Fight Aging! Newsletter, November 23rd 2020

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  • A Recommended Tour of the State of Development of Senolytic Therapies
  • Investing in the Age of Longevity, Panels at Longevity Week 2020
  • Senescent Cells Contribute to Lowered NAD+ Levels in Aging
  • Being 75 Will Be Great, and the Younger You are Now, the Better It Will Be When You Get There
  • Overhyping the Effects of Hyperbaric Oxygen Treatment on Aging
  • Data on the Prevalence of Liver Fibrosis in Middle Age
  • Kimer Med is Crowdfunding Early Stage Work to Commercialize DRACO Antiviral Technology
  • Cardiovascular Risk and Blood Cholesterol in Old and Older Individuals
  • More Physical Activity, Less Progression to Dementia
  • Tau Protein and Blood-Brain Barrier Dysfunction in Aging
  • Extracellular Vesicle Signals in Older Individuals Alter Hematopoietic Stem Cell Activity
  • H3K4me2 Regulates Recovery of Cell Function Following Repair of DNA Damage
  • Several Alzheimer's Associated Gene Variants Appear to Affect the Efficiency of Microglia
  • Towards an Effective Vaccine for Cytomegalovirus
  • Correlating Declining Sense of Smell with Other Aspects of Age-Related Degeneration

A Recommended Tour of the State of Development of Senolytic Therapies

Today's article is a cut above the usual popular science standard in terms of detail and accuracy, capturing a snapshot of the present development of senolytic therapies. It is lengthy and touches on a range of present initiatives, companies, research programs, and clinical trials. Senolytics are one of the most important developments to emerge from the medical research community in quite a long time, in that they are the first rejuvenation therapy worthy of that classification. A senolytic treatment is one that selectively destroys senescent cells. These cells accumulate in old tissues, and while never rising to very large numbers, nonetheless contribute meaningfully to chronic inflammation and cell and tissue dysfunction of aging through the senescence-associated secretory phenotype (SASP).

Researchers have robustly and repeatably achieved rejuvenation in animal models via the use of senolytics, meaning reversal of measures of numerous age-related diseases, and extension of life span. Near any senolytic approach works, so long as it can remove senescent cells while avoiding harmful side-effects. Senescent cell accumulation is clearly an important process in aging, and a comparatively easy target for therapies intended to produce rejuvenation in the old.

A small number of human trials of first generation senolytic drugs have taken place in the past couple of years, some complete and published, some not. The initial trial data has been a mix of promising where it involved the use of the dasatinib and quercetin combination as a senolytic therapy, and an abject failure in the case of UNITY Biotechnology's attempt at treating osteoarthritis with a localized senolytic drug. The charitable viewpoint is that they tested the hypothesis that local administration could work, and have now demonstrated that it doesn't, because senescent cells in the rest of the body are delivering the lion's share of inflammatory signaling. The less charitable viewpoint is that the UNITY principals made poor decisions about drug choice and trial design, and that those choices looked like poor decisions ahead of time.

A single trial failure can put a damper on an entire class of treatment, causing investors to pull back, but in this case it seems quite clear that the the UNITY Biotechnology trial was not a good test of senolytics in humans. It wasn't even a good test of the ability of senolytics to treat osteoarthritis, given what we know of how it was conducted. And meanwhile, senescent cells are clearly proven in animal studies to cause the condition. Given what we know of the similar biochemistry of cellular senescence in mice and humans, the role of senescent cells in inflammation, and the role of inflammation in age-related diseases, it would be quite astounding to find that humans did not benefit greatly from clearance of senescent cells, in much the same way as occurs in mice. This is a very exciting area of development, and a very exciting time for the field of rejuvenation research.

Send in the senolytics

Unity Biotechnology was one of the darlings of the nascent anti-aging biotech sector. In August, that idea took a hit when Unity announced that its lead drug candidate had failed to beat a placebo in reducing joint pain and stiffness, according to interim results from a trial of patients with osteoarthritis of the knee. The company's stock plunged more than 60% on the news, nearly one-third of Unity staff were laid off, and its experimental drug UBX0101 - the first novel 'senolytic' agent ever to enter clinical testing - was swiftly abandoned.

That setback threw a pall over the entire senolytic field. A research note cited "substantially greater risk to the senolytic hypothesis." However, other experts were more sanguine about a class effect, highlighting issues with trial design, study population and UBX0101 itself - a small-molecule inhibitor of MDM2 designed to boost the activity of the proapoptotic p53 protein - as possible explanations for study failure. In the meantime, more than two dozen other startups continue to pursue approaches to target senescent cells - strategies that range from cell destruction and containment to senescence prevention and even reversal. "There are lots of different ways to tackle this, and I think that the initial failure of Unity's first clinical trial shouldn't be a discouragement. The field is young, it's still early, and there's a lot left to be discovered and tried," says Tim Cash, CSO of Senolytic Therapeutics.

Like Unity, most of these startups drew inspiration from a 2011 paper and a follow-up report showing the promise of senescent cell clearance to protect against age-related organ deterioration in normal aging mice as well. "I refer to those mice as the mice that launched a thousand ships," says Matthew Scholz, cofounder and CEO of Oisín Biotechnologies, a senolytics-focused gene therapy company. When it comes to raising funds, many of those senolytic 'ships' have hit rocky waters in recent months. Because of the UBX0101 trial failure, some investors - already burned once by the hype that surrounded the ill-fated anti-aging company Sirtris Pharmaceuticals and fearing a repeat with companies such as Unity - have shied away from pouring additional money into the antisenescence drug market.

Yet industry insiders say the problem with Unity's trial had more to do with the specifics of that drug and its study protocol than with the strategy of senolysis writ large. "Of course, we've been anxiously following their progress through the clinic, and we're disappointed too," says Lewis Gruber, CEO and CSO of SIWA Therapeutics, a company developing an antibody drug directed against a type of advanced glycation end product found on the surface of senescent cells. "But the actual technical results are, at least so far, not of concern to us. We don't see it as a problem for senolytics in general."

