Fight Aging! Newsletter, June 11th 2018

Fight Aging! provides a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress towards the medical control of aging in order to prevent age-related frailty, suffering, and disease, as well as improvements in the present understanding of what works and what doesn't work when it comes to extending healthy life. Expect to see summaries of recent advances in medical research, news from the scientific community, advocacy and fundraising initiatives to help speed work on the repair and reversal of aging, links to online resources, and much more.

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  • Oisin Biotechnologies CSO John Lewis at Undoing Aging
  • Can a Reasonable Argument be Made for Variations in Human Longevity to be Significantly Driven by DNA Repair?
  • A Recent Profile of Unity Biotechnology and its Work on Senolytic Therapies
  • Antibodies Targeting Oxidized Lipids Slow the Development of Atherosclerosis
  • A Selection of Recent Research in the Alzheimer's Field
  • An Interview with Jim Mellon, and Update on Juvenescence
  • Why is Alzheimer's Disease Peculiarly Human?
  • Arguing for Nicotinamide Riboside to Improve Hematopoietic Stem Cell Function
  • Another Potential Approach to Remineralization of Lost Tooth Enamel
  • Why Do Only Some People Suffer Alzheimer's Disease?
  • Building Useful Worker Devices From Nanoparticles and Cell Components
  • Mortality Following Stroke as an Example of the Importance of Raised Blood Pressure as a Mediating Mechanism of Aging
  • Efforts Continue to Associate Copy Number Variations with Human Longevity
  • Immunosenescence and Neurodegeneration
  • Ending Aging Now Translated into Portuguese

Oisin Biotechnologies CSO John Lewis at Undoing Aging

Oisin Biotechnologies is one of a number of companies to have emerged from our community in recent years, from the network of supporters and researchers connected to the Methuselah Foundation and SENS Research Foundation. The Oisin principals are working with a platform capable of selectively destroying cells based on the internal expression of specific proteins. Their initial targets are senescent cells, one of the root causes of aging, and cancerous cells, one of the consequences of aging. They will be taking a therapy for cancer into clinical trials initially, as it is somewhat less challenging to move viable cancer treatments through the regulatory process than is the case for many other conditions. This will allow them to prove out and iterate on the technology in preparation for later trials of a senolytic therapy capable of clearing near all senescent cells in near all tissues. In this video, taken at the Undoing Aging conference hosted by the SENS Research Foundation and Forever Healthy Foundation earlier this year, Oisin Biotechnologies CSO John Lewis talks about their technology and recent results.

John Lewis, CSO of Oisin Biotechnologies, presenting at Undoing Aging 2018

Good evening everybody. It's a real pleasure to be here at this meeting; I really thank Aubrey de Grey and Michael Greve for the invitation to speak. I couldn't really have asked for a better sequence of speakers, as the prior presenter did a fantastic job of covering why senescent cells are important, and also why they are such a pain in the ass to work with scientifically. I'm a career academic scientist working in oncology and I'm relatively new to the senescence field, although I have a lot of experience in killing cells, and that's what I'd like to tell you about today: how Oisin Biotechnologies is working to develop very selective therapies to kill senescent cells and cancer.

I don't really have to give much of a background on what a senescent cell is, or what they do. These are cells that arise through programming in the body, a reaction to outside stresses - oxidative stress, genotoxic stress, and they basically prevent us from developing cancers. It is really important to note as well that as cells become senescent in the body, in response to these stresses, they also can send out factors that can spread. I'll reiterate the fact that we don't have great markers for identifying senescent cells. There are some common features we can use, scientifically, to identify them in this case, because of an accumulation of active enzymes in lysosomes. We can stain for active β-galactosidase. But really these are very heterogeneous populations, and they arise from a variety of different pathways. I don't want to go into detail about signaling, I just want to highlight the fact that the induction of this cell cycle arrest is mediated through a number of factors: p16, p53, p21. We've thought about this, and we've asked what are the common pathways that we could potentially target in order to create a selective therapy that can start to ablate these cells. Obviously, I don't need to go into the fact that while senescent cells have been implicated in aging and age-related processes, there are also very specific diseases that are consequences of aging and other phenotypes that an anti-senescence therapy could address clinically.

It was a really salient point in the last talk that p16 cells may not be the whole story. But you have to look at the data that has been shown in the past few years - and this is what really convinced me - that, sure, all senescent cells may not express p16, but it is very clear in a mouse model that if you engineer it such that you can selectively ablate all of the p16 expressing cells, you get dramatic changes in phenotype. For me, that was very impactful. In this case, Jan van Deursen's work, if you genetically engineer mice to express a suicide gene driven by a p16 promoter, using what is called INK-ATTAC, an inducable caspase-9 system, that allows them to then give a dimerizer that activates apoptosis in cells that have activated p16, that are putatively senescent, and these mice showed very dramatic changes in their phenotype. Significant improvements in healthspan, 25% median increase in lifespan, although some heterogeneity, 50% less cancer, and also functional phenotypes as well: delayed cataract formation, decreased frailty, decreased loss of hair.

I think that as a prelude to the next talk, some data that came out recently that really solidified for me that this was something worth going after as a therapy is Peter de Keizer's work, published last year, using a p53- and FOXO4-dependent mechanism. He was able to use an accelerated aging model, mice that are losing their hair, that are becoming frail, and show that treatment with an anti-senescence approach after these phenotypes have already manifested can reverse these phenotypes. This to me really solidifed the fact that this was a worthwhile development route to take for a therapy.

So that is the basis for Oisin's technology. As a team we thought that if we're going to develop a therapy that we can use for disease, then we were also thinking about the general anti-aging community and where this might be used some time in the future after it is proven clinically. So we wanted to utilize a strategy that is similar, leveraging successful animal models developed to date. Obvious we wanted to develop something that has a low toxicity profile, something that is well tolerated, and something that can be repeat dosed again and again. Something that is non-immunogenic, ideally didn't have overly off-target effects. Obviously many senescence phenotypes are tissue-specific, and the ability to target a therapy to different tissues would be a strength.

What I'm going to tell you about today is Oisin's technology that we developed. It is called the SENSOlytic platform. It is a lipid nanoparticle (LNP) platform that contains a non-integrating DNA plasmid. It is functionalized to be activated by a chemical inducer of dimerization that induces a very rapid and irreversible apoptotic response. Probably the most important part of this is the drug delivery system - the ability to deliver plasmid DNA systemically to many different tissues without significant toxicity. Oisin has developed a platform plasmid-based technology, and contrary to RNAi or delivery of messenger RNA, plasmids can be exquisitely engineered to only be activated in situations where specific pathways are activated, such as p16, p21, or p53. But they can also be engineered with enhancers or repressors and really tuned to specific tissues and diseases. We've created a system and a library of constructs that are active in various circumstances. The two I'm going to show you data on today are a version of the p16 promoter driving a suicide gene and a version of the p53 promoter driving a suicide gene.

We built a library of plasmids that are basically a specific selective promoter tied to an iCas9 inducable suicide gene that is then induced, or dimerized, through a chemical inducer of dimerization. Many of you may have seen this before, but iCas9 is a modified caspase, so it is truncated, the recruitment domain has been chopped off and replace with an FKBP dimerization domain. These domains interact very strongly with this chemical inducer of dimerization, AP20187, or its clinical analog, AP1903, that has already been shown to be safe in phase II clinical trials. What's really nice about this system is that you transiently express using a plasmid in the target cell, it is only expressed in cells with that pathway active, so p16 or p53 in our case. Then basically nothing happens until you add the dimerizer. The small molecule dimerizer is very well tolerated, goes systemic in a matter of minutes, and induces an irreversible apoptotic response. The iCas9 will then dimerize under these conditions, self-cleave, go to the apoptosome, and carry out a very rapid cell death with two to three hours. It is very hard from cells to escape from this. They can't evolve or otherwise get away from it. It is definitely final.

Some of our in vitro proof of concept experiments utilized placental lung myofibroblast cell line IMR-90. In this case we were inducing senescence using 10 grays of radiation and transfecting cells with a p16-driven iCas9. iCas9 is a little smaller than caspase-9 and can be detected with caspase-9 antibodies. In cells that haven't been treated with radiation, we don't see any expression of the iCas9. In cases where we cells are becoming senescent, expressing p16, we see induction of iCas9, and when we add a little bit of dimerizer to these cells, it is gone. It is very rapidly clearing from these cells. Then when we look at the ability for this to actually kill these cells, in viability assays, we see that every cell successfully transfected with the plasmid dies. We've shown through a number of other experiments, I'm just showing one example here, if we do flow cytometry, to look at the pathway of death, we confirm that we are inducing apoptosis in these cells.

