!

Wonderful news, the MitoMouse project has successfully reached its initial 50,000 goal and is well on the way towards the first stretch goal! This now means the project will launch at the lab and the MitoMouse strain will be created. The next step for this ambitious project is to actually create progeny from the SickMice and MitoMice in order to have an effective model to test the mitochondrial repair approach, which has already been shown to work in cells, in living animals. If successful it would be vindication for mitochondrial repair therapy and move the therapy closer to translation to humans.

MitoMouse: SENS Transgenic Mouse Project

Mice of the C57/BL6MT-FVB strain (let's call them "SickMice") have a mitochondrial gene defect (a mutation in the mitochondrial ATP8 gene) and exhibit several age-related symptoms including lower fertility, arthritis, type II diabetes, and neurological impairments. Since mitochondria are only inherited from the mother, cross-breeding female SickMice with male mice from other models will result in the same mitochondrial dysfunction.

We will use the maximally modifiable model to create a new transgenic mouse (the "allotopic ATP8 transgenic mouse - Mitomouse"). This mouse will have the ATP8 gene that is important for mitochondrial function 'hidden' in the cell nucleus and thus capable of being passed on to offspring irrespective of gender.

Our hypothesis is that both male and female offspring from SickMice crossed with MitoMice will result in rescued mitochondrial function. This would prove the viability of the MitoSENS strategy by showing that functional backup copies of mitochondrial DNA genes in the nucleus can replace their mutated counterparts in live animals.

Aubrey de Grey on the TAME Metformin Trial

As you may or may not have heard, the TAME metformin trial recently received the remaining 40 million in philanthropic funding that is needed to progress. The trial will cost 75 million in total, and to my eyes this is quite the waste of funding. Aubrey de Grey of the SENS Research Foundation is far more polite on this topic in today's editorial, which isn't too surprising given our respective views on regulation.

I'll set aside for the moment the point that metformin is a weak treatment with a small effect size on life span, unreliable animal data, life span data in humans arising from a single trial for diabetics rather than healthy individuals, and side effects that are significant in comparison to the small effect size. The point of the TAME exercise is convince the FDA to accept aging as an indication - or something close enough that people can work with it. That never needed a trial to exist in order to take place. The important work has been a process of Nir Barzilai, his collaborators, and fellow travelers such as the Longevity Dividend folk negotiating with FDA bureaucrats, against a backdrop of increasing patient advocacy and activism for aging to be classified as a legitimate target for therapy.

Further, this labor of filling in a ditch dug by the FDA isn't even needed. The same end could be just as well achieved by putting rejuvenation therapies through the FDA process for any relevant age-related indication, and then engaging in a running battle over the off-label use that will come to be the overwhelming majority of all use for these treatments. That is exactly what will soon happen for the dasatinib and quercetin combination, as the world wakes up to just how large and reliable the benefits are for patients undergoing this sort of first generation senolytic therapy. The way forward will be established for these very cheap, revolutionary therapies, and then can be followed by everyone else developing a rejuvenation therapy. Under this sort of pressure, the FDA will change because they have to.

Since the TAME trial is forging ahead, we can hope that the philanthropists involved may choose to do the same for senolytic therapies - which would have been a far better choice, had the required information been widely available back in 2015, when the TAME trial originated. Nonetheless, it remains the case that there are far, far, far better uses for 75 million in this field.

TAME: a genuinely good use of 75 million dollars

The TAME trial is an attempt to determine whether metformin, the well-known anti-diabetes drug, actually has much more wide-ranging benefits against the health problems of late life - so wide-ranging, in fact, that they could uncontroversially be described as addressing aging itself. But then, hang on, metformin is an old drug. I mean, a really old drug - it has been off patent since forever. There is no way in hell to make money out of it. So, how would we fund a clinical trial of it? Well, yes: the only way is philanthropic. This will only happen if there are people out there who are sufficiently convinced of the importance of such a trial that they will pony up the requisite capital even though doing so is completely bereft of financial upside.

But the logic is persuasive in another way: precisely because metformin is such an old drug, a trial can immediately focus on efficacy, in contrast to the need for stringent tests of safety to come first in the case of a new drug. And, sure enough, pretty much as soon as the idea of such a trial was formulated, nearly half of the required 75 million was pledged by the long-standing supporter of gerontology research, Paul Glenn, via (as has long been his custom) the American Federation for Aging Research (AFAR). At that point, however, the pursuit of funds stalled for a couple of years - in particular, the National Institute on Aging twice rejected applications for the remaining money - but, as noted above, the remaining support materialised very recently, courtesy of an anonymous donor.

A question remains, however: is this, in fact, the best use of 75 million in the crusade against aging? Well, that's a few times the total amount that SENS Research Foundation has raised in its entire history, so it will not surprise you that I cannot quite look you in the eye and answer that question in the affirmative. But it is certainly not a waste of money either: indeed, I do feel able to declare that it is a pretty good use.