For starters, MDM2 may not have been the best target for senescent cell destruction. The protein is one of the most important negative regulators of p53, responsible for the ubiquitination and degradation of the proapoptotic tumor suppressor. As such, inhibiting MDM2 risks unleashing indiscriminate cell killing in off-target, non-senescent tissues. To avoid that kind of toxicity, Unity relied on a local delivery strategy. But according to biomedical engineer Jennifer Elisseeff from Johns Hopkins University in Baltimore, Maryland, local injections of UBX0101 are not sufficient to improve knee function in old mice with osteoarthritis. In her lab, systemic administration of another senolytic agent, navitoclax, was needed to tamp down the general inflammation in the body that was hampering tissue repair.

Then there's the drug itself. Other senescence researchers say that, in their hands, MDM2 inhibitors such as nutlin-3a have only weak senolytic activity. And there's evidence from Judith Campisi's lab to suggest that the drug could also work through attenuation of the SASP. If that mechanism predominates over cell elimination, a single dose of UBX0101, as administered in the trial, might thus offer only temporary relief before the inflammatory secretome would come flaming back.

Yet the early success of dasatinib and quercetin in human trials at least shows that the concept of senolysis is possible in patients. And it gives anti-aging researchers hope that more pronounced benefits will be seen with therapeutics rationally designed to modulate senescence in some way. "It'll happen sooner or later. The technology is just too good."

Investing in the Age of Longevity, Panels at Longevity Week 2020

This past week was Longevity Week in London, a yearly collection of events hosted by Jim Mellon's associates and allies that, this year, was held online given the present restrictions on gathering that continue to enacted in response to COVID-19. As is the case for near all infectious disease, this pandemic falls most heavily on the old and the frail. Perhaps understandably COVID-19 was a primary theme in the Longevity Forum discussions, now posted online.

The Longevity Forum itself is less focused on the science of aging and more focused on society, policy, and funding the scientific and medical development that will be needed to bring rejuvenation therapies into widespread use. There were still scientific discussions taking place in the broader context of Longevity Week, and I participated in one of the panels hosted by the Master Investor organization. We touched on the overlap between the science of aging and investment in clinical translation of that science in order to effectively treat aging as a medical condition. Both of Master Investor panel discussions are now published online, and you might take a look at those and other events from the recent Longevity Week.

Investing in the Age of Longevity 2020 | The Science of Ageing

We are on the cusp of a revolution in our understanding of the causes and consequences of aging. As aging research gathers pace, this panel discussion brings together some of the leading experts in the field of gerontology to discuss the cutting edge scientific work being done to advance the fight against aging.

Investing in the Age of Longevity 2020 | The Opportunity for Investors

The progress being made in extending life- and health-spans represents both a challenge and an opportunity. How can we ensure our investments see us comfortably through an extended life and how can we capitalise on the huge financial possibilities that successful treatments for aging would present? This panel brings together three of the leading investors in the field of Longevity to discuss the opportunities and potential pitfalls.

Senescent Cells Contribute to Lowered NAD+ Levels in Aging

Mitochondria are the power plants of the cell, packaging the chemical energy store molecule adenosine triphosphate that is used to power cellular processes. NAD+ is important to mitochondrial function, but levels fall with age for reasons that have yet to be fully explored. The outcome is less efficient mitochondria, a decline that is implicated in the onset and progression of numerous age-related diseases. Reduced mitochondrial function means less functional cells, tissues, and organs, and particularly so in energy-hungry parts of the body such as the brain and muscles.

The research and development community has become increasingly interested in ways to boost NAD+ levels in order produce benefits to metabolism and tissue function in older individuals. So far, supplements based on vitamin B3 derivatives are the most studied approach, with results in old people that appear to be in the same ballpark as those produced by structured exercise programs. Combining those two approaches might be better still, but there is no evidence as yet as to whether or not that is the case, and these are still not radical reversals of the impact of aging. We all understand the bounds of the possible when it comes to what exercise can do for an older individual. It might be technically rejuvenation, in some ways, but only mildly so.

Can the medical community do better by identifying and targeting the deeper causes of NAD+ decline? In today's research materials, scientists demonstrate that at least some of this decline is due to the chronic inflammation that is characteristic of aging. They specifically call out the inflammatory signaling generated by senescent cells as a contributing cause, and reinforce the known link between CD38 expression and loss of NAD+. This is great work, and exactly the sort of thing we'd like to see more of in the future, strengthening the connections between known deeper causes of aging and known manifestations of aging, and thus bolstering the case for targeting those deeper causes in order to effectively treat aging.

Chronic inflammation causes a reduction in NAD+

NAD+ (nicotinamide adenine dinucleotide), a key metabolite central to an efficient and healthy metabolism, declines with age. This previously unexplained phenomena is associated with numerous age-related diseases and has spawned the development of many nutritional supplements aimed at restoring NAD+ to more youthful levels. Researchers have now identified chronic inflammation as a driver of NAD+ decline. They show that an increasing burden of senescent cells, which is also implicated in the aging process, causes the degradation of NAD via the activation of CD38 (cyclic ADP ribose hydrolase) a protein that is found on the cell membranes both inside and on the surface of many immune cells.

Experiments were done in mice and involved metabolic tissue from visceral white fat and the liver which were examined during aging and acute responses to inflammation. The work was validated in primary human macrophages. "Our initial hypothesis was that CD38 activation would be driven by inflammation. But we found that in this case, the activation occurred with both acute and age-related inflammation. That was a surprise."