So we have a plasmid that is very selective for p16-expressing cells. We can kill them very rapidly upon adding of the dimerizer. The question is how do we make this into a drug that works in people. It really is the delivery mechanism that is critical to making this both effective and safe. We opted to use a lipid nanoparticle platform. Lipid nanoparticles have been used for years and I'd say that mostly there's been a lot of promise and a lot of investment and very few successes. Alnylam Pharmaceuticals in Boston has just had a recent phase III successful trial with an RNAi drug, and the issue is that lipid nanoparticles tend to accumulate in the liver preferentially, and their mechanism of delivering nucleic acids into cells is a positive charge. It is a sort of a very simple technology. They've created lipids that have a positive charge. If you use a constitutive positive charge they punch holes in membranes very easily, so they associate and punch holes, disrupt endosomes, disrupt plasma membranes, so you can get stuff into cells very effectively, except they are really toxic. So there is a very low maximum tolerated dose in humans.

In response to this, several companies have developed what is called a conditionally cationic lipid. This is a lipid that is generally neutral in the bloodstream, gets taken up into endosomes, and becomes cationic in that acidic environment. These are the subject of the current clinical programs that are making their way through clinical trials for lipid nanoparticles. They work, but they are still quite toxic. The ideal delivery system is one that can use neutral lipids that are non-toxic, but use an alternative mechanism for cellular delivery of nucleic acids. I'm going to give you a tiny bit of background as to how we got to this this point. If you have a lipid nanoparticle and it has to get inside a cell, it has to get past an intact plasma membrane with all of its defenses. Viruses have evolved over millions of years to be able to solve this problem, and have evolved a variety of fusion proteins. Unfortunately, these fusion proteins are beautiful and gigantic and elegant and the way that they bring membranes together and create pores and mix lipids is really fantastic, but to attach this to a lipid nanoparticle is insane, because they are multi-protein, multi-subunit, they have gigantic active domains that are highly immunogenic.

Fortunately, there is a Canadian researcher who has been studying all his life these fusogenic orthoreoviruses and what he discovered in this particular class of viruses was that they don't use the fusion protein to enter cells, but once they enter cells in their reptilian or bird hosts, they cause all of the cells around them to rapidly fuse together. He spent his career characterizing this class of fusion-associated transmembrane proteins that are two orders of magnitude smaller than the smallest fusion protein produced by another virus, but are sufficient to induce cell-to-cell fusion, and most importantly, lipid nanoparticle to cell fusion.

While incorporating these proteins into a neutral lipid nanoparticle platform, you will find that neutral lipids by themselves are extremely poor at delivering things. In this example we're delivering an mCherry plasmid to cancer cells, and so without the fusogenic protein there is no delivery, with it we get fantastic delivery. So it increases delivery of a neutral lipid formulation by 80-350 times, and these are well tolerated in vivo. So this is an example, we're delivering an mRNA expressing luciferase, injecting into the tail vein. We get systemic expression of luciferase throughout the body. You get some accumulation in lungs and liver, but we get broad expression in many tissues including skin and soft tissues throughout the body.

This platform is what we are using to deliver the anti-senescence payload. The platform is called Fusogenix. It uses a neutral lipid formulation that is non-toxic and well tolerated. It uses these fusogenic proteins to deliver intracellularly. I'm not going to go into all the data. It actually took us three years to create an antibody against these proteins, they are really not immunogenic whatsoever. The reason for this is because most of it is a transmembrane domain. They are lipophilic, so they pack lipids around them, and they have a low profile to the immune system. We spent a lot of time working on these, engineering these fusogenic proteins to make them better. I'm not going to get into it all, but we're at the point now where we have a manufacturing platform to create these at scale, lypholize them even, and ship them around for use.

Let me show you data now taking the p16-activated caspase-9 and putting it in vivo in mice. In this case we've done an experiment now with 16 mice, an aged mouse cohort 80 weeks old. We've divided them into three groups, we're giving them a control LNP, we actually not giving them a dimerizer, or two doses, 5 and 10 mg/kg - and 10 mg/kg, if you know this field, is quite a huge dose. We treated these animals a single time by tail vein injection. We waited 96 hours, and then we gave them a single dose of dimerizer, also intravenously. Then we waited two more days, and we collected tissues, blood, and in this case we're doing a sensitive RT-PCR and controlling it with some housekeeping genes. We get a convincing dose-dependent reduction in p16 expression in a variety of tissues.

I'm going to show a couple of images where we spend a lot of time optimizing β-gal staining in mice. These are the prettiest images we've got, but we saw in multiple tissues a dose-dependent reduction in the expression of β-galactosidase. So very, very encouraging data. Obviously, creating data in the lab is great, but if we're going to translate this into humans, there's a lot of things that must be figured out. Toxicology is extremely important. It is important for a drug that you are going to deliver more than once to make sure that you don't create any neutralizing antibodies. So we've done a ton of studies looking at repeat dosing, and we don't produce any anti-drug antibodies whatsoever, so we can give this in repeated doses over time without any reduction in efficacy. CARPA assays are up there: CARPA is something that I learned about recently, complement activation-related pseudoallergy, an immune reactivity response that many patients who receive nanoparticle therapies like doxil can have. We've run all the assays for this, and it has a lower profile than doxil, so it is very well tolerated that way.

I'm happy to say that we've done some pilot non-human primate studies, giving ten times the maximum estimated human dose, and it was extremely well tolerated. We are just going through that information. Those monkeys actually got the treatment, both the p53 and p16 alone and in combination, and the dimerizer, so we will look at that and get some rich data. We're in the process of working through that now.

I'll keep coming abck to this point: the tolerability of these formulations is really important. I show this slide because it shows all of the efforts put into clinical trials of lipid nanoparticles and why they failed. If you look at the first three programs, these were really promising ten years ago, using cationic liposomes and lipid nanoparticles. If you can see by their maximum tolerated dose, way below 1 mg/kg, and these programs all failed due to liver-related toxicity. The second generation in the middle, conditionally cationic lipids, these were tolerated to a more or less better extent, and some of those programs have been successful and will result in approved drugs, but all of the targets are liver. Because the lipid nanoparticles preferentially accumulate in the liver, you're going to see dose-limiting toxicity if you don't use a neutral lipid formulation. Then you can see work using a neutral lipid formulation similar to ours, and they were not able to find a maximum tolerated dose in the one study. Based on our non-human primate studies, we expect our formulation to be equally as well tolerated.

We're currently evaluating a variety of constructs to see which one is the best to bring into humans, and - obviously it has been talked about at this conference - the creation of biomarkers that are viable endpoints for clinical trials, and also viable in animal models to look at efficacy. We're keen to talk to anybody who has a great biomarker. We have cohorts of mice in which we are looking at the life span and health span of these mice. We are thinking about the transition to the clinical stage where we're getting GMP manufacture going and doing our GLP toxicity analysis.

So I'm going to switch to cancer for a second because this is our route to the clinic. My day job is as a prostate cancer researcher. The one thing that really intrigued me about the crossover between senescence and cancer is the activation of the p53 pathway. p53 is the most mutated gene in cancer, and there are a lot of cancers that have a high burden of p53 mutation. I put prostate up there because it is actually relatively low, an average might be 10%, the vast majority of prostate cancers are low-grade. Once you get to metastatic disease, that mutation rate is well over 50%. So this is a viable target for cancers. While the p53 protein itself hasn't been a great target for oncology therapies, I think the pathway is great. If you think about p53, you can get two kinds of mutations. With all the stress cells have through replication and mutation burden, they will activate p53, to either resolve the damage or go through apoptosis. So cells either mutate or get rid of p53 to get around this. As a result the actual activation pathways that are driving this are highly upregulated. So can we exploit this activation to kill cancer cells?

I'm skipping over all the in vitro data as I only have three slides left, and I want to show you some in vivo data, as that's really important. In this case, we are using a very similar formulation to the one I showed before. There is an engineered p53 promoter driving this iCas9 suicide gene, wrapped in a neutral lipid nanoparticle. In this case we're growing gigantic prostate cancer tumors in an immunocompromised mouse. These are NOD/SCID mice. We're growing them up to over 500 m^3, so big tumors. We're doing a single intratumoral injection of the nanoparticle, waiting three days, and then doing a systemic injection of the dimerizer. We saw most of the tumors reduced 90-95% in 48 hours - and this is not amazing for an intratumoral injection, but I was very pleased because this means we're successfully transfecting the plasmid into the majority of tumor cells, which I thought was very exciting.