First, I think there is a reasonable chance that the trial will succeed, albeit modestly. There's no way that a brief course of metformin will give people a decade of extra life, but all that's really needed here is a statistically significant improvement versus controls, and with that kind of money the study can be powered well enough to achieve that threshold. The other rationale for this trial is arguably even greater. It is that the description of the trial incorporates a de facto definitition of aging as the clinical endpoint, which has been more-or-less approved by the FDA, and which can thus be copied and pasted into any future trial for an intervention against aging. That endpoint was the result of a highly arduous negotiation with the FDA that was led by the inestimable Nir Barzilai.

A Mouse Lineage with Very Long Telomeres Exhibits Longer Life Span

Researchers here report on the generation of a mouse lineage with much longer telomeres than is normally the case. Telomeres are the caps of repeated DNA sequences at the ends of chromosomes; a little is lost with each cell division, and cells self-destruct or become senescent when telomeres become too short. This acts as a limit on the ability to replicate for most cells in the body. Stem cells use telomerase to maintain long telomeres, however, allowing them an indefinite number of cell divisions, used to deliver daughter somatic cells with long telomeres into tissues. Thus average telomere length in a tissue is some function of the pace of cell division and the pace at which stem cells generate replacement cells.

This division of cells into a privileged minority and a restricted majority is the way in which all higher forms of animal life control the risk of mutation and the unfettered replication of cancer to a sufficient degree to allow evolutionary success. Over the past decade or more, researchers have been exploring ways to alter the balance of telomere length and telomerase activity in mice, and have found that enhanced telomerase activity extends life, reduces cancer risk, and improves health. As a consequence a number of groups are working on delivery of telomerase gene therapies to human patients, though there remains the question of whether the balance of cancer risk is the same in humans as in mice. The two species have quite radically different telomere dynamics.

In this study, the enhanced mice live somewhat longer than their unmodified peers, though not as much longer as is the case for the application of telomerase gene therapy. The mice do also exhibit reduced cancer risk, however. The scientists here class telomere shortening as a cause of aging, which is not a point universally agreed upon. Reductions in average telomere length in tissues looks much more like a downstream consequence of reduced stem cell activity than an independent mechanism.

Researchers obtain the first mice born with hyper-long telomeres and show that it is possible to extend life without any genetic modification

Given the relationship between telomeres and ageing - telomeres shorten throughout life, so older organisms have shorter telomeres - scientists launched a study generating mice in which 100% of their cells had hyper-long telomeres. The findings show only positive consequences: the animals with hyper-long telomeres live longer in better health, free from cancer and obesity. "This finding supports the idea that, when it comes to determining longevity, genes are not the only thing to consider. There is margin for extending life without altering the genes".

Telomeres form the end of chromosomes, in the nucleus of each cell in the body. Their function is to protect the integrity of the genetic information in DNA. Whenever the cells divide the telomeres, they are shortened a little, so one of the main characteristics of ageing is the accumulation of short telomeres in cells. Up to now, all interventions on the length of telomeres have been based on altering the expression of genes, through one technique or another. In fact, researchers developed a gene therapy that fosters the synthesis of telomerase, obtaining mice that live 24% longer without developing cancer of other illnesses associated with age.

In 2009, researchers worked with the so-called induced pluripotent stem cells - cells from an adult organism which have been given back pluripotency or the capacity to generate a full organism - and they observed that after a certain number of divisions in culture plates, these cells acquired telomeres twice as long as normal. Intrigued, they confirmed that the same occurred in normal embryonic cells - also pluripotent - as they are kept in cultivation after being removed from the blastocyst. The team found that during the pluripotency stage, there are certain epigenetic marks on the telomeric chromatin that facilitate their lengthening by the telomerase enzyme. For this reason, the telomeres of pluripotency cells in cultivation were extended to twice the normal length.

The question was whether the embryonic cells with hyper-long telomeres could produce live mice? Some years ago, the group demonstrated that they could, and have now managed to obtain mice with hyper-long telomeres in 100% of their cells. The mice are slimmer than normal because they accumulate less fat. They also show lower metabolic ageing, with lower levels of cholesterol and LDL, and an increased tolerance to insulin and glucose. Damage to their DNA as they age is less and their mitochondria, another Achilles heel of ageing, function better. The average longevity of mice with hyper-long telomeres is 13% higher than usual. The metabolic alterations observed are also relevant as this is the first time that a clear relationship between the length of telomeres and metabolism has been found. The genetic route of insulin and glucose metabolism is identified as one of the most important in relation to ageing.

Mice with hyper-long telomeres show less metabolic aging and longer lifespans

Short telomeres trigger age-related pathologies and shorter lifespans in mice and humans. In the past, we generated mouse embryonic (ES) cells with longer telomeres than normal (hyper-long telomeres) in the absence of genetic manipulations, which contributed to all mouse tissues. To address whether hyper-long telomeres have deleterious effects, we generated mice in which 100% of their cells are derived from hyper-long telomere ES cells. We observe that these mice have longer telomeres and less DNA damage with aging. Hyper-long telomere mice are lean and show low cholesterol and LDL levels, as well as improved glucose and insulin tolerance. Hyper-long telomere mice also have less incidence of cancer and an increased longevity. These findings demonstrate that longer telomeres than normal in a given species are not deleterious but instead, show beneficial effects.

