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- Request for Startups in the Rejuvenation Biotechnology Space, 2020 Edition
- Activating Quiescent ILC2 Immune Cells in the Aging Mouse Brain Improves Cognitive Function
- Nicotinamide Mononucleotide Supplementation Restores Lost Fertility in Aged Female Mice
- A Gentler Approach to Transplanting Young Hematopoietic Stem Cells into Old Mice Modestly Extends Life Span
- Evidence for Bacterial DNA to Promote Tau Aggregation in Neurodegeneration
- The Epigenetic Profile of Werner Syndrome is Very Different from that of Aging
- An Interview with Hanadie Yousef of Juvena Therapeutics
- Greater Height Correlates with a Lesser Risk of Dementia
- A Comparison of Biological Age Measurement Approaches
- An Interview with Lewis Gruber of SIWA Therapeutics
- An Approach that Prevents Earlier than Expected Cell Death in Alzheimer’s Disease
- A Short Review of the Development of Senolytic Therapies to Reverse Aspects of Aging
- EnClear Therapies Raises 10 Million to Develop a Means to Filter Molecular Waste from Cerebrospinal Fluid
- Reduced Generation of New Oligodendrocytes May Contribute to Declining Memory with Age
- Correction of Mitochondrial Dysfunction as an Approach to Treat Heart Failure
Request for Startups in the Rejuvenation Biotechnology Space, 2020 Edition
This is the latest in a series of yearly posts in which I suggest areas of development for biotech startups I’d like to see actively developed as a part of the longevity industry in the near future. Today, this year, is a good time to be starting a company focused on the production of a novel therapeutic approach to intervening in the aging process. There is a great deal of funding for seed stage investment, and many compelling projects lacking champions, yet to be carried forward from academia into preclinical development. Numerous scientific and industry crossover conferences are now held every year, at which it is possible to meet a mix of entrepreneurs, scientists, and investors, all interested in advancing the state of the art. The industry, and its pool of potential funds for later stage investment, are both growing rapidly, driven by the energetic activities of patient advocates such as Aubrey de Grey and activist investors such as Jim Mellon and his allies. The public at large is becoming ever more aware of the potential to change the progression of aging. This will become a very large industry in the years ahead, and rejuvenation will eventually become the largest portion of medicine as a whole. There is tremendous opportunity here, both for returns on investment, and to change the human condition for the better.
A Viable Approach to Medical Tourism for the Era of Rejuvenation Therapies
Rejuvenation therapies, by their nature, have a far greater market size than any existing medical technology intended to treat the clinically ill. Many more people will undergo rejuvenation treatments than presently undergo medical procedures or take medications. This opens the door for radical change and improvement in the poorly organized, scattered, and unhelpful medical tourism industry. A population of potential customers an order of magnitude larger than is the case today is a great opportunity for any company to successfully smooth the road of regulatory arbitrage, allowing people in restrictive regulatory regions to effectively make use of reputable services available in other countries. The first rejuvenation therapies already exist, but discovery, validation, and access are all challenging. There is considerable room for improvement.
Restoration of Hematopoietic Stem Cell Function
Hematopoietic stem cell populations are responsible for producing blood and immune cells, as well as other important cell types, such as endothelial progenitor cells that help to maintain blood vessel integrity. All of this degrades with aging, but the standard approach to bone marrow transplantation, involving chemotherapy to destroy existing stem cells, is too harsh to be used as a basis for any therapy based on replacement of cells. There are potential alternatives, however, a fair number of them. For example, mobilizing stem cells to leave the bone marrow produces enough spare room in stem cell niches to allow a meaningful fraction of transplanted stem cells to engraft, resulting in extension of life and improved function in mice. The function of the immune system is so vital in aging that treatments to restore hematopoiesis are of great importance.
A Low Impact Method of Destroying the Peripheral Immune System
The peripheral immune system becomes cluttered with senescent and dysfunctional cells with advancing age, one of the numerous issues that must be addressed in order to repair an aged immune system. There is plenty of evidence for the selective destruction of specific dysfunctional cells to be beneficial. The entire B cell complement can be cleared to remove dysfunctional and harmful B cells, for example. The lost B cells are quickly replaced with functional B cells even in later life. What is needed is a way to clear out the peripheral immune system in entirety without undue side-effects, a form of therapy that should be useful not just to clear out the problem cells from an aged immune system, but also to effectively treat autoimmune disease. This goal can at present be accomplished via the application of high dose immunosuppressive drugs, but with significant side-effects that make it unsuitable for widespread use in a frail population. Thus something akin to suicide gene therapies or other targeted means of low-impact cell destruction is needed instead.