The real proof is to be able to do with a systemic injection, and we've done those studies. This is just an example of four mice in that cohort. We've grown these same very large tumors, growing them to a size of 500 m^3. In this case we're giving four daily tail vein injections of the LNP and on the fifth day we're giving them a single dose of the dimerizer, systemically. Again, we saw remarkable results, between 50-98% tumor reduction in just two days. This resulted in a significant prolongation of survival with a single dose in these animals. On average, six mice per group, almost a 70% reduction in tumor volume.

One thing that is really important as well: primary tumors don't kill patients in most situations. It is the metastatic disease, so we're really interested in seeing whether we can hit metastatic cancers. Obviously this will be the population we go into for the first clinical trials as well. So we have done a number of models looking at the ability of these LNPs to control metastatic disease, in this case we've got a prostate cancer systemic metastasis model, and an immunocompetent melanoma model. In both cases with a multiple dosing regimen, we were able to control this disease effectively.

We're on the path. Obviously, the long term goal of Oisin is to develop senescence-clearing therapies for aging and age-related diseases. But I think in the short term it is really important, not only for the nanoparticle technology, but also for this platform technology, to prove it in the clinic - safety and efficacy. So we've already got a phase I/phase IIb cancer trial designed, and we're right now gearing up for GLP toxicology that will be enabling for those studies. We're hoping to dose our first person in early 2019. We're excited about accelerating the translation of this technology. One thing I'll mention as well, there are many cancers in which this can work in. In Canada, we can actually do a phase I trial with all types of cancer, basically, so colorectal, prostate, lung, etc. We'll be looking for the biggest signal and most important cancer to be able to expand that cohort and then do the phase II.

Can a Reasonable Argument be Made for Variations in Human Longevity to be Significantly Driven by DNA Repair?

As I'm sure you are all aware, we humans do not exhibit a uniform pace of aging. Setting aside mortality caused by anything other than aging, the vast majority of recorded life spans at the present time fall within a range of three decades, 65-95. A comparatively tiny number of exceptional outliers age to death at younger or older ages. Some of this variation can be attributed to secondary aging, which is to say the way in which circumstances and lifestyle choices interact with the biology of aging. Visceral fat tissue and smoking cause greater chronic inflammation, accelerating all of the common age-related conditions, for example. On the other hand, calorie restriction modestly slows most aspects of aging. The rest is due to differences in primary aging, meaning intrinsic differences in genetics that lead to differences in the operation of cellular mechanisms that occur more independently of lifestyle and environment. Some human mutants have lower blood cholesterol, and thus slower onset of atherosclerosis, for example.

Most accelerated aging conditions take the form of a mutational malfunction in DNA repair - cells become damaged and dysfunctional much more rapidly than is the case in normal individuals. The present consensus, not unchallenged, is that stochastic mutation has a meaningful role in aging. This may be a matter of problematic acquired mutations in stem cells expanding widely throughout a tissue as a result of being inherited by daughter cells. If stochastic mutation is important in aging, then it may be reasonable to argue a role for variations in DNA repair mechanisms in the natural differences observed in human life span. Indeed, some past studies have done just that. It is very challenging to make a case for how large any given contribution to aging and longevity might be, however. Short of accurately and narrowly removing a specific contribution and watching to see what happens as a result, informed speculation is about the best that can be achieved.

Personally, I'm not convinced that there is all that much gold to be found in mining the causes of natural variation in human life span. Near all evidence to date (with one or two spectacular exceptions) suggests that individual genetic variations have at best modest effects, and more usually tiny and highly conditional effects. Variations correlated with longevity in one study usually don't appear in another, and "correlated" in this context might mean that it raises the odds of reaching the age of 100, while being so corroded by aging to a ghost of what you once were, to be 2% rather than 1%. This doesn't seem like a goal worth chasing when there are better options available. Instead of searching for ways to alter cellular metabolism in ways that would make more people live and age like today's centenarians, the research community should be finding ways to reverse the mechanisms of aging - to repair the damage, to restore the normal operation of youthful metabolism.

Genomic Approach to Understand the Association of DNA Repair with Longevity and Healthy Aging Using Genomic Databases of Oldest-Old Population

Longevity is usually defined as living until life expectancy that is typically over 85 years old. Exceptional longevity such as centenarians is considered when one is more than 95 years old with a healthy life. Several researchers have emphasized the importance of in-depth studies on longevity to cope with an aging society because such studies could suggest various biomedical clues for living a long and healthy life. Oldest-old individuals, often centenarians, represent an adequate model to investigate the complex phenotype of healthy longevity. Among enormous population-based studies on centenarians, one major focus is on people with exceptionally long lives without functional impairment. Several landmark studies on healthy centenarians have found that the progression of major diseases such as cancer, cardiovascular disease, and stroke is delayed in the oldest group compared to that in the other younger or same-aged control groups, suggesting a substantial relationship between healthspan and longevity.

Although successful longevity traits are modulated by various factors, such as environmental, behavioral, and/or endogenous causes, genetic factor might be a major factor that contributes to healthy aging. Within the past few decades, many researchers have tried to identify longevity-associated genes using diverse species, ranging from less complex organisms to higher organisms. With development in genomic technology, genetic factors associated with longevity have been suggested in human population studies and human genome-wide association studies. It has been found that variants of APOE and FOXO3A are highly associated with longevity. This finding has been consistently replicated in many different population-based studies. Despite the complexity of healthy longevity in human due to various influences, genetic factors are thought to be exceedingly important to understand the genetic basis of longevity.

Accumulation of DNA damage is associated with functional decline in the aging process. Thus, maintenance of genomic integrity might be a crucial factor for healthy life and longevity. Genome instability generally increases with age. DNA repair machineries control genome stability. Previous studies on centenarians have shown that oldest-old population have enhanced DNA repair activity with significant lower frequency in genomic and cellular damage compared to their younger counterparts. Thus, DNA repair plays an important role in understanding exceptionally long-lived individuals.

In this review, we focus on major DNA repair machineries associated with longevity. We also explored longevity-associated population studies using genome-wide approaches. With brief introductions of genomic databases in aging and longevity field, ample genomic resources of normal long-lived human population were utilized for DNA repair-focused approach. Herein, we suggest a new aspect of longevity study to investigate the complex interplay between DNA repair and longevity by processing human genetic variations based on previous studies, providing a brief interpretation of their molecular networks.

A Recent Profile of Unity Biotechnology and its Work on Senolytic Therapies

It was only partially in jest that I recently noted Unity Biotechnology as a financial institution with a sideline in rejuvenation research, specifically the targeted destruction of senescent cells. The principals have raised a truly enormous amount of funding in the past year and a half, and recently filed for IPO. They have not yet presented even preliminary human data. Typically the ordering of these matters tends to be at least a little different; there are some raised eyebrows in the community. But if the Unity Biotechnology founders can raise the funds and use them well to advance the state of the art, then more power to them. From their SEC filings we know a little more than we did as to the specific classes of pharmaceutical developed at the company, or at least those they are prepared to talk about today. One is the line of development that started with Bcl-2 inhibitors such as navitoclax, and the other is a more novel approach to senescent cells, one that is as much about suppressing their harmful signaling as it is about destroying the cells.

In using pharmacological methods, Unity Biotechnology has an approach to senescent cell clearance that is objectively worse than, say, the programmable gene therapy pioneered by Oisin Biotechnologies. Pharmaceutical approaches are slow and expensive to tinker into better shape when they turn out to be overly tissue specific or have problematic side-effects. Nonetheless, it is entirely possible to build an enormous business on the back of a first generation senolytic pharmaceutical, because if it clears even 25% of senescent cells from just a few tissue types it will still be far more useful than any other class of medication for inflammatory, fibrotic, and other age-related diseases of those tissues. But the competition in the form of Oisin Biotechnologies will arrive in the clinic a couple of years later with a form of therapy that can destroy all senescent cells in all tissues, and that can be adapted quickly and at low cost.