Depletion of Microglia Greatly Reduces Tau Pathology in Mouse Models of Alzheimer's Disease

Today's research adds to the body of work supporting a vital role for microglia in the progression of Alzheimer's disease from early stages characterized by amyloid-β aggregation and mild cognitive impairment to later stages characterized by tau aggregation and severe neurodegeneration. Microglia are one of the classes of supporting immune cell in the brain. They are similar to macrophages of the innate immune system that are present in the rest of the body, outside the central nervous system, but microglia undertake a much more varied set of tasks beyond clearing up debris, hunting pathogens, and the usual portfolio of immune cell activities. Much of the maintenance and alteration of synaptic connections between neurons is dependent on the presence of microglia, for example.

It is becoming clear that inflammatory dysfunction in microglia is a part of the growing metabolic disarray that allows tau protein to aggregate in the brain, and thereby lead to the death of neurons. It is a matter for debate as to whether this occurs because of amyloid-β aggregation, or whether amyloid-β aggregation is just another consequence of microglial dysfunction that occurs for other underlying reasons.

Studies published earlier this year, carried out in animal models of Alzheimer's disease, suggest that cellular senescence of microglia is very influential in the progression of neurodegeneration. Some of the early senolytic drugs, such as dasatinib, can cross the blood-brain barrier, and so it is possible to test selective destruction of senescent cells in the brain as an approach to therapy. The results offer the possibility that presently available low-cost senolytics may turn out to be more effective than most present approaches to treatment of neurodegenerative conditions.

Microglia can be inflammatory without being senescent, however. Like macrophages, microglia can switch between modes of behavior, known as polarizations, with the two of greatest interest being M1, inflammatory and aggressive in pursuit of pathogens, and M2, anti-inflammatory and focused on regeneration and repair. Numerous studies have suggested that aging is characterized by excessive proportions of M1 macrophages and microglia, though exactly why this is the case - how it connects to rising levels of the underlying molecular damage of aging - remains an open question.

Targeting immune cells may be potential therapy for Alzheimer's

Under ordinary circumstances, tau contributes to the normal, healthy functioning of brain neurons. In some people, though, it collects into toxic tangles that are a hallmark of neurodegenerative diseases such as Alzheimer's. Researchers had shown that microglia limit the development of a harmful form of tau. But they also suspected that microglial cells could be a double-edged sword. Later in the course of the disease, once the tau tangles have formed, the cells' attempts to attack the tangles might harm nearby neurons and contribute to neurodegeneration.

To understand the role of microglial cells in tau-driven neurodegeneration, researchers first studied genetically modified mice that carry a mutant form of human tau that easily clumps together. Typically, such mice start developing tau tangles at around 6 months of age and exhibiting signs of neurological damage by 9 months. Then, the researchers turned their attention to the gene APOE. Everyone carries some version of APOE, but people who carry the APOE4 variant have up to 12 times the risk of developing Alzheimer's disease compared with those who carry lower-risk variants. The researchers genetically modified the mice to carry the human APOE4 variant or no APOE gene. APOE4 amplifies the toxic effects of tau on neurons.

For three months, starting when the mice were 6 months of age, the researchers fed some mice a compound to deplete microglia in their brains. Other mice were given a placebo for comparison. The brains of mice with tau tangles and the high-risk genetic variant were severely shrunken and damaged by 9 months of age - as long as microglia were also present. If microglia had been eliminated by the compound, the mice's brains looked essentially normal and healthy with less evidence of harmful forms of tau despite the presence of the risky form of APOE. Further, mice with microglia and mutant human tau but no APOE also had minimal brain damage and fewer signs of damaging tau tangles. Additional experiments showed that microglia need APOE to become activated. Microglia that have not been activated do not destroy brain tissue or promote the development of harmful forms of tau.

Microglia drive APOE-dependent neurodegeneration in a tauopathy mouse model

Chronic activation of brain innate immunity is a prominent feature of Alzheimer's disease (AD) and primary tauopathies. However, to what degree innate immunity contributes to neurodegeneration as compared with pathological protein-induced neurotoxicity, and the requirement of a particular glial cell type in neurodegeneration, are still unclear. Here we demonstrate that microglia-mediated damage, rather than pathological tau-induced direct neurotoxicity, is the leading force driving neurodegeneration in a tauopathy mouse model. Importantly, the progression of phosphorylated tau pathology is also driven by microglia.

In addition, we found that APOE, the strongest genetic risk factor for AD, regulates neurodegeneration predominantly by modulating microglial activation, although a minor role of apoE in regulating phosphorylated tau and insoluble tau formation independent of its immunomodulatory function was also identified. Our results suggest that therapeutic strategies targeting microglia may represent an effective approach to prevent disease progression in the setting of tauopathy.