Senescent cells, which stop dividing in response to DNA damage, spew a multitude of pro-inflammatory proteins, called the senescence-associated secretory phenotype or SASP. Evolution selected cellular senescence as a protective measure against cancer; but as senescent cells accumulate in tissues over the course of a lifetime, the SASP drives low grade chronic inflammation which is associated with age-related disease, including late life cancer. "These inflammatory proteins in the SASP induce macrophages to proliferate, express CD38, and degrade NAD+. It's a maladaptive process. But drugs that target the SASP or CD38 may offer us another way to deal with the decline of NAD+."

Senescent cells promote tissue NAD+ decline during ageing via the activation of CD38+ macrophages

Declining tissue nicotinamide adenine dinucleotide (NAD) levels are linked to ageing and its associated diseases. However, the mechanism for this decline is unclear. Here, we show that pro-inflammatory M1-like macrophages, but not naive or M2 macrophages, accumulate in metabolic tissues, including visceral white adipose tissue and liver, during ageing and acute responses to inflammation. These M1-like macrophages express high levels of the NAD-consuming enzyme CD38 and have enhanced CD38-dependent NADase activity, thereby reducing tissue NAD levels.

We also find that senescent cells progressively accumulate in visceral white adipose tissue and liver during ageing and that inflammatory cytokines secreted by senescent cells (the senescence-associated secretory phenotype, SASP) induce macrophages to proliferate and express CD38. These results uncover a new causal link among resident tissue macrophages, cellular senescence, and tissue NAD decline during ageing and offer novel therapeutic opportunities to maintain NAD levels during ageing.

Being 75 Will Be Great, and the Younger You are Now, the Better It Will Be When You Get There

There is a certain constituency in this world of ours whose members look at the far side of middle age with a fatalistic gloom, envisaging the last, decrepit light before the darkness. The age of 75 stands out in the present discussion on this topic only for a noted op-ed touting a hoped end to life at that point. That voice isn't alone. Many people, perhaps even most people, express the desire to die on some schedule in late life, if asked. Perhaps a few years older than their peers, because hierarchy is important to we primates, but nonetheless, the present view is that after middle age we should be shutting up shop, tiding up the shelves for the next tenant, and generally getting out of the way, in the most permanent fashion possible.

This view starts with the desire not to suffer, and then broadens out from that into a consensus view on the shape of human life that is considered less carefully and challenged perhaps less often than it should be. Everyone is taught from youth - via schooling, stories, myth, and the all too real health issues of older relatives - that old age is a degeneration, a fall into a broken body and a broken mind, filled with pain and an ultimate return to the weakness and dependency of childhood. That this is set in stone, never to be changed. This is an insufferable fate for most, and so it is decided that death, historically the only other option on the table, is a liberation.

But there are other options on the table when taking into consideration the fact that we live in an era of exceptionally rapid progress in all technologies. There is cryonics, for one, potentially reversible low-temperature preservation of the body and brain for a future capable of rebuilding and restoring a youthful life. Then there is progress in more established medical science: simply said, the therapies for age-related disease and dysfunction ten years from now will be far better than those that exist today, and that trend will continue, decade by decade. We are also presently in the midst of an enormous and beneficial disruption in this trend, in that the research and development community is now directly targeting the mechanisms that cause aging, whereas in the past they did not.

I am middle aged. My old age, creeping ever closer with each passing year, will likely be one of comparative fitness, vigor, and youthful function. The nascent longevity industry of today, producing a handful of ways to turn back the molecular damage that causes aging, will become a world-spanning colossus in the years ahead. It will provide a broad range of effective rejuvenation therapies that will put an end to the chronic inflammation and immune system failures of aging, to the frailty and loss of mitochondrial function, and a host of diseases and declines and causes of suffering and mortality will near vanish along the way. The first rejuvenation therapies already exist; the first few score companies developing such therapies already exist. It is easy to see a lengthy future from where we stand now, if one only cares to learn a little about the work presently underway.

Why I Hope to Be Alive at 75

Ezekiel Emanuel is best known for writing a controversial article in 2014, headlined "Why I Hope to Die at 75", in which he strongly rejects the desire to live beyond the age of 75 and expresses his opinion that continuing to live after such an age is meaningless. At age 63, he is getting closer to the age at which he thinks life is pointless, and I believe that a large reason why he is so pessimistic about life beyond 75, whether he realizes it or not, is based on the current state of medicine. This line of reasoning does not take into account how medicine, and in particular how we treat aging could change in the next decade or two.

Current medicine does a great job at keeping people alive for longer, but they often have to live with one or more chronic diseases. Given that, I am not surprised that Emanuel is not enamored with living a long life, especially as that could entail being disabled, bed-bound, or otherwise suffering a poor quality of life as the result of debilitating age-related diseases. However, things could be different in the not so distant future, and being 75 could see the majority of people far more fit, healthy, and vibrant than ever before in human history thanks to advances in aging research. Therapies that directly target aging could potentially make people biologically younger (in particular their immune systems) and much more able to withstand COVID-19 and other diseases.

The decline of the immune system is a key reason why the elderly are most susceptible to infectious diseases such as COVID-19, and there has been considerable interest in the rejuvenation of the immune system in recent years. Dr. Greg Fahy from Intervene Immune has had some early success with thymus rejuvenation in a small human pilot study and demonstrated that it is possible to cause the thymus, which shrinks and loses its capacity to produce T cells during aging, to regrow and resume production of those cells. Another example of immune rejuvenation is currently being developed by Samumed, a biotechnology company that is developing drugs that target the Wnt pathway to restore it to youthful function.

These are only some of the examples of why healthy life expectancy could rise significantly in the near future, and there are plenty of reasons to remain future positive. This is the future direction of medicine and healthcare, a world where being 75 does not mean you are thrown on the scrap heap and where people like Emanuel will no longer feel that life has no meaning. I am confident that in such a world, being 75 would not be the burden he thinks it will be, and this is why I hope to be alive at 75.