The Unity folk know this, and the potential market is so very large (every human being much over the age of 40) that I think it probably won't dent their success all that much. There will be many enormous companies and many senolytic therapies coexisting in that market. It is plausible that the more interesting challenge for the Unity Biotechnology staff is to create a therapy that is meaningfully better than the dasatinib and quercetin combination, better enough to justify the very large cost multiple that the company will have to charge in order to keep their investors satisfied. Dasatinib is out of patent protection, its pharmacology is very well characterized in humans, and it runs to a 100-200 cost for a single dose that would be usefully taken perhaps once a year at most. Should the human studies, such as those running at Betterhumans, show it to be effective, that may cause issues for Unity or any other small molecule development concern. None of the other candidate drugs have yet done much better than dasatinib and quercetin in animal studies. The existence of dasatinib will drag down the prices it is possible to charge for anything that performs in the same class - which so far is everything, to a first approximation.

A Biotech Entrepreneur Aims To Help Us Stay Young While Growing Old

The idea behind Unity - preventing aging - sounds crazy, but it's backed by dozens of scientific papers. There are aging cells, called senescent cells, that build up throughout the body and contribute to what we think of as old age-things like achy joints, waning vision, even perhaps Alzheimer's. Kill those senescent cells with drugs, Nathaniel David reasons, and people might be able to grow old without becoming infirm. "Like, how awesome would it be? The problem is you have to take the first baby step to demonstrate it's possible. That's what chapter one is: demonstrate in a human being that the elimination of senescent cells takes a heretofore inescapable aspect of aging and can either halt it or reverse it." Unity's chief executive and chairman, Keith Leonard, 56, interrupts. "Just that. It's easier to talk to the FDA about treatment of a disease once it's diagnosed than it is to work really early and prevent disease. But prevention is what we'd love to get to."

It's an amazing goal, backed by great science, not to mention 222 million in venture capital and 85 million raised from a May initial public offering, which valued Unity at 700 million, flat with its last fundraising. When a medicine is just beginning human tests, the odds it will make it to market are 10%. But David's career has turned into a blueprint for success in biotech, transforming ideas from university laboratories into viable companies, investment gains and, maybe, drugs. David's five companies have raised 1.5 billion and made investors close to 2 billion without ever actually turning a profit. "He's probably the best person in the world at finding great academic science and shaping it into a fundable story and a sellable business plan," says Kristina Burow, managing director at Arch Venture Partners. She has known David since he was in graduate school and has backed four of his startups.

The idea for Unity arrived in David's email inbox in 2011, from multiple senders at the same time. Jan M. van Deursen had genetically engineered mice so that many types of senescent cells would die. The results of this experiment and of others that followed were striking. Van Deursen introduced David to Judith Campisi, at San Francisco's Buck Institute, who had helped establish the senescent-cell field. Arch founded Unity in 2011, with Van Deursen and Campisi as cofounders. For five years the company didn't even have offices; all the work was done at the scientists' labs.

There's a good reason for the skepticism, no matter how cool Unity's science is: Investors have been hoodwinked by antiaging science before. In 2007, a company called Sirtris went public based on the hype around antiaging compounds related to red wine. GlaxoSmithKline bought Sirtris for 720 million in 2008, but it never resulted in any drugs and was shut down in 2013. Unity needs to show that a medicine can have a clear effect in humans. Its first attempt, UBX0101, will target arthritis. Now, in the first human test, it will be injected into the knees of 30 patients, who will fill out surveys about how much pain they feel, have fluid removed from their knees and undergo MRI scans. They'll be compared with ten patients who will get a placebo injection. Any signs that the drug is making patients better will be seen as a reason to move into further studies. Unity expects to enter two more drugs into human studies by the end of next year. Candidate diseases include glaucoma, where killing senescent cells seems to lower the pressure that builds up in the eye, and lung diseases, where it may coax lung cells to stop making scarred, fibrous tissue.

Unity has raised so much money precisely because its executives know it may take multiple tries to find a medicine. It's not known what the risks of killing senescent cells are; it's possible they could include, for instance, slow wound healing. There's no way to know until human tests begin.

Antibodies Targeting Oxidized Lipids Slow the Development of Atherosclerosis

In the SENS rejuvenation research view of atherosclerosis, a primary cause is the presence of oxidized lipids in the bloodstream. Rising levels of oxidative stress with aging, with mitochondrial dysfunction as a primary cause, means an increasing number of oxidized lipid molecules. Atherosclerosis begins when these lipids irritate the blood vessel walls, attracting macrophage cells to clean up the problem. The normal process involves macrophages ingesting the problem lipids and either breaking them down or handing them off to high-density lipoprotein (HDL) particles to be carried to the liver where they can be dealt with. Unfortunately, some species of oxidized lipid cannot be processed well by macrophages, and the cells become overwhelmed. They either die or become inflammatory foam cells, making the area of damage worse. The fatty plaques of atherosclerosis that narrow and weaken blood vessels are formed of dead macrophages and the lipids that they should have removed.

The SENS approach is to find ways to break down the problem oxidized lipids, remove them before they can cause harm to the macrophages that are critical to maintenance of blood vessel walls. Some progress in this LysoSENS program for atherosclerosis has been accomplished, mostly focused on 7-ketocholesterol, a particularly harmful species of oxidized lipid. Other groups are starting to pay attention to this line of research, which is a good thing. In the study reported here, scientists used antibodies to thin out a class of oxidized lipid from the bloodstream, and demonstrated that this slows the pace at which atherosclerosis progresses in a mouse model of the condition. This is important evidence that strongly supports the SENS position.

In atherosclerosis, lipids such as cholesterol move in a loop: from the liver to LDL particles, then into atherosclerotic lesions, then taken up by macrophages and passed off to HDL particles, then finally back to the liver. All of the available anti-atherosclerosis technologies interfere in the front half of that loop, the movement of lipids through the bloodstream in LDL particles. They globally reduce cholesterol levels, and that somewhat slows the advance of atherosclerosis. It doesn't do it well, however. Even extremely low cholesterol levels, such as those produced by PCSK9 inhibition, don't significantly reduce existing atherosclerotic plaque - they allow a little reduction, but that is about it. Thus other strategies are needed, and the work here is good evidence for approaches that in some way protect macrophages from oxidized lipids, a methodology that should allow those cells to better clear existing plaque.

Antibody Blocks Inflammation, Protects Mice from Hardened Arteries and Liver Disease

Some phospholipids - the molecules that make up cell membranes - are prone to modification by reactive oxygen species, forming OxPL. This event is particularly common in inflammatory conditions such as atherosclerosis, in which artery-blocking plaques form. Prior to this study, researchers were unable to control phospholipid oxidation in a way that would allow them to study its role in inflammation and atherosclerosis.

Researchers engineered mice with two special attributes: 1) they have a gene mutation that makes them a good model for atherosclerosis and 2) they generate a piece of an antibody called E06 that's just enough to bind OxPL and prevent their ability to cause inflammation in immune cells, but not enough to cause inflammation on its own. They fed the mice a high-fat diet.

Here's what happened: Compared to control mice, the mice with E06 antibodies had 28 to 57 percent less atherosclerosis, even after one year and despite having high levels of cholesterol. The antibody also decreased aortic valve calcification (hardening and narrowing of the aortic valves), hepatic steatosis (fatty liver disease) and liver inflammation. E06 antibody-producing mice had 32 percent less serum amyloid A, a marker of systemic inflammation. The E06 antibody also prolonged the life of the mice. After 15 months, all of the E06 antibody-producing mice were alive, compared to 54 percent of the control mice.

Oxidized phospholipids are proinflammatory and proatherogenic in hypercholesterolaemic mice

Oxidized phospholipids (OxPL) are ubiquitous, are formed in many inflammatory tissues, including atherosclerotic lesions, and frequently mediate proinflammatory changes. Because OxPL are mostly the products of non-enzymatic lipid peroxidation, mechanisms to specifically neutralize them are unavailable and their roles in vivo are largely unknown. We previously cloned the IgM natural antibody E06, which binds to the phosphocholine headgroup of OxPL, and blocks the uptake of oxidized low-density lipoprotein (OxLDL) by macrophages and inhibits the proinflammatory properties of OxPL.

Here, to determine the role of OxPL in vivo in the context of atherogenesis, we generated transgenic mice in the Ldlr-/- background that expressed a single-chain variable fragment of E06 (E06-scFv) using the Apoe promoter. E06-scFv was secreted into the plasma from the liver and macrophages, and achieved sufficient plasma levels to inhibit in vivo macrophage uptake of OxLDL and to prevent OxPL-induced inflammatory signalling.