The Resurrection of Aducanumab Doesn't Change the Picture for Amyloid-β Clearance in Alzheimer's Disease

It took a long time and many failed attempts for the research community to get to the point at which amyloid-β could be successfully cleared from the brains of Alzheimer's patients. Unfortunately, the data to date strongly suggests that this isn't an effective approach to therapy, at least not on its own, even though it is clearly the case that the increased levels of amyloid-β in the aging brain should be removed. It is a characteristic difference between old brain tissue and young brain tissue, and there is plenty of evidence for it to be harmful.

This failure to achieve clinical success may be because amyloid-β aggregation ceases to be an important factor in later stage disease, once tau aggregation and neuroinflammation are firmly established. It may be because patients frequently have other neurodegenerative conditions, such as vascular dementia, that mask any benefits obtained by removing amyloid-β. It may be that amyloid-β accumulation is a side-effect of glial cell dysfunction, and it is glial cell dysfunction rather than amyloid-β accumulation that drives the condition from its early to later stages.

There has been a fair amount of discussion over the recent move of aducanumab back across the line of FDA approval, following an earlier declaration of failure. There is the usual skepticism regarding motivation on the part of the biotech companies involved. Yet this doesn't make much difference to the present situation with regard to amyloid-β clearance. Aducanumab is either a marginal therapy that just passes the minimum standards for regulatory approval, or a marginal therapy that doesn't. It is modestly slowing progression, not working miracles. Either way, clearance of amyloid-β on its own isn't enough, or it isn't the right point of intervention for this condition.

'Reports of My Death Are Greatly Exaggerated.' Signed, Aducanumab

On October 22, Biogen stunned the Alzheimer's field by announcing that aducanumab - presumed dead last March after failing a futility analysis - appears to have worked in one of its two Phase 3 trials, after all. Based on the results of a new analysis, and interactions with the FDA, Biogen will file for regulatory approval in early 2020. Why the revival? The interim futility analysis was flawed and did not adequately take into account the effect of two late protocol amendments that boosted the number of people receiving the highest dose of this biologic drug. A new analysis included three more months of data, as well as data from the participants who did not complete the full course of treatment. It showed that one of the two trials, called EMERGE, in fact met its primary and secondary endpoints. Oddly, the identical ENGAGE trial, which started one month earlier, was a tad larger, yet had slightly fewer people who took an uninterrupted course of the maximum dose, remained negative.

In each trial, about half the participants on aducanumab were randomly assigned to titrate up to a low dose of drug - 3 mg/kg for ApoE4 carriers, 6 mg/kg for noncarriers. This difference was because ApoE4 carriers are more susceptible to ARIA, the fluid retention in the brain that accompanies treatment with many amyloid-removing therapies. In the high-dose group, ApoE4 carriers initially titrated up to 6 mg/kg; noncarriers to 10 mg/kg. However, in March 2017, about 18 months into the trial, the protocol was amended to allow ApoE4 carriers to titrate up to 10 mg/kg, as well. This was based on accumulating data from several studies suggesting that ARIA is a manageable side effect that usually resolves without harm.

Analysis of the more recent, larger data set suggested that duration of treatment at the high dose was the key factor. In addition, interruption of treatment played a role. In EMERGE, participants on the low dose had a trend of declining more slowly than those on placebo on the primary outcome, the CDR Sum of Boxes, but this was well shy of statistical significance. Participants on the high dose declined 23 percent more slowly than those on placebo, with a significant p value of 0.01. Secondary endpoints were similar. The high-dose group declined about a quarter less on the ADAS-Cog13, a cognitive battery, and up to 46 percent more slowly on the ADCS Activities of Daily Living, a caregiver assessment.

The Role of Adipogenic Progenitor Cells in Muscle Stem Cell Aging

The stem cells responsible for maintaining muscle tissue decline in function with age, becoming ever less active. This loss of function contributes to sarcopenia, the characteristic decline in muscle mass and strength that takes place with advancing age. Researchers here report on investigations of the role of adipogenic progenitor cells in the decline of muscle stem cell function. These progenitor cells are a necessary part of the muscle stem cell niche, but their behavior changes for the worse with advancing age, disrupting the balance of intracellular signaling needed for stem cell function.

Declining stem cell function during aging leads to impaired tissue function and contributes to delayed tissue repair following damage. In adult skeletal muscle, loss of myofiber integrity caused by mechanical injuries or diseases are repaired by resident muscle stem cells (MuSCs), called satellite cells, which promptly exit from quiescence after disruption of muscle architecture to expand, differentiate, and drive tissue regeneration. The fate of MuSCs fundamentally depends on the "niche", their local environment, which is orchestrated by diverse cellular and acellular elements.

Fibro/adipogenic progenitors (FAPs) constitute a population of interstitial mesenchymal cells in skeletal muscle which are devoid of myogenic potential, but support muscle stem cell commitment and can differentiate to the adipogenic or fibrotic lineages. A recent study demonstrated an important function of FAPs in maintaining long-term homeostasis of skeletal muscle: long term in-vivo depletion of FAPs decreased the number of MuSCs and reduced muscle mass and strength, suggesting a critical role of FAPs in maintaining the stem cell pool and sustaining myofiber growth and turnover.