Overhyping the Effects of Hyperbaric Oxygen Treatment on Aging

An interesting open access paper was recently published on the effects of hyperbaric oxygen treatment on telomere length and cellular senescence in immune cells taken from blood samples. I use the word "interesting" quite deliberately, because that is exactly and all that this research is. The paper is appropriately formal and modest on that front, but this attitude doesn't extend to the rest of the publicity, unfortunately. When one runs a business based around offering hyperbaric oxygen treatment, one must make hay while the sun shines, and extract every last drop of marketing juice from every study funded. Hence there are media articles out there at the moment breathlessly telling us that hyperbaric oxygen treatment reverses aging. This is ridiculous, and only makes it harder for the better end of the industry to make progress.

Per the paper, hyperbaric oxygen treatment causes average telomere length to grow by ~20% and markers of cellular senescence to decrease by ~35% in populations of circulating immune cells. This doesn't tell us that hyperbaric oxygen treatment is an amazing rejuvenation therapy, any more than the NAD+ and mitochondrial function data for exercise tells us that exercise is an amazing rejuvenation therapy. In both cases we already know the bounds of the possible. We know that these interventions don't turn older people into notably younger people. If we're calling exercise and hyperbaric oxygen treatment rejuvenation therapies, then the term "rejuvenation therapy" is meaningless.

What this does reinforce is the point that peripheral blood immune cell parameters can be very disconnected from the overall state of aging. We know that telomere length as assessed in these cells is a truly terrible measure of aging. Circulating immune cells are prone to large variations in the pace of celular replication in response to circumstances. Immune cells replicate aggressively when provoked by the presence of pathogens or other issues requiring a coordinated immune response. Telomere length shortens with every cell division in somatic cells: in immune cells, telomere length thus has a very wide spread across individuals, varies day to day, is just as influenced by infection status and other environmental factors as it is by aging. It is just not all that helpful as a measure of aging, and downward trends with age are only seen in the statistics for large study populations.

It seems plausible that the same is true of cellular senescence in immune cells. Cells become senescent when they hit the Hayflick limit on cellular replication. Throughout much of life, the senescence of immune cells is likely more determined by replication pace (and thus immune challenges, the burden of infection) than by aging. And that is before we even get to the point that the authors of this paper used a less than standard measure of senescence, one for which it is possible to argue that it may or may not actually be representative of the burden of senescent cells in immune populations. Overall this data is all interesting, but I suspect that it tells us more about the poor relevance of the metrics chosen to anything other than the deeper aspects of immune function.

If hyperbaric oxygen treatment removed ~35% of senescent cells throughout the body, it would already be well known as a reliable therapy for arthritis, a way to reverse chronic kidney disease, a way to suppress inflammatory conditions, and an effective treatment for numerous chronic diseases of aging. In mice, removing a third of senescent cells via senolytic drugs produces reliably large and beneficial outcomes, while hyperbaric oxygen treatment does not. So clearly it is not globally clearing senescent cells - and nor should any responsible party be trying to present reductions in senescent immune cells as indicative of global senolytic effects throughout the body. What is observed here is an effect limited to the way in which the immune system is functioning. There is some evidence for hyperbaric oxygen treatment to improve resistance to infectious disease such as influenza, and that is interesting in and of itself, but I feel that much of what is going on here is an attempt by certain parties to jump onto the longevity industry bandwagon, rather than responsibly focusing on a realistic view of what can be achieved with their chosen intervention.

Hyperbaric oxygen therapy increases telomere length and decreases immunosenescence in isolated blood cells : a prospective trial

Hyperbaric oxygen therapy (HBOT) utilizes 100% oxygen in an environmental pressure higher than one absolute atmospheres (ATA) to enhance the amount of oxygen dissolved in body's tissues. Repeated intermittent hyperoxic exposures, using certain HBOT protocols, can induce physiological effects which normally occur during hypoxia in a hyperoxic environment, the so called hyperoxic-hypoxic paradox. In addition, it was recently demonstrated that HBOT can induce cognitive enhancements in healthy aging adults via mechanisms involving regional changes in cerebral blood flow. On the cellular level, it was demonstrated that HBOT can induce the expression of hypoxia induced factor (HIF), vascular endothelial growth factor (VEGF), and sirtuin (SIRT), stem cell proliferation, mitochondrial biogenesis, angiogenesis, and neurogenesis. However, no study to date has examined HBOT's effects on telomere length and senescent cell accumulation.

Thirty-five healthy independently living adults, aged 64 and older, were enrolled to receive 60 daily HBOT exposures. Whole blood samples were collected at baseline, at the 30th and 60th session, and 1-2 weeks following the last HBOT session. Peripheral blood mononuclear cells (PBMCs) telomeres length and senescence were assessed. Telomeres length of T helper, T cytotoxic, natural killer and B cells increased significantly by over 20% following HBOT. The most significant change was noticed in B cells. There was a significant decrease in the number of senescent T helpers by -37.30% post-HBOT. T-cytotoxic senescent cell percentages decreased significantly by -10.96% post-HBOT.

In conclusion, the study indicates that HBOT may induce significant senolytic effects that include significantly increasing telomere length and clearance of senescent cells in the aging populations.

Data on the Prevalence of Liver Fibrosis in Middle Age

Fibrosis is a consequence of age-related disarray in tissue maintenance processes, leading to the deposition of scar-like collagen that disrupts tissue structure and function. It is an ultimately fatal issue for which there are only poor treatment options at present. Hopefully that will change with further exploration of the relationship between accumulation of senescent cells in aged tissues and the development of fibrosis. In mice, the use of senolytic therapies to selectively destroy senescent cells has reversed fibrosis in a number of different organs.