Compared to Ldlr-/- mice, Ldlr-/-E06-scFv mice had 57-28% less atherosclerosis after 4, 7 and even 12 months of 1% high-cholesterol diet. Echocardiographic and histologic evaluation of the aortic valves demonstrated that E06-scFv ameliorated the development of aortic valve gradients and decreased aortic valve calcification. Both cholesterol accumulation and in vivo uptake of OxLDL were decreased in peritoneal macrophages, and both peritoneal and aortic macrophages had a decreased inflammatory phenotype. Serum amyloid A was decreased by 32%, indicating decreased systemic inflammation, and hepatic steatosis and inflammation were also decreased. Finally, the E06-scFv prolonged life as measured over 15 months. Because the E06-scFv lacks the functional effects of an intact antibody other than the ability to bind OxPL and inhibit OxLDL uptake in macrophages, these data support a major proatherogenic role of OxLDL and demonstrate that OxPL are proinflammatory and proatherogenic, which E06 counteracts in vivo.

A Selection of Recent Research in the Alzheimer's Field

Today I'll point out a few recent examples of research into Alzheimer's disease; they are representative of present shifts in emphasis taking place in the field. There is a great deal of reexamination of existing mechanisms, alongside a search for new mechanisms. This is prompted by the continued failure to obtain meaningful progress towards patient improvement via clearance of amyloid, which some are interpreting as a need to look elsewhere for a viable basis for therapy. I believe it probably has more to do with the condition arising from multiple processes that have similarly sized contributions to cognitive decline: amyloid, tau, immune dysfunction, and vascular aging. Partially address one, and it may be hard to prove that a useful difference was made in patients because the other mechanisms are still present, still causing harm.

The Alzheimer's-related portion of the broader field of aging research represents a sizable fraction of the output of the medical life science community these days. That is because much of the budget of the NIA has for some time been directed towards the study of Alzheimer's disease, and that in turn influences the strategy taken by larger private funding sources and research programs. The grant-seeking portion of the scientific world, which is to say most of it, sedately follows the availability of funds in much the same way as flowers follow the sun. Over time, the funding landscape shapes the endeavor of science just as much as the state of the science shapes availability of funding.

It has often appeared to me somewhat arbitrary as to which aspects of aging are considered an emergency, a priority. The modern public consensus on the need for a massive cancer research institution and a timeline for bringing cancer under medical control is in fact quite modern - it didn't exist much prior to the 1930s. Presentation of the various forms of dementia as a major public concern is a much more recent development. Yet these issues have long existed. We might view it as progress that at least a few pieces of degenerative aging have been pushed over time from the "way things are, cannot be changed" bucket into the "addressable, must fix" bucket. But most people have yet to take the necessary next step, which is to consider aging as a whole a medical condition with clear root causes, a state of ill health that the research community can work towards treating. The dominant conceptual approach of breaking down aging into named diseases has obscured the most important possibility, that aging as a whole can be repaired and reversed.

Research links Tau aggregates, cell death in Alzheimer's

Although scientists have studied for years what happens when tau forms aggregates inside neurons, it still is not clear why brain cells ultimately die. One thing that scientists have noticed is that neurons affected by tau accumulation also appear to have genomic instability. Previous studies of brain tissues from patients with other neurologic diseases and of animal models have suggested that the neurons not only present with genomic instability, but also with activation of transposable elements.

"Transposable elements are short pieces of DNA that do not seem to contribute to the production of proteins that make cells function. They behave in a way similar to viruses; they can make copies of themselves that are inserted within the genome and this can create mutations that lead to disease. Although most transposable elements are dormant or dysfunctional, some may become active in human brains late in life or in disease. That's what led us to look specifically at Alzheimer's disease and the possible association between tau accumulation and activated transposable elements."

The researchers began their investigations by studying more than 600 human brains. One of the evaluations is the amount of tau accumulation across many brain regions. In addition, researchers comprehensively profiled gene expression in the same brains. The researchers found a strong link between the amount of tau accumulation in neurons and detectable activity of transposable elements. Other research has shown that tau may disrupt the tightly packed architecture of the genome. It is believed that tightly packed DNA limits gene activation, while opening up the DNA may promote it. Keeping the DNA tightly packed may be an important mechanism to suppress the activity of transposable elements that lead to disease.

Brain cholesterol associated with increased risk of Alzheimer's disease

While the link between amyloid-beta and Alzheimer's disease is well-established, what has baffled researchers to date is how amyloid-beta starts to aggregate in the brain, as it is typically present at very low levels. "The levels of amyloid-beta normally found in the brain are about a thousand times lower than we require to observe it aggregating in the laboratory - so what happens in the brain to make it aggregate?" The researchers found in in vitro studies that the presence of cholesterol in cell membranes can act as a trigger for the aggregation of amyloid-beta.

Since amyloid-beta is normally present in such small quantities in the brain, the molecules don't normally find each other and stick together. Amyloid-beta does attach itself to lipid molecules, however, which are sticky and insoluble. In the case of Alzheimer's disease, the amyloid-beta molecules stick to the lipid cell membranes that contain cholesterol. Once stuck close together on these cell membranes, the amyloid-beta molecules have a greater chance to come into contact with each other and start to aggregate - in fact, the researchers found that cholesterol speeds up the aggregation of amyloid-beta by a factor of 20. "The question for us now is not how to eliminate cholesterol from the brain, but about how to control cholesterol's role in Alzheimer's disease through the regulation of its interaction with amyloid-beta. We're not saying that cholesterol is the only trigger for the aggregation process, but it's certainly one of them."

Since it is insoluble, while travelling towards its destination in lipid membranes, cholesterol is never left around by itself, either in the blood or the brain: it has to be carried around by certain dedicated proteins, such as ApoE, a mutation of which has already been identified as a major risk factor for Alzheimer's disease. As we age, these protein carriers, as well as other proteins that control the balance, or homeostasis, of cholesterol in the brain become less effective. In turn, the homeostasis of amyloid-beta and hundreds of other proteins in the brain is broken. By targeting the newly-identified link between amyloid-beta and cholesterol, it could be possible to design therapeutics which maintain cholesterol homeostasis, and consequently amyloid-beta homeostasis, in the brain.

As mystery deepens over the cause of Alzheimer's, a lab seeks new answers

For more than 20 years, much of the leading research on Alzheimer's disease has been guided by the "amyloid hypothesis." But with a series of failed clinical trials raising questions about this premise, some researchers are looking for deeper explanations into the causes of Alzheimer's and how this debilitating condition can be treated. Among these investigators are researchers focused on axonal transport - the complicated, internal highway system that conveys precious, life-giving materials from one part of a nerve cell to another. Breakdowns in this transport system can lead to "traffic jams," and some scientists hypothesize that such blockages precede the formation of plaques in neurological diseases like Alzheimer's.

Using the neurons of fruit fly larvae, researchers have been investigating the role of presenilin - another Alzheimer's-linked protein - in axonal transport for several years. "We are looking at processes that occur before cell death, before you start to see plaques in the brain. A lot of the treatments being developed for Alzheimer's are targeting beta-amyloid, but maybe we should be targeting processes that happen earlier on, before plaques are formed."

The researchers' latest study provides details on how presenilin interacts with GSK-3β, and reports that a specific molecular structure within presenilin - a loop region - is necessary for proper traffic control. Presenilin has an important role in Alzheimer's: The protein aids in the production of beta-amyloid, which, when overproduced, causes plaques to form in patients' brains. But the latest work shows that presenilin may also have another role - this one positive - in regulating the flow of traffic within brain cells and preventing blockages that over time can lead to death of the cell and disease. "What does this protein normally do? As we learn more about presenilin, it's possible that our research will result in new, more targeted opportunities for treating or preventing Alzheimer's disease."

An Interview with Jim Mellon, and Update on Juvenescence

This interview with Jim Mellon opens with an update on some of the recent investment activities of Juvenescence, founded last year in order to participate in the enormous market opportunity afforded by the development of the first working rejuvenation therapies. It is in Mellon's self-interest to help educate the world about the size of this market, and draw in other, larger entities that will help to carry his portfolio companies to the finish line. So he is doing just that, and in doing so benefits us all. His advocacy will help all fronts in fundraising for research and development in this field.

That advocacy continues, as it remains the case that the investment community as a whole is slow to wake on the topic of treating aging as a medical condition. The more agile portions of it are starting to move, but the larger interests are still on the sidelines. Yet any viable rejuvenation therapy will be a bigger prospect that any blockbuster drug of the past few decades, and the first of these therapies are already either in development or even arguable available in the case of the first senolytic pharmaceuticals. The target market is every human being over the age of 40, for treatments that will have to be reapplied every so often, indefinitely. There won't be a bigger opportunity for gain until the orbital frontier opens up.