The decline of MuSC function and muscle regenerative capacity during aging is under the control of a wide range of signals, out of which many arise from extrinsic cues coming from the local or systemic environment. A recent study investigated how aging influences the fate of FAPs and their cross-talk with MuSCs to regulate the balance between myogenesis, adipogenesis and fibrosis in skeletal muscle. Aging causes a clonal selection of FAPs, which favors their fibrogenic over adipogenic conversion. Interestingly, aged FAPs fail to efficiently amplify following muscle injury and aging alters the capacity of FAPs to support MuSC amplification and commitment. Both in-vitro co-culture and in-vivo transplantation of young FAPs rejuvenate aged MuSC function, but aged FAPs lose the ability to efficiently support MuSCs. The fact that the support of FAPs to MuSCs is communicable via conditioned medium suggested that soluble factors regulate this paracrine cross-talk.

Future research will be necessary to further dissect FAP function during homeostasis and tissue repair and unravel how the heterogeneity of this population is orchestrated in health and disease. In particular, the signals that mediate FAP dysfunction and the spatio-temporal control of their fate and interactions with MuSCs will be key to understand how aging of different compartments of the stem cell niche contribute to global regenerative capacity.

TET2 Regulates the Neuroinflammatory Response in Microglia

TET2 upregulation has been shown to improve neurogenesis and cognitive function in old mice. So it is interesting that researchers here link increased expression of TET2 with the inflammatory response of microglia in the brain. The broader context is that is becoming increasingly clear that dysfunctional and inflammatory microglia contribute significantly to the progression of neurodegenerative conditions. This is one of many examples of apparently contradictory results to illustrate the point that cellular biochemistry is very complex. Contradictions usually indicate that there is much left to be understood about the way in which the systems studied fit together in practice.

Microglia, the resident immune cells in the central nervous system, are key players in maintaining homeostasis in the brain. Microglia play a wide variety of roles under physiological and pathological conditions. In the healthy brain, microglia are responsible for neuronal activity-dependent synapse pruning during postnatal development. Upon neuronal injury or infection, microglia become rapid responders that initiate an innate inflammatory response. If the inflammatory response is exaggerated or chronic, it becomes detrimental for the surrounding neuronal population, as in Parkinson's disease and Alzheimer's disease.

Epigenomic mechanisms regulate distinct aspects of the inflammatory response in immune cells. Despite the central role for microglia in neuroinflammation and neurodegeneration, little is known about their epigenomic regulation of the inflammatory response. Here, we show that Ten-eleven translocation 2 (TET2) methylcytosine dioxygenase expression is increased in microglia upon stimulation with various inflammogens through a NF-κB-dependent pathway.

We found that TET2 regulates early gene transcriptional changes, leading to early metabolic alterations, as well as a later inflammatory response independently of its enzymatic activity. We further show that TET2 regulates the proinflammatory response in microglia of mice intraperitoneally injected with lipopolysaccharide. We observed that microglia associated with amyloid β plaques expressed TET2 in brain tissue from individuals with Alzheimer's disease and in 5xFAD mice. Collectively, our findings show that TET2 plays an important role in the microglial inflammatory response and suggest TET2 as a potential target to combat neurodegenerative brain disorders.

Cardiac Glycosides, a Category that Includes Several Approved Drugs, are Found to be Senolytic

Researchers here report on the discovery that the class of drugs known as cardiac glycosides are senolytic, capable of selectively destroying the lingering senescent cells that contribute to aging and age-related disease. These cardiac glycosides are not a good candidate for use by the self-experimentation community, however, despite the existence of low-cost generic drugs in this category. They are unpleasant compounds, quite toxic, and when used in medicine come attached to a long list of side effects that sound well worth avoiding. It may nonetheless be the case that new senolytic drugs will be developed from these starting points, given the present enthusiasm for this line of work, by building upon the mechanisms to find less toxic small molecules that have the desired interactions with cellular biochemistry.

Senescence is a cellular stress response that results in the stable growth arrest of old and damaged cells. The past decade has revealed that senescent cells play important roles in a growing list of diseases from cancer, to arthritis, atherosclerosis, and many more. Previous studies have shown that the specific elimination of senescent cells with drugs or using genetic tricks makes mice live healthier for longer. Eliminating senescent cells results in improvements in fibrosis, cataracts, atherosclerosis and in more than 20 other diseases.

After examining a library of drugs that are already used in the clinic and testing them on normal and senescent cells, the researchers identified ouabain as a potential candidate to selectively kill senescent cells. Ouabain belongs to a family of natural compounds called cardiac glycosides that include also digoxin and digitoxin. Cardiac glycosides are used in the clinic to treat cardiac arrythmias and atrial fibrillation. In this study it was found that cardiac glycosides selectively eliminate many types of senescent cells, including when senescence has been triggered by irradiation, cancer itself, or chemotherapeutic drugs - such as etoposide or doxorubicin. The fact that ouabain can eliminate different types of senescent cells emphasises its potential as a broad spectrum senolytic.