A substantial minority of participants from the Framingham Heart Study, (nearly nine percent), had potentially clinically significant liver fibrosis (scarring). This the first study of this size and scale done in the United States. More than 3,000 middle-aged Framingham Heart Study participants (over a three-year period) underwent a test or vibration-controlled transient elastography that quantifies how much fat is in the liver and also measures the stiffness of the liver. Liver stiffness correlates with the degree of liver scarring. "We found that liver fibrosis was associated with more adverse cardiometabolic risk factors, even after accounting for liver fat which is a known risk factor for cardiometabolic disease. In particular, we observed that approximately one-quarter of the participants with diabetes had evidence of possibly clinically significant liver fibrosis."

These findings support the consideration of screening for liver fibrosis in high-risk groups, though additional studies are needed to determine the benefits/costs of screening. "Liver biopsy is the gold standard for diagnosing liver fibrosis; however, new non-invasive tests exist that can quickly and painlessly help doctors determine if you are at risk for having clinically significant liver fibrosis." If liver fibrosis is identified early, before cirrhosis is established, it is treatable. Greater recognition of and awareness of liver fibrosis as a consequence of nonalcoholic fatty liver disease will hopefully allow more patients to receive treatment to prevent complications of advanced liver disease.

Kimer Med is Crowdfunding Early Stage Work to Commercialize DRACO Antiviral Technology

Kimer Med is a New Zealand biotech startup in the very early stages of work on improvement and commercialization of the DRACO antiviral technology. This approach works by selectively destroying cells that host viral replication, and has been shown to be effective for a few presently challenging viral infections in animal models. In principle it is a platform extensible to any viral infection. Unfortunately DRACO fell into the usual chasm, made up of a lack of funding for later stage academic research, a lack of strong-willed iconoclasts willing to go to bat for it, and a lack of interest in the pharmaceutical industry for anything that isn't neatly packaged and ready to go.

The Kimer Med principals are providing the strong-willed iconoclast component of the mix, but there is work yet to do in order to attract investors: nailing down intellectual property, proving that replication and improvement of the original DRACO formulation works as they claim, and so forth. So the team is giving crowdfunding a try for their early development plan. This has long been a technology of interest for the longevity community for some years, as it might be a way to address herpesviruses like cytomegalovirus that appear to be important in the age-related decline of the immunity system. So take a look at the crowdfunding page, and give some though to helping out.

We are working on a broad-spectrum antiviral drug. You can help us achieve a future free of the suffering caused by viruses. SARS-CoV-2 is just the tip of the iceberg. We also plan to tackle HIV, Hepatitis B, Influenza, Herpes, CMV, EBV, the common cold, and others. Viruses infect animals, too, both pets and livestock. Today, almost a hundred years after the discovery of penicillin and sulfa, although we have a few antivirals, none of the current commercial products have a breadth of activity that even slightly measures up to the spectrum of those first antibiotics. In fact, new antivirals currently have to be customized for each different virus. For example, Tamiflu only works for the flu, not SARS-CoV-2, and viruses are already developing resistance.

However, a few years ago, researchers at MIT's Lincoln Lab came up with an antiviral protein that works much differently from conventional antiviral drugs. Their published research showed this compound to be effective against 15 different viruses, including Influenza H1N1, Rhinovirus (the common cold), Dengue, Adenovirus, and others - a true broad-spectrum antiviral. With the advent of Covid-19, as well as with the significant human, animal and financial burden of many other viruses, and the ongoing risk of the appearance of new ones, the time is right to pick up where Lincoln Lab left off, and complete the commercial development of this compound. We believe this protein is non-toxic and that it should also be effective against SARS-CoV-2. Based on the way it works, there is good reason to believe it could be effective against a very wide range of viruses.

The next step is funding for fabrication and testing, including against SARS-CoV-2. We've already done the legwork of identifying the suppliers we will need, and the costs and associated regulations. Most or all of this work can be contracted-out, so we don't even need a laboratory of our own yet. We are anticipating the need to fine-tune our fabrication process a bit, followed by additional testing in the lab, and then quickly moving on to in vivo testing. Once successful in lab animals, we plan to progress to safety trials in people. We want to make this drug safe and available for use in humans as soon as we practically can.

This compound's effectiveness has already been replicated and published by two other labs. In one, they tested against PRRSV. In the other, against Influenza. Previous lab testing shows that the compound has been effective against every virus tested, including a wide-cross section of virus types. However, unknowns do remain. This is why we need your help. In addition to confirming effectiveness, we want to look at things like dosing. As with most drugs, there may also end up being certain contraindications or limitations, which we will need to identify, and work around if we can.

Cardiovascular Risk and Blood Cholesterol in Old and Older Individuals

The approach of lowering blood cholesterol via statins and similar medications slows the onset of atherosclerosis and consequent stroke and heart attack, but it isn't anywhere near as large an effect as we would like. This class of therapy isn't a cure and cannot be a cure, in the sense of removing existing atherosclerotic lesions, the fatty deposits that catastrophically weaken and narrow blood vessels. The latest approaches, such as PCSK9 inhibitors, can in the extreme case lower blood cholesterol to as little as 10% of human normal, but the outcome is still only a minor reversal of existing lesions. Some benefit is better than no benefit, and blood cholesterol lowering medications have changed the shape of late life human mortality for the better, but this approach of lowered blood cholesterol is not the right direction for the future of this field.

An observational study suggests that among people who have not had a previous cardiovascular event, those aged 70 to 100 years may gain the most benefit from taking medications that lower cholesterol compared to younger age groups, in terms of the number of heart attacks and cardiovascular events that could potentially be prevented per person treated. The study, involving more than 90,000 people living in Copenhagen, Denmark, including 13,779 people aged between 70 and 100 years, concluded that people aged over 70 years had the highest incidence of heart attack and cardiovascular disease of any age group. Heart attacks per 1,000 people per year irrespective of LDL cholesterol levels: Age 80-100, 8.5; age 70-79, 5.2; age 60-69, 2.5; age 50-59, 1.8; age 20-49, 0.8 - i.e. in people aged 80-100 years, there were 8.5 heart attacks per 1,000 people each year.