What's making you so optimistic that you and I will live to be 100 or 110?

The first book I wrote about biotech came out at the end of 2012. When the latest book came out, we were looking at just five years of a gap. And in those five years, artificial intelligence - which didn't exist in 2012 - is now very much in the frame for the development of new compounds. A cure for hepatitis C did not exist in 2012. Now, if you've got the money - and even if you don't have the money, because drugs are coming down in price - you can be cured of hepatitis C. Cancer immunotherapy did not exist in 2012, and is fast becoming the standard of care in blood cancers and will ultimately become as important in solid tumors as well, improving cancer survival rates by a dramatic amount. And lastly, most importantly, CRISPR gene editing did not exist in 2012. If you think about what's happened in the last five years, all remarkable technologies, just imagine what's going happen in the next five years.

How do you expect Juvenescence Ltd. will capitalize on this?

We are very early in this land grab. We are very hopeful that we can get at least two or three compounds into the clinic and out of the clinic within the next few years which will have indications beyond longevity, because it's very hard for anyone to say "I can keep you alive for 30 or 40 years" without hanging around to see if it works. I've done a few things in my life, but this is by far the most interesting and exciting. Rather than associating old people with being decrepit, people will be robust for a lot longer and will live a lot longer. I'm not a subscriber to Aubrey de Grey's view that the first person to be 1,000 is alive today. But I do absolutely believe that the first people who will live to be over 150 are amongst us now. That is just quite amazing. It's going to change everything in the world.

Not long ago I interviewed an actuary about how the financial assumptions underlying pensions or life insurance. He pointed out that gains in life expectancy are leveling off.

Every bit of our life expectancy increase in the last century or so has come from environmental factors. Better sanitation, lower infant mortality, better nutrition, less manual labor and therefore less accidents. None of it has occurred from biological change. It's only now that biological change is about to happen. The question then becomes: who benefits, and who doesn't? In the United States, you suffer from tremendous health inequality. New drugs like senolytics or rapalogs are probably going to have 10 years of patent life. Now if we have a long life, 10 years is not that long. So even if those drugs may expensive to begin with and therefore available only to so-called elites, they will in due course become rather like anti-ulcer drugs are today and available to everyone. In the 1980s, anti-ulcer drugs were extremely expensive prescription drugs. Now you can go into Walgreens and buy them for nothing, basically. That will apply to all these drugs.

Why is Alzheimer's Disease Peculiarly Human?

Recent (and not yet fully accepted) evidence suggests that chimpanzees and dolphins might suffer Alzheimer's disease, or at least a condition that is similar enough to be comparable. Other than possibly those two species, humans are the only mammals to experience Alzheimer's, the aggregation of amyloid-β and tau proteins into solid deposits that alter brain biochemistry for the worse. Why is this the case? What is it about our particular evolutionary path that resulted in this outcome? Might that teach us anything that could be used to suppress the development of the condition?

In this article, Alzheimer's is painted as a consequence of antagonistic pleiotropy during the divergence of our species from other primates. Antagonistic pleiotropy is the name given to the theorized tendency for evolution to produce systems that are advantageous to young individuals but harmful to old individuals. Examples include systems that do not maintain themselves well, such as cells that lack enzymes to digest certain harmful forms of molecular waste, systems that have finite resources that run out, such as the adaptive immune system's capacity to remember past pathogens, and systems that interact poorly with the damaged environment of old tissues, causing further damage - which is just about everything else.

While granting human species some advantages over our primate cousins, recent genomic adaptations appear to have come at a cost. "I find the idea that genes that have been involved in the development of the human brain and in making the human brain different from the brains of great apes might also be genes that have the byproduct of raising the risk of Alzheimer's is one of those ironic twists that seem to be pretty common in evolutionary biology."

In 1957, evolutionary biologist George Williams proposed a theory: adaptations that made species more fit in the early years of life likely made them more vulnerable to diseases in the post-reproductive years. However, there has been little research to support his theory. As a test of this theory, researchers started by focusing on enhancers, pieces of DNA with the ability to boost the activities of certain genes, and therefore, the levels of resulting proteins. Previous research had identified enhancers as key to as key to human evolution after diverging from the last common ancestor with chimpanzees. Using FANTOM, an annotated database with information on expression levels of human-specific enhancers, researchers compared human data with that of primates to find the fastest evolving enhancers. Comparisons with primates including chimpanzee, gorilla, orangutan, and macaque genomes revealed 93 such enhancers expressed within neurons and neuronal stem cells that had evolved rapidly in humans.

Genes lying close to these enhancers, and therefore possibly under their control, were important for brain development. It is plausible that the enhancers were positively selected for during evolution because of their effects on these brain-related genes. However, they also found evidence of proximal associations between the enhancers and genes implicated in Alzheimer's, Parkinson's disease, type 2 diabetes, hypertension, and osteoporosis. According to Williams's theory, these aging-related diseases would manifest later in life and would go unnoticed during the Darwinian selection process because of the advantage they bestowed in the early years.

In order to see if there is indeed a functional (rather than merely correlative) connection between the enhancers and aging-related diseases, the team used the Cancer Genome Atlas and GTEx, both large databases, to draw up gene maps highlighting all the genes coexpressed with each enhancer. The researchers targeted one such enhancer associated with brain development and also with genes known to be linked to brain diseases. When the researchers used CRISPR to delete the enhancer in human cell lines, protein abundance from its related genes fell. Importantly, some of these genes are usually suppressed by a gene called REST, which keeps Alzheimer's at bay. However, in the presence of the functional enhancer, these genes are boosted. Thus, while this enhancer may be important for brain development, it seemingly opposes REST's protective function against Alzheimer's.

Arguing for Nicotinamide Riboside to Improve Hematopoietic Stem Cell Function

Researchers here argue for enhanced levels of NAD+ to boost stem cell function through improved mitochondrial function. This is an area of metabolism that has gained increasing attention of late, a second pass at the whole topic of sirtuins, mitochondrial function, and metabolism in aging. I'd say the jury is still out on whether it is worth pursing aggressively in human medicine. One or two early trials seem promising, in the sense of obtaining benefits that look similar to those derived from exercise, but the magnitude and reliability of those benefits is the important question.

The bone marrow stem cell population responsible for generating blood and immune cells, hematopoietic stem cells, declines in activity with age, as is the case for other stem cell populations. Some of this is due to intrinsic damage, but the evidence to date suggests that, up until very late life, the majority of the loss of activity can be overridden - it is an evolved response to rising levels of damage, possibly arising because it reduces cancer risk, rather than the direct consequence of damage. Thus researchers are in search of ways to safely override this response, via a variety of means.

Mitochondria are generally characterized as the powerhouse of the cell, since this is the site where energy is produced from ATP. In addition to energy production, mitochondria play a key role in several important cellular processes, including growth, signaling, differentiation, reactive oxygen species (ROS) production, apoptosis, and cell cycle control. Interestingly, unlike other cellular organelles, mitochondria have their own DNA, mitochondrial DNA (mtDNA), and several studies have indicated an association between the accumulation of mtDNA mutations and mammalian aging.

Historically, mitochondria have not been considered important in restoring the functions of aged hematopoietic stem cells (HSCs); however, emerging studies on rejuvenating HSCs suggest an association between sirtuins (SIRTs) and mitochondrial activities. In addition, a study on the deregulation of the mitochondrial stress-mediated metabolic system demonstrated that SIRT7 strongly influences the regenerative capacity of HSCs. Although the functions of musculoskeletal stem cells (MuSCs) and HSCs are distinct, alteration of the SIRT1-associated nuclear/mitochondrial axis appears to be a common hallmark of aging in both cell types.

Recent research suggests the possibility of restoring the mitochondrial functions of aged stem cells, including MuSCs, nerve tissue stem cells (NSCs), and melanocyte stem cells (McSCs), by NAD+ supplementation without genetic manipulation. The remedial effect of the NAD+ precursor nicotinamide riboside (NR) enhances mitochondrial functions in stem cells, including respiration, membrane potential, ATP production, and the mitochondrial unfolded protein response (UPR); however, these effects are not observed in stem cells with a SIRT1 deficit. Moreover, NR was found to suppress the process of senescence in adult NSCs and McSCs.