"These drugs are already used in the clinic, so they could be repurposed to treat a long list of diseases including cancer. This is something we are keen to explore with our clinical collaborators. Moreover, many patients are being treated with digoxin and an epidemiologist could look retrospectively and ask the question of whether those patients who were treated with digoxin are doing better than those who weren't."

Treating Periodontitis Reduces Inflammatory Markers and Blood Pressure in Hypertensive Patients

Researchers here provide evidence for periodontitis, gum disease, to contribute to hypertension, chronic raised blood pressure, via inflammatory mechanisms. Aggressively treating the periodontitis in hypertensive patients reduces both blood pressure and inflammatory markers. Periodontitis has previously been linked with a modestly increased risk of dementia, as well as increased cardiovascular mortality risk. In both cases, increased inflammation is strongly suspected to be the linking mechanism.

Experimental and observational clinical evidence suggests a prominent role of inflammation in the development of hypertension. In particular, activation of immune cells has been demonstrated in hypertension. Hypertension is more prevalent in patients with immune-mediated disorders, such as psoriasis, rheumatoid arthritis or systemic lupus erythematosus. Thus, chronic inflammatory disorders, could provide a substrate for the pro-hypertensive inflammation.

Periodontitis is one of the most common inflammatory conditions worldwide, representing the sixth most prevalent condition worldwide with prevalence of 20-50%. It is linked to cardiovascular inflammation and endothelial dysfunction. Therefore, if causally associated, periodontitis could significantly contribute to the global hypertensive burden and interventions targeting oral inflammation would have an important role in the prevention of hypertension and its complications. Observational evidence suggests that moderate-severe periodontitis is associated with increased odds for hypertension.

Because of this, it is imperative to establish if periodontitis can cause hypertension. Our group has recently shown that immune activation induced by a keystone periodontal pathogen (Porphyromonas gingivalis) promotes the development of hypertension in mice. Small interventional studies concluded that intensive periodontal therapy may lead to blood pressure reduction, although sufficiently powered evidence in well-defined hypertensive cohorts is lacking. We thus performed a randomized intervention trial on the effects of treatment of periodontitis on blood pressure. One hundred and one hypertensive patients with moderate to severe periodontitis were randomized to intensive periodontal treatment (IPT) or control periodontal treatment (CPT) with systolic blood pressure (SBP) as the primary outcome.

Intensive periodontal treatment improved periodontal status at 2 months, compared to CPT. This was accompanied by a substantial reduction in mean SBP in IPT compared to the CPT (mean difference of -11.1 mmHg). Systolic BP reduction was correlated to periodontal status improvement. Diastolic blood pressure and endothelial function (flow-mediated dilation) were also improved by IPT. These cardiovascular changes were accompanied by reductions in circulating IFN-γ and IL-6 as well as activated and immunosenescent CD8+ T cells, previously implicated in hypertension.

Processing Epidemiological Data to Show that Obesity and High Blood Pressure Cause Shorter Life Spans

Researchers here demonstrate an approach that can be used with large human epidemiological databases to demonstrate that, as expected, both greater amounts of visceral fat tissue and raised blood pressure cause reductions in life span. The underlying mechanisms have been explored at length by the research community. Visceral fat tissue produces chronic inflammation through a variety of mechanisms, including a raised burden of cellular senescence, while raised blood pressure produces damage to fragile tissues in the brain, kidney, and other organs, and accelerates the progression of atherosclerosis.

Researchers are exploring the cause and effect relationships between common health indicators and lifespan, by analyzing polygenic risk scores (PRS), a numerical score of a person's risk for disease based on multiple genetic variants. To find a clinically actionable indicator of genetic risk, researchers started by examining samples from BioBank Japan, which has a heavy East Asian representation. They used the genetic data of 180,000 people to perform genome-wide association studies for 45 common health indicators. By analyzing the PRS of each indicator, they identified the ones that most strongly affected lifespan.

"If you only look at raw clinical data associated to lifespan, you cannot show which attribute is cause and which is effect. For instance, when a patient is dying, their blood pressure is low, so you can't necessarily know if blood pressure is the cause of their death. By using PRS, we can get closer to identifying the cause, because PRS is less susceptible to the acquired confounding factors such as decline in general health."

For the individuals in BioBank Japan, researchers found that high blood pressure and obesity had the most significant associations to reduced lifespan. To improve the diversity of their study and ensure that these associations held across populations, the researchers collaborated with the UK Biobank and FinnGen, and performed a trans-ethnic association study of PRS and lifespan. This increased the sample size to 700,000 and, with the help of additional analyses, reinforced the conclusion that blood pressure and obesity are causally related to reduced lifespan.

REST Regulates Neural Activity and Influences Life Span

Researchers here report their findings on the activity of the REST gene, which both regulates neural activity and appears to influence life span, likely through indirect effects on the well-studied processes of insulin signaling. As such, this is interesting for the connection to neural activity, but otherwise irrelevant to the future of developing means to lengthen human life span. Effect sizes related to insulin signaling are much larger in short-lived lower species than they are in long-lived higher species, and they are in any case only a way to modestly slow aging, not a road to rejuvenation.