The study also estimates that the number of older people who need to receive a moderate-intensity statin therapy to prevent one heart attack in five years is fewer than for younger age groups. One heart attack will be prevented for every 80 people aged 80 to 100 years treated. In people aged 50 to 59 years, 439 need to be treated to prevent one incidence of heart attack, the researchers estimate.

In a separate systematic review and meta-analysis, researchers show that cholesterol-lowering therapies are as effective at reducing cardiovascular events in people aged 75 years or older as they are in younger people. The study, which included data from more than 21,000 people aged 75 years or older from 29 randomised controlled trials, found that cholesterol-lowering medications reduced the relative risk of major vascular events in older patients by 26% per 1mmol/L reduction in LDL cholesterol, which is comparable to the risk reduction in patients younger than 75 years (15% per 1mmol/L reduction in LDL cholesterol).

Together, the findings strengthen evidence that cholesterol-lowering medications can benefit older adults, who have historically been underrepresented in clinical trials of these therapies, and could help reduce the burden of cardiovascular disease in an aging population.

More Physical Activity, Less Progression to Dementia

Researchers here note a correlation between greater exercise in late life and reduced risk of progressing from mild cognitive impairment to dementia. As is the case for most human data, causation cannot be shown, but animal data on the benefits of exercise are unambiguous. It seems safe to suggest that human physiology works much the same way, and that the correlation exists because exercise provides benefits that slow down processes of age-related neurodegeneration.

Physical activity has been suggested to prevent the conversion of mild cognitive impairment (MCI) to dementia in patients. We investigated the association between the continuance and regularity of physical activity and the risk of developing dementia in patients with MCI. We analyzed 6-year followed up data for 247,149 individuals in the National Health Insurance Service (NHIS) cohort of Korea who were enrolled between January 1, 2009, and December 31, 2015.

The patients were divided into four groups: those who did not engage in physical activity consistently (Never-PA group), those who initiated physical activity (Initiation-PA group), those who ceased physical activity (Withdrawal-PA group), and those who performed physical activity consistently (Maintenance-PA group). We also divided the patients into two groups: those who engaged in physical activity irregularly (Irregular-PA) and those who undertook physical activity regularly (Regular-PA).

Our analysis shows that continued physical activity in patients with MCI is associated with a lower risk of dementia of the Alzheimer type (DAT). It appears that the decision to start physical activity leads to a lower risk of DAT, while ceasing physical activity may cause the risk of DAT to increase again. In addition, a higher frequency of physical activity appears to prevent conversion from MCI to DAT (moderate-intensity physical activity more than 5 days per week or vigorous-intensity physical activity more than 3 days per week).

We observed that the Maintenance-PA group had 18% fewer dementia conversions than the Never-PA group, while the Initiation-PA group had 11% less dementia conversion than the Never-PA group. We interpret this to indicate that continuing physical activity occurring at both time points was more effective than initiating a new physical activity between the two time points. Evidence suggests that the longer the duration of physical activity, the greater the effect of physical activity on cognitive function. The findings for the Initiation-PA group may therefore reflect the shorter duration of physical activity compared to the Maintenance-PA group.

There are at least two major mechanisms by which continuous physical activity may prevent the conversion from mild cognitive impairment to dementia. Physical activity increases the expression of neurotrophic factors such as brain-derived neurotrophic factor (BDNF), insulin-like growth factor 1 (IGF-1), and vascular endothelial growth factor (VEGF). BDNF is important for maintaining neuronal development and for exercise-related improvements in cognitive function. IGF-1 and VFGF play important roles in neurogenesis and angiogenesis and influence the induction of hippocampal BDNF.

Physical activity also increases cerebral blood flow (CBF). After 12 weeks of physical activity, CBF has been shown to increase in the anterior cingulate cortex and hippocampal CBF increased in elderly patients with subjective memory complaints after 16 weeks of physical activity. CBF is thought to maintain cerebral perfusion to help maintain brain volume.

Tau Protein and Blood-Brain Barrier Dysfunction in Aging

Aggregation of phosphorylated tau protein into neurofibrillary tangles (and consequent toxicity leading to widespread cell death) is characteristic of late stage Alzheimer's disease, while dysfunction of the blood-brain barrier is a feature of aging thought to begin much earlier in the progression of the condition. The blood-brain barrier is a specialized set of cells lining the blood vessels of the central nervous system, allowing only certain molecules and cells to pass. When this barrier starts to leak, unwanted materials make their way into the brain, generating chronic inflammation and consequent issues in brain tissue. It is interesting to see discussion of potential effects of tau aggregation on blood-brain barrier leakage, as it wouldn't be the first significant causative mechanism that came to mind, given that tau is late and blood-brain barrier dysfunction is early in Alzheimer's disease. One could argue that tau aggregation and blood-brain barrier dysfunction are both downstream of chronic inflammation, while still being the case that both cause further chronic inflammation.

The blood-brain barrier (BBB) plays a crucial role in maintaining the specialized microenvironment of the central nervous system (CNS). In aging, the stability of the BBB declines and the permeability increases. The list of CNS pathologies involving BBB dysfunction is growing. The opening of the BBB and subsequent infiltration of serum components to the brain can lead to a host of processes resulting in progressive synaptic, neuronal dysfunction, and detrimental neuroinflammatory changes. Such processes have been implicated in different diseases, including vascular dementia, stroke, Alzheimer's disease (AD), Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, hypoxia, ischemia, and diabetes mellitus.

The BBB damage is also observed in tauopathies that lack amyloid-β overproduction, suggesting a role for tau in BBB damage. Tauopathies represent a heterogeneous group of around 20 different neurodegenerative diseases characterized by abnormal deposition of microtubule-associated protein tau (MAPT) in cells of the nervous system. Neuropathology of tauopathies is defined as intracellular accumulation of neurofibrillary tangles (NFTs) consisting of aggregated hyper- and abnormal phosphorylation of tau protein and neuroinflammation.