These findings have reinforced the notion that NAD+ precursors can function as a pharmacological tool to enhance SIRT activities. This, in turn, paves the way for clinical translation of NAD+ precursor treatment through further investigations of hematopoietic tissues. We review evidence relating mitochondrial dysfunction to HSC aging, and propose a strategy for mitochondrial-targeted recovery as a potentially safe, effective, and non-invasive method for the control or prevention of aging-related hematopoietic diseases.

Another Potential Approach to Remineralization of Lost Tooth Enamel

It seems that the research community has made some progress in recent years towards methods of rebuilding tooth enamel. This would in principle allow for reconstruction rather than replacement of damaged teeth, and let dental caries be regrown rather than drilled and patched. I noted one possible approach earlier this year, and the work here is the basis for another. These are fairly low-level methodologies, depending on the fine molecular details of mineralization in living organisms. The open access paper makes for interesting reading, albeit rather heavy going for anyone not up to speed on the chemistry involved. It remains to be seen how rapidly this approach can move towards the clinic.

Enamel, located on the outer part of our teeth, is the hardest tissue in the body and enables our teeth to function for a large part of our lifetime despite biting forces, exposure to acidic foods and drinks and extreme temperatures. This remarkable performance results from its highly organised structure. However, unlike other tissues of the body, enamel cannot regenerate once it is lost, which can lead to pain and tooth loss. These problems affect more than 50 per cent of the world's population and so finding ways to recreate enamel has long been a major need in dentistry.

Now a new approach can create materials with remarkable precision and order that look and behave like dental enamel. The materials could be used for a wide variety of dental complications such as the prevention and treatment of tooth decay or tooth sensitivity - also known as dentin hypersensitivity. "This is exciting because the simplicity and versatility of the mineralisation platform opens up opportunities to treat and regenerate dental tissues. For example, we could develop acid resistant bandages that can infiltrate, mineralise, and shield exposed dentinal tubules of human teeth for the treatment of dentin hypersensitivity."

The mechanism that has been developed is based on a specific protein material that is able to trigger and guide the growth of apatite nanocrystals at multiple scales - similarly to how these crystals grow when dental enamel develops in our body. This structural organisation is critical for the outstanding physical properties exhibited by natural dental enamel. Enabling control of the mineralisation process opens the possibility to create materials with properties that mimic different hard tissues beyond enamel such as bone and dentin. As such, the work has the potential to be used in a variety of applications in regenerative medicine.

Why Do Only Some People Suffer Alzheimer's Disease?

Alzheimer's disease might be argued to be a lifestyle condition, but it is not as much of a lifestyle condition as type 2 diabetes - it is not as reliably connected to lifestyle choices. Not everyone who lets themselves go, becoming fat and sedentary, winds up with a diagnosis of Alzheimer's disease, despite it being clear from the data and what is known of the mechanisms involved that both of those environmental circumstances are contributing risk factors. So why do only some people with the risk factors suffer Alzheimer's disease? Why do some people without the risk factors suffer from Alzheimer's disease? Is there anything useful to be learned at this stage from comparing the biochemistry of various groups with and without the condition?

These are questions very focused on how exactly the condition progresses, which stands a little in opposition to the strategy of attacking all of the known root causes of disease - in other words striving to remove all of the accumulated protein aggregates thought to cause the condition. In the case of Alzheimer's disease, that strategy hasn't been doing so well to date; the amyloid clearance field is a graveyard of failed clinical trials. Does this mean there is vital information yet to be discovered, or does it mean that the research community hasn't been clearing enough molecular waste, and both tau and amyloid must be reduced in the aging brain in order to see benefits? Arguments can be made either way.

The two primary histopathological changes to the brain due to Alzheimer's disease (AD) are the deposition of amyloid and tau. These two AD-related brain changes are the primary underlying causes of neurodegeneration and cognitive dysfunction which ultimately leads to dementia. As human longevity increases, and AD dementia increasingly becomes a major societal burden, finding pathways that lead to brain aging without AD pathologies (ADP) are critical.

Currently, much of the research has been focused on resilience or cognitive reserve, wherein the focus has been on discovering how and why individuals are able to remain clinically unimpaired or cognitively normal despite ADP. However, it is important to investigate, using surrogates of amyloid and tau pathologies via cerebrospinal fluid (CSF) and positron emission tomography (PET), why majority of individuals develop ADP as they age and how some oldest old individuals are able to age without significant ADP. The latter individuals are called "exceptional agers" without ADP.

There are three testable hypotheses. First, discovering and quantifying links between risk factors and early ADP changes in midlife using longitudinal biomarker studies will be fundamental to understanding why the majority of individuals deviate from normal aging to the AD pathway. Second, a risk factor may have quantifiably greater impact as a trigger and/or accelerator on a specific component of the biomarker cascade (amyloid, tau, neurodegeneration). Finally, and most importantly, while each risk factor may have a different mechanism of action on AD biomarkers, "exceptional aging" and protection against AD dementia will come from "net sum" protection against all components of the biomarker cascade.

While important strides have been made in identifying risk factors for AD dementia incidence, further efforts are needed to translate these into effective preventive strategies. Using biomarker studies for understanding the mechanism of action, effect size estimation, selection of appropriate end-points, and better subject recruitment based on subpopulation effects are fundamental for better design and success of prevention trials.

Building Useful Worker Devices From Nanoparticles and Cell Components

The medical nanorobots of decades to come will be a close fusion between natural and artificial molecular machinery. They will exist because it is possible to build worker devices that are more effective and efficient at a given task that evolved cells and cellular structures. Today, however, the state of the art involves melding simple cell structures with nanoparticles or other molecular machines. A great deal of innovation and experimentation is taking place, but it isn't always clear which of these many projects will make the leap into commercial development, versus serving as an inspiration or bridge to later efforts in the lab. In many ways this is still the barnstorming era of biotechnology, in which we should expect many strange feats, works of art, and dead ends along the way to the standard tools of the 2040s and beyond.

Scientists have developed tiny ultrasound-powered robots that can swim through blood, removing harmful bacteria along with the toxins they produce. These proof-of-concept nanorobots could one day offer a safe and efficient way to detoxify and decontaminate biological fluids. Researchers built the nanorobots by coating gold nanowires with a hybrid of platelet and red blood cell membranes.

This hybrid cell membrane coating allows the nanorobots to perform the tasks of two different cells at once - platelets, which bind pathogens like MRSA bacteria (an antibiotic-resistant strain of Staphylococcus aureus), and red blood cells, which absorb and neutralize the toxins produced by these bacteria. The gold body of the nanorobots responds to ultrasound, which gives them the ability to swim around rapidly without chemical fuel. This mobility helps the nanorobots efficiently mix with their targets (bacteria and toxins) in blood and speed up detoxification.

Researchers created the hybrid coating by first separating entire membranes from platelets and red blood cells. They then applied high-frequency sound waves to fuse the membranes together. Since the membranes were taken from actual cells, they contain all their original cell surface protein functions. To make the nanorobots, researchers coated the hybrid membranes onto gold nanowires using specific surface chemistry. The nanorobots are about 25 times smaller than the width of a human hair. They can travel up to 35 micrometers per second in blood when powered by ultrasound. In tests, researchers used the nanorobots to treat blood samples contaminated with MRSA and their toxins. After five minutes, these blood samples had three times less bacteria and toxins than untreated samples.

Mortality Following Stroke as an Example of the Importance of Raised Blood Pressure as a Mediating Mechanism of Aging

Raised blood pressure, hypertension, is an important mechanism involved in the transmission of age-related damage from low-level biochemical changes to high level structural damage and organ failure. The importance of blood pressure in this context is why significant reductions in mortality rate can be achieved by means of lowering blood pressure, by overriding cellular reactions or cell signaling, that fail to address any of the underlying root causes of hypertension. These root causes are largely the set of biochemical changes that act to stiffen blood vessels, as hypertension appears to be near entirely a consequence of loss of elasticity in the vascular system. They include cross-linking, cellular senescence, and a range of less well understood shifts in the capabilities and behavior of vascular smooth muscle cells. If reductions in blood pressure now can achieve useful results, imagine the far greater benefits that will result once rejuvenation therapies exist capable of repairing the low-level damage that causes vascular stiffness. Not only hypertension will be addressed, but also all of the other issues that this damage in cells and tissues gives rise to.

Treating high blood pressure in stroke survivors more aggressively, could cut deaths by one-third, according to new research. "The potential to reduce mortality and recurrent stroke is immense, because more than half of all strokes are attributable to uncontrolled high blood pressure." In the AHA/ACC guideline for hypertension, released in 2017, the threshold for stage 1 hypertension, or high blood pressure was changed to at or above 130 mmHg for the top number or 80 mmHg for the bottom number. The previous threshold for high blood pressure was, at or above 140/90 mmHg.