Researchers began their investigation by analyzing gene expression patterns in donated brain tissue from hundreds of people who died at ages ranging from 60 to over 100. The information had been collected through three separate research studies of older adults. Those analyzed in the current study were cognitively intact, meaning they had no dementia. Immediately, a striking difference appeared between the older and younger study participants: The longest-lived people - those over 85 - had lower expression of genes related to neural excitation than those who died between the ages of 60 and 80.

Next came the question that all scientists confront: correlation or causation? The team conducted a barrage of experiments, including genetic, cell and molecular biology tests in the model organism Caenorhabditis elegans; analyses of genetically altered mice; and additional brain tissue analyses of people who lived for more than a century.

These experiments revealed that altering neural excitation does indeed affect life span-and illuminated what might be happening on a molecular level. All signs pointed to the protein REST. REST, which is known to regulate genes, also suppresses neural excitation, the researchers found. Blocking REST or its equivalent in the animal models led to higher neural activity and earlier deaths, while boosting REST did the opposite. And human centenarians had significantly more REST in the nuclei of their brain cells than people who didn't make it past their 70s or 80s.

The researchers found that from worms to mammals, REST suppresses the expression of genes that are centrally involved in neural excitation, such as ion channels, neurotransmitter receptors and structural components of synapses. Lower excitation in turn activates a family of proteins known as forkhead transcription factors. These proteins have been shown to mediate a "longevity pathway" via insulin/IGF signaling in many animals. It's the same pathway that scientists believe can be activated by caloric restriction.

Libella Gene Thereapeutics Moving Ahead with a Small Phase 1 Trial of Telomerase Gene Therapy

Libella Gene Therapeutics is developing telomerase gene therapy as a clinical treatment, work that results from more than a decade of studies in mice that show extended life, reduced cancer risk, and improved health. Telomerase acts to lengthen telomeres, the repeated DNA sequences at the ends of chromosomes that shorten with each cell division. Average telomere length in the somatic cells making up any given tissue is a function of the rate of cell division versus the pace at which stem cells produce new daughter somatic cells with long telomeres. Since stem cell activity declines with age, it is no surprise to see telomere length shorten.

Telomerase gene therapy acts in part by extending the working life of somatic cells, and thus the prospect of active cells, burdened with damage due to a longer working life, and the attendant cancer risk has always been a concern. That telomerase gene therapy reduces cancer incidence in mice may be the result of improvements in immune function, particularly cancer immunosurveillance, that outweigh any increase in cancer risk due to increased activity of damaged cells. Mice and humans have very different telomere dynamics, however, so it remains to be seen whether or not the same balance of outcomes is the case in our species. The best way to find out, as ever, is for brave volunteers to try the therapy.

The clinical trial (NCT04133649) has just began recruitment stage. The procedure will consist of a single intravenous injection, followed by six safety and efficacy evaluations. Participants will receive adeno-associated virus (AAV) containing gene expressing telomerase reverse transcriptase enzyme. AAV is expected to move from the circulatory system to tissues, invade cells, and establish telomerase expression inside cells. Viruses will not modify the genome - AAV's genetic material normally exists separately in the cell cytoplasm (as an episome).

Formally, the study is phase I trial, which limits the main goal - whether it is successful or failed attempt - to safety only. In this case, the primary goal was declared as the incidence of adverse effects. Determination of dosing and tolerability is an important first step in all gene therapies. High doses of viral particles result in significant immunological reaction. Moreover, liver damage is a common adverse effect in early gene therapies, because of liver's participation in blood filtering. In addition, telomerase introduces additional risk on its own. In 85% cases of cancers, telomerase is found upregulated, which raises concerns about potential oncogenicity of AAVs with hTERT gene.

The trial is accompanied by two similar phase I attempts (NCT04133454, NCT04110964), which target Alzheimer's disease and critical limb ischemia. Patients participating in the trial will be enrolled in their country of origin and will travel to Colombia. Patients will stay in Colombia for a few days while the treatment is administered and hospitalized for observation. Patients will then return to their country of origin and will be followed-up per the study protocol.

Significant Differences in Memory Formation are Observed in Young Mice versus Old Mice

The brain is exceptionally complex, and thus the ways in which it changes in response to the damage and dysfunction of aging are also exceptionally complex. Memory is no exception, as illustrated here. This is one of the many reasons why the best hope for extending healthy life span significantly in the near future is to reverse the underlying damage, a comparatively simple set of processes, though not without its challenges. This should at the very least enable prevention of the deterioration and change of the aging brain, even if some of those downstream consequences of damage turn out to be irreversible via normal maintenance processes once the causative damage is repaired.

Long-lasting changes at synapses enable memory storage in the brain. Although aging is associated with impaired memory formation, it is not known whether the synaptic underpinnings of memory storage differ with age. Using a training schedule that results in the same behavioral memory formation in young and aged mice, we examined synapse ultrastructure and molecular signaling in the hippocampus after contextual fear conditioning.