Disruption of the BBB found in tauopathies is driven by chronic neuroinflammation. Production of pro-inflammatory signaling molecules such as cytokines, chemokines, and adhesion molecules by glial cells, neurons, and endothelial cells determine the integrity of the BBB and migration of immune cells into the brain. The inflammatory processes promote structural changes in capillaries such as fragmentation, thickening, atrophy of pericytes, accumulation of laminin in the basement membrane, and increased permeability of blood vessels to plasma proteins. Here, we summarize the knowledge about the role of tau protein in BBB structural and functional changes.

Extracellular Vesicle Signals in Older Individuals Alter Hematopoietic Stem Cell Activity

Stem cell activity declines with age, due in part to damage to these cells and their niches, but perhaps to a greater degree due to changes in the signaling environment resulting from rising levels of molecular damage and consequent dysfunction throughout the body. Not all of these signaling changes are obviously harmful; some are attempts to compensate. Some of those attempts produce benefits, slowing the overall pace of decline, but also unwanted side-effects. Researchers here note that the contents of extracellular vesicles released by cells change with age, and that hematopoietic stem cells react to vesicles from older individuals with signs of increased activity. This may compensate in part for a trajectory of declining integrity and activity, but it may also contribute to the risk of cancers and other immune dysfunction arising from the clonal expansion of mutations in hematopoietic cell populations.

Hematopoietic stem cells (HSCs) maintain balanced blood cell production in a process called hematopoiesis. As humans age, their HSCs acquire mutations that allow some HSCs to disproportionately contribute to normal blood production. This process, known as age-related clonal hematopoiesis, predisposes certain individuals to cancer, cardiovascular, and pulmonary pathologies. There is a growing body of evidence suggesting that factors outside cells, such as extracellular vesicles (EVs), contribute to the disruption of stem cell homeostasis during aging.

The present study demonstrates that healthy individuals maintain circulating EVs consistent in terms of size, particle concentration, and total protein per particle between 20-85 years of age. In contrast, blood EV protein profile composition changes over time in humans, and our in silico analyses, suggests that certain organs or cell types may be responsible for this change, by altering EV production and releasing EVs into the bloodstream. Most strikingly, the blood circulating EVs produced from middle and older-aged individuals stimulate HSC colony-forming ability in contrast to younger individuals and untreated controls.

This work highlights that blood EVs impart important extracellular signals to HSCs as humans age. We posit that EVs may provide a compensatory stimulus that counter-balances a decrease in HSC functionality in individuals approaching middle-age. Current work is investigating how these activation signals, provided by the EVs, may impact the trajectory of expansion of mutations via clonal hematopoiesis, which may have profound implications in the development of hematological-based malignancies later in life. We demonstrate, for the first time a fundamental age-specific difference in blood EVs that specifically affects HSCs in individuals after 40 years of age, prior to the detection of classically defined clonal hematopoiesis.

H3K4me2 Regulates Recovery of Cell Function Following Repair of DNA Damage

Researchers here investigate the regulation of mechanisms governing restoration of cell function following DNA repair. They find that H3K4me2, an epigenetic modification of histone H3, is important, and suggest that this could be a target for slowing the impact of DNA damage on the progression of aging. It is interesting to read this work in the context of data from last year that indicates detrimental epigenetic change with age may be an unfortunate side-effect of the repair process for double-strand breaks in DNA. It seems likely that, in the years ahead, an arm of the longevity industry will arise focused on manipulating DNA repair and surrounding mechanisms via known points of regulation such as histone H3.

The genome in every human cell is damaged on a daily basis, for example in the skin by UV radiation from the sun. Damage to the DNA causes diseases such as cancer, influences development, and accelerates aging. Congenital malfunctions in DNA repair can lead to extremely accelerated aging in rare hereditary diseases. Therefore, preservation and reconstruction processes are particularly important to ensure development and to maintain tissue function. DNA is rolled up into structures called chromatin, wound around the histone packaging proteins like cables on cable drums. This packaging is regulated by methyl groups. Various proteins are responsible for placing methyl groups on histones or removing them. The number of groups on the packaging proteins affects the activity of genes and thus the protein production of the cell.

In experiments with nematodes, the research team showed that after repairing damaged DNA, two methyl groups were increasingly found on the DNA packages. Furthermore, they found that errors in placing these two methyl groups on the histones (H3K4me2) accelerated the damage-induced aging process, while increased position of this histone alteration prolongs the lifespan after DNA damage. By controlling the proteins that either set or remove these methyl groups, the resistance to DNA damage - and thus the aging process of the animals - could be influenced.

Further analysis of the role of these two methyl groups showed that the enrichment of H3K4 after genome damage with two methyl groups supports the cells in restoring the balance after DNA damage. "Now that we know the exact changes in chromatin, we can use this to precisely limit the consequences of DNA damage. I hope that these findings will enable us to develop therapies for hereditary diseases characterized by developmental disorders and premature aging. Due to the fundamental importance of DNA damage in the aging process, such approaches could also counteract normal aging and prevent age-related diseases."

Several Alzheimer's Associated Gene Variants Appear to Affect the Efficiency of Microglia

Microglia are innate immune cells of the brain, similar to macrophages in the rest of the body, but with a larger portfolio of activities. They are not just chasing down pathogens and cleaning up molecular waste, but are also deeply involved in maintaining the function and connectivity of neurons in brain tissue. Here, researchers note that several genetic variants that are either problematic or protective when it comes to Alzheimer's disease risk and progression affect the ability of microglia to clear amyloid-β aggregates from brain tissue. While therapies targeting amyloid-β accumulation have so far failed to produce meaningful clinical benefits in patients, perhaps because other processes have taken over as the dominant cause of pathology in later stage Alzheimer's disease, increased aggregation of amyloid-β is clearly associated with the condition, and is equally clearly the cause of toxic biochemistry that can harm cells.