Overall, while many more people will be diagnosed with hypertension under the new guideline, there will be only a small increase in the percentage of people who require medication. However, blood pressure-lowering medications are recommended for all stroke survivors with blood pressures of 130/80 mmHg or higher, and additional drugs if needed to reduce blood pressure below that threshold.

In the new study, researchers used data from the National Health and Nutrition Examination Surveys to estimate the nationwide impact of applying that approach. The surveys, conducted between 2003 and 2014, included blood pressure measurement and asked participants about their stroke history and blood pressure treatment. If clinicians fully shift from the previous guidelines to the new ones, the researchers calculated the impact on stroke would be: (a) a 66.7 percent increase in the proportion of stroke survivors diagnosed with hypertension and recommended for pressure-lowering medication (from 29.9 percent to 49.8 percent); (2) a 53.9 percent increase in the proportion of stroke survivors already taking pressure-lowering drugs who will be prescribed additional medication to reach their target blood pressure (from 36.3 percent to 56 percent); and (3) a 32.7 percent reduction in deaths, based on the difference in death rates in stroke survivors above and below the 130/80 mmHg target blood pressure (8.3 percent vs. 5.6 percent).

Efforts Continue to Associate Copy Number Variations with Human Longevity

Copy number variation is a type of genetic difference between individuals in which a section of DNA, usually one that is already duplicated multiple times in most people, has a different number of repeats. Researchers have studied copy number variation and relationships with longevity, both in general, in the sense of looking for correlations, and in specific, looking at copy number variations in a single gene. As is the case for most genetic correlations in the matter of human longevity, the vast majority of results suggest only tiny effects on mortality and fail to reproduce between study populations. That tells us that most naturally occurring individual genetic contributions to longevity are both small and highly conditional. The study here is representative of the type, and thus I would say that there is no great expectation that the results will be replicated in other data sets.

Human lifespan has long been observed as a complex trait with approximately 25% genetic contributions. To date, only very few genes have been shown consistently associated with it. Recent studies reported that copy number variation (CNV) may directly contribute to human lifespan. CNV is a general term for all the chromosomal rearrangements, such as deletions, duplications. CNVs can change gene structures, thus affecting gene expression and phenotypes. In human, CNVs have been implicated in numerous diseases, such as autism and diabetes. CNVs also contribute significantly to the genome instability of cancer cells.

A few studies have investigated the association of CNV with human lifespan using genome-wide approaches. One reported this association in 11442 human samples representing two cohorts. They found large deletions in 11p15.5 among the oldest people. Another study uncovered a deletion in the CNTNAP4 gene in a female group of 80 years of age, but not the male group. Recently, a study in Caucasians revealed an insertion allele of the CNTNAP2 gene in esv11910 CNV of males, but not females.

In this study, we investigated the association of CNVs and longevity in Han Chinese by genotyping 4007 individuals obtained from the Chinese Longitudinal Healthy Longevity Survey (CLHLS) database. We have identified a few CNVs, and most of them were new. These CNV regions encode nineteen known genes, and some of which have been shown to affect aging-related phenotypes such as the shortening of telomere length (ZNF208), the risk of cancer (FOXA1, LAMA5, ZNF716), and vascular and immune-related diseases (ARHGEF10, TOR2A, SH2D3C). In addition, we found several pathways enriched in long-lived genomes, including FOXA1 and FOXA transcription factor networks involved in regulating aging or age-dependent diseases such as cancer.

Immunosenescence and Neurodegeneration

How greatly does the onset of dementia depend on the age-related decline of the immune system? The most evident contributions to neurodegeneration are vascular aging and the accumulation of protein aggregates such as amyloid-β, tau, and α-synuclein. These are only indirectly connected to the aging of the immune system, in the sense that immune function influences in some way near all aspects of tissue function, and its progressive failure tends to make everything at least a little less functional. Chronic inflammation appears to play a direct and important role in the progression of most neurodegenerative conditions, however, and there at least we can point to the immune system as a primary issue.

The immune system is responsible for defending against pathogens such as bacteria, viruses, and fungi to eliminate broken and harmful cells, like senescent cells and toxic or allergenic substances. Immunosenescence is a term that describes a different state of the immune system in aged people, in association with detrimental clinical outcome, due to reduced ability to respond to new antigens. Although immunosenescence is a phenomenon present in the majority of individuals, factors like genetic, environment, lifestyle, and nutrition are responsible for their heterogeneity among individuals and cause a higher susceptibility to develop infections and progression of disease pathology.

The age-related dysregulation of immune responses impacts the resistance to infections, diminishes responses to vaccination, increases the susceptibility to autoimmunity and cancer, and promotes the development of an inflammatory phenotype. Researchers have introduced the term "inflammaging", related to the immunosenescence, to describe a low-grade, asymptomatic, chronic, and systemic inflammation, characterized by increased levels of circulating cytokines and other proinflammatory markers. The relationship between aging and chronic disorders, including atherosclerosis, dementia, neurodegeneration, and many others, has its bases in senescent remodeling of immune system.

The increased proinflammatory environment could be the major contributing factor to the development of aging-associated diseases. Given the well-established communication between the immune system and brain, the age-related immune dysregulation may bring neurodegeneration. Several studies have demonstrated that immunosenescence and inflammaging can induce an overactivation of central nervous system (CNS) immune cells, promoting neuroinflammation. In Alzheimer's disease patients, the microglial aging and dysfunction lead to amyloid-β accumulation and loss of peripheral immune response, contributing to disease pathogenesis. Furthermore, in Parkinson's disease, the interaction between aging and over time decreased immune response suggests a disease predisposition for neurodegeneration.

Recently, several studies have reported the relationship between delayed immunological aging and reduced expansion of senescent late-stage differentiated T cells and active lifestyle and has been suggested that aerobic exercise training might attenuate cognitive impairment and reduce dementia risk. Although it is unknown whether effects of exercise are direct, such as a targeted removal of dysfunctional T cells, or indirect, such as lower inflammatory activity, it may be hypothesized that these changes can provide benefits for health, including mitigate cognitive impairment.

New strategies to combat immunosenescence and neurodegeneration are focused on cellular and genetic therapies, such as genetic reprogramming and bone marrow transplantation, but cell reprogramming has still poor efficiency, and clinical translation shows several ethical and safety questions that may be answered. Thus, a better understanding of immunosenescence mechanisms will be necessary to develop new, unconventional, or pharmacological therapy strategies, for peripheral and CNS immunosenescence delay. Additional studies are required to determine the effectiveness and optimal conditions to improve the function of the aged immune system and undertake the challenges of immunosenescence.

Ending Aging Now Translated into Portuguese

Ending Aging is an important book, a concise explanation of the SENS approach to the development of rejuvenation therapies. It is aimed at laypeople, but with enough depth for scientists to use it as a starting point for their own further reading as well. It covers the extensive evidence gathered by the research community over the decades to support the concept that aging is caused by the accumulation of a few classes of molecular damage to cells and tissues. It outlines proposed therapies that could, if fully developed, repair or work around that damage in order to remove its contribution to aging.

Since its publication in English, volunteers have translated Ending Aging into a number of other languages, and a Portuguese edition is now the latest to be published. Scientific translation is particularly challenging, and people who have both the requisite scientific knowledge and are multilingual do not exist in great numbers - so many thanks to the team who persevered to carry out this work.

Some months ago, we announced an initiative by Nicolas Chernavsky and Nina Torres Zanvettor to translate Ending Aging into Portuguese. As of today, the translated book is available in an electronic format on Amazon and is ready to reach millions more readers.

A classic book about the possibility of repairing the damage of aging is now available in the native tongue of hundreds of millions more people. The book Ending Aging, by the British biogerontologist Aubrey de Grey and Michael Rae, has been published in Portuguese on June 5th. The book presents a series of possible strategies to repair the cellular and molecular damage that occurs in the human body throughout life. With these strategies, age-related diseases, such as Alzheimer's disease, Parkinson's disease, cancer, cardiovascular diseases, and diabetes, could be avoided.

Since it was published in 2007 in its original English version, the book has become a classic of biogerontology and has already been translated into German, Spanish, Russian and Italian. With the additional 250 million people that speak Portuguese as their native tongue, the number of people that can access the book's content more easily continues to rise.


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