Only in young, but not old mice, contextual fear memory formation was associated with synaptic changes that characterize well-known, long-term potentiation, a strengthening of existing synapses with one input. Instead, old-age memory was correlated with generation of multi-innervated dendritic spines (MISs), which are predominantly two-input synapses formed by the attraction of an additional excitatory, presynaptic terminal onto an existing synapse. Accordingly, a blocker used to inhibit MIS generation impaired contextual fear memory only in old mice.

Memory reconsolidation has been suggested to update memory storage. Reconsolidation involves initial destabilization followed by protein-synthesis-dependent restabilization. Destabilization can be analyzed when restabilization is blocked. To our knowledge, destabilization has only been studied at a young age. An earlier study suggested that reconsolidation is impaired in aged rats and humans. However, this study did not block protein synthesis to assess memory destabilization.

Here, we show that memory destabilization is impaired in aged mice. We detected this impairment using a re-exposure protocol that induces destabilization of strong contextual fear memory in young mice. Thus, in old age, memory destabilization may not only be impaired, it may be completely blocked. It is conceivable that impaired memory destabilization in aging is due to the involvement of MISs, as the reversal of these multi-input synapses into one-input synapses might not be induced by retrieval. An MIS-based memory-storing mechanism may explain why memory updating, a fundamental cognitive process, is impaired in old age.

Deoxydihydroceramide is Required for Much of the Cell Death Following Hypoxia

Researchers here provide evidence to show that a single type of ceramide, deoxydihydroceramide, is responsible for the tissue death following deprivation of oxygen, hypoxia, such as occurs after a heart attack. Suppressing levels of this ceramide rapidly enough in response to the event can reduce the damage. This is one of a number of lines of research focused on attempting to preserve cells following transient hypoxia by sabotaging the mechanisms that lead to cell death.

Heart attack and stroke are the primary cause of death worldwide. When a blood clot forms, it blocks the blood vessel and blood circulation. The non-irrigated tissues no longer receive oxygen and rapidly undergo necrosis, from which they cannot recover. But what causes the necrosis under these conditions? Not all animals are so sensitive to the absence of oxygen, worms can live three days without oxygen, some turtles can live several months, and certain bacteria indefinitely.

The researchers saw that in worms a particular species of ceramide, deoxydihydroceramide, accumulated to dangerous levels under anoxia, that is when tissues were completely deprived of oxygen. Upon an infarct, the synthesis of deoxydihydroceramide increases and becomes toxic for cells. Using mass spectrometry, researchers observed that this ceramide blocks certain protein complexes and provokes defects in the cytoskeleton of cells and the proper function of mitochondria, causing tissue necrosis.

Based on these results, researchers injected an inhibitor of ceramide synthesis in mice just before a heart infarct. They found that the mice that received the injection have 30% less tissue necrosis when compared to control mice that received an injection without the inhibitor. The researchers are now working on an inhibitor that will target more specifically deoxydihydroceramide, which is likely to have fewer side effects and maintain the normal body functions of ceramides.

Investigating the Mechanisms by which Klotho Increases Autophagy

Expression of the klotho gene declines with age, while approaches that increase levels of the klotho protein have been demonstrated to slow aging in mice. Some fraction of this outcome stems from increased activity of the cellular housekeeping processes of autophagy, responsible for recycling metabolic waste and damaged molecular machinery and cellular components. Many of the methods of modestly slowing aging in laboratory species are characterized by upregulated autophagy, and some, such as calorie restriction, require functional autophagy in order to slow aging.

In order to study autophagy, researchers have created a mouse model that has increased levels of autophagy. This is performed by mutating a component of what is called the beclin 1-BCL2 regulatory complex. When BCL2 binds beclin 1, autophagy is turned off. The engineered mutation in beclin 1 prevents BCL2 from binding, and allows beclin 1 to continue to promote the formation of the autophagosome, which results in continuously higher levels of autophagy in the mice.

The results of this study demonstrate that the mice with increased levels of autophagy have a significantly increased lifespan. Studies showed that not only do these beclin 1 mutant mice live longer, but also healthier, having better kidney and heart function as well as less spontaneous tumor formation. Additionally, their premature lethality and infertility is rescued. These results suggest that promoting autophagy in this manner can promote mammalian healthspan and lifespan and should be further studied.

The researchers then wondered if known anti-aging compounds could be producing their effects through a pathway similar to their genetic mouse model. Klotho, a membrane protein, was one such compound they examined. It has previously been shown that animals genetically engineered to be deficient in klotho have reduced lifespan and that administering klotho could extend lifespan. Additionally, it was observed that administering klotho promoted more autophagy. Researchers took klotho-deficient mice and observed a noticeable increase in beclin 1-BCL2 binding, leading to less autophagy. By taking these klotho deficient mice and mutating beclin 1 they were able to rescue the effects of klotho deficiency and return autophagy to normal. Furthermore, by administering klotho to human HeLa cells they were able to reduce beclin 1-BCL2 binding showing that this effect is not isolated to mice, but applicable to humans as well.

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