Alzheimer's disease is the most common form of dementia with more than 40 million affected people worldwide. To this day, there are no existing therapies for the effective prevention or treatment of the disease. Many recently identified Alzheimer's disease-associated risk genes are expressed preferentially or exclusively in microglia, the immune cells of the brain. A recent study investigated the role of the microglia-specific Plcg2-P522R genetic variant in Alzheimer's disease and found that it enhances several immune cell-specific functions.

A genome-wide association study from 2017, which included a Finnish cohort of Alzheimer's disease patients and healthy controls, identified Alzheimer's disease-associated risk loci in three genes, TREM2, ABI3, and PLCG2, which are mainly expressed in microglia. Several genetic variants of the TREM2 gene have been found to increase the risk for Alzheimer's disease. These TREM2 variants lead to a partial loss of function of the receptor and impair the activation of microglia. Consequently, the removal of β-amyloid, which accumulates in the brain during Alzheimer´s disease, is reduced. Recently, it has been shown that the phospholipase C gamma 2 (PLCγ2) enzyme is involved in the signaling pathway initiated by TREM2. The PLCG2-P522R variant reduces the risk of developing Alzheimer's disease, but its effects on immune cell functions have not been previously described.

"It is interesting how several Alzheimer's disease-associated risk genes affect microglial cell functions through the same signaling pathway. It shows that targeting this pathway and the cellular functions it regulates may have significant therapeutic potential in the future."

Towards an Effective Vaccine for Cytomegalovirus

Cytomegalovirus is a persistent herpesvirus that is problematic in a few populations, largely harmless in the short term for everyone else, largely unnoticed by those infected, and widely prevalent in the population. Near everyone is infected by the time old age arrives. Unfortunately, CMV appears to be a major factor in the age-related decline of the adaptive immune system, possibly by causing ever more immune cells to become uselessly specialized to target it, leaving too few immune cells for other tasks. This sort of runaway resource misallocation in the immune system is a large problem in the elderly, given that the thymus, where new T cells of the adaptive immune system mature, is near entirely atrophied by late life, reducing the supply of new cells to a trickle. Effective vaccination will help this situation, but there is good reason to think that, for the oldest to benefit, it must be accompanied by selective destruction of cytomegalovirus-focused immune cells, and restoration of the supply of new immune cells.

A research team says it has identified a key marker that will help speed effective vaccine designs for cytomegalovirus (CMV), the most common congenital infection worldwide. The researchers describe an immune surrogate that demonstrates when a vaccine has elicited the necessary antibodies that protect against CMV infection. The finding is already being applied to screen potential vaccines.

"Despite the high global burden of disease, vaccine development to prevent infection remains hampered by challenges in generating protective immunity. The most efficacious CMV vaccine candidate tested to date is a soluble glycoprotein B (gB) subunit vaccine with MF59 adjuvant (gB/MF59), which achieved 50% protection in multiple phase 2 clinical trials. The vaccine-elicited immune responses that conferred this protection have remained unclear. We investigated the humoral immune correlates of protection from CMV acquisition in populations of CMV-seronegative adolescent and postpartum women who received the gB/MF59 vaccine. We found that gB/MF59 immunization elicited distinct CMV-specific immunoglobulin G (IgG)-binding profiles and IgG-mediated functional responses in adolescent and postpartum vaccinees, with heterologous CMV strain neutralization observed primarily in adolescent vaccinees."

"We determined that protection against primary CMV infection in both cohorts was associated with serum IgG binding to gB present on a cell surface but not binding to the soluble vaccine antigen, suggesting that IgG binding to cell-associated gB is an immune correlate of vaccine efficacy. Supporting this, we identified gB-specific monoclonal antibodies that differentially recognized soluble or cell-associated gB, revealing that there are structural differences in cell-associated and soluble gB are relevant to the generation of protective immunity."

"Our results highlight the importance of the native, cell-associated gB conformation in future CMV vaccine design. CMV has been recognized as a top priority for vaccine development for more than 20 years, yet we remain without an approved vaccine. This work provides a way to assure that current and future vaccine candidates stimulate an effective immune response."

Correlating Declining Sense of Smell with Other Aspects of Age-Related Degeneration

Sense of smell declines with advancing age, a loss of capacity already correlated with broader neurodegeneration and progression towards cognitive impairment and dementia. Here, researchers correlate the loss of sense of small with numerous other aspects of aging, as well as type 2 diabetes, a condition associated with a greater risk of age-related disease and mortality because most diabetics are significantly overweight. Excess fat tissue accelerates aging via mechanisms such as increased generation of senescent cells and increased chronic inflammation.

Olfactory dysfunction is common in aging and associated with dementia and mortality. However, longitudinal studies tracking change in olfactory ability are scarce. We sought to identify predictors of interindividual differences in rate of olfactory identification change in aging. Participants were 1780 individuals, without dementia at baseline and with at least 2 olfactory assessments over 12 years of follow-up (mean age = 70.5 years; 61.9% female), from the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K). Odor identification was assessed with the Sniffin' Sticks. We estimated the impact of demographic, health, and genetic factors on rate of olfactory change with linear mixed effect models.

Advancing age, manufacturing profession, history of cerebrovascular disease, higher cardiovascular disease burden, diabetes, slower walking speed, higher number of medications, and the APOE ε4 allele were associated with accelerated odor identification decline. Multi-adjusted analyses showed unique associations of age, diabetes, and ε4 to olfactory decline. In 1531 participants who remained free of dementia during follow-up, age, cardiovascular disease burden, and diabetes were associated with accelerated decline. Of these, age and diabetes remained statistically significant in the multi-adjusted model.

In conclusion, demographic, vascular, and genetic factors are linked to rate of decline in odor identification in aging. Although some olfactory loss may be an inevitable part of aging, our results highlight the importance of vascular factors for the integrity of the olfactory system, even in the absence of dementia.


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