Build a Physician Network to Bring Low-Cost Senolytics to the Masses
The evidence for dasatinib and quercetin to meaningfully clear senescent cells, one of the causes of degenerative aging, is presently compelling. Soon we will know whether or not fisetin performs well in humans. All of these substances cost little. As yet, only a few groups are trying to build physician networks or services that will deliver these and other actual or potential senolytic treatments to patients. To my eyes this is an important exercise in logistics and exercising the right to off-label use of approved drugs. Functional senolytics have the capacity to greatly improve the state of health for every older person, and it is reasonable to believe, based on the evidence, that at least a few of the portfolio of potentially senolytic low-cost drugs and supplements can achieve this goal right now. Yet they are not being widely used. Tens of millions of patients in the US alone are suffering when their situation could be improved. At the very least, many more people should be made aware that senolytics exist, so as to be able to make a decision based on present evidence as to whether or not to try this form of therapy.
A Competitor for Revel Pharmaceuticals in Glucosepane Cross-link Breaking
Persistent cross-links between extracellular matrix proteins are likely very influential on both late life mortality, due to stiffening of blood vessels and consequent hypertension, and on the loss of elasticity in skin, a sizable component of skin aging. One of those topics is much more important than the other, but, as any survey of the community will tell you, opinions differ on which one it is. The market size for methods of reversing either outcome of aging is very large, and breaking cross-links is a plausible way forward given what is known of their biochemistry. Revel Pharmaceuticals is presently the only startup biotech company working on development of ways to break down the primary form of persistent cross-link in human tissues, those based on glucosepane. Competing with Revel in the discovery of compounds that can break glucosepane cross-links is a very feasible prospect: this part of the field is presently at the same point that senolytics were five to ten years ago, and most likely has a similar trajectory ahead of it.
Interfere with Telomere Lengthing to Defeat All Cancers
The requirement for telomere lengthening is the Achilles’ heel of cancer. All cancer cells must abuse at least one of the two available mechanisms of telomere lengthening, telomerase and alternative lengthening of telomeres (ALT), in order to continue unfettered replication. Successfully sabotage this process and any cancer will wither as a result, no matter how advanced it is in its progression. This is truly the best basis for the development of a single, universal cancer therapy, and numerous potential approaches exist at various stages of development. Some have made it to the point of preclinical work, such as the program at Maia Biotechnology, but most have yet to make the leap from academia to industry. There is considerable opportunity here to revolutionize the treatment of cancer.
Break the Link Between DNA Repair and Epigenetic Change
One of the more interesting of recent discoveries in the field of aging research is that DNA double strand break repair causes epigenetic changes characteristic of aging. This opens the door to investigations of the intricate and complex DNA repair mechanism of the cell nucleus, in search of points of intervention that might stop this process of epigenetic change from occurring, or slow it down, or perhaps even reverse it. A sizable literature on DNA repair exists, and this part of our biochemistry is comparatively well mapped. Somewhere in there are the starting points for therapies that might be very influential on the state of degenerative aging – perhaps the basis for reversing epigenetic changes and cellular dysfunction in ways other than the approach of in vivo reprogramming that is growing in popularity.
Restore Lost Mitochondrial Function to a Much Greater Degree than can be Achieved via NAD+ Upregulation
At present NAD+ upregulation is a popular topic, as is the application of mitochondrially targeted antioxidants. Both approaches appear to sufficiently restore the quality control mechanism of mitophagy in old cells to allow some degree of restored mitochondrial function throughout an aged body. How sizable is the effect? In the same ballpark as exercise, judging from the few small human trials conducted to date, focused on the cardiovascular system: blood pressure, blood vessel compliance, vascular smooth muscle function, pulse wave velocity. We might take this as an encouraging sign that if mitochondrial function was actually fully restored, the benefits could be sizable. There are any number of possible approaches that might prove to be much more effective than NAD+ upregulation: tinker directly with gene expression changes that appear to impair mitophagy; epigenetic reprogramming in vivo; delivery of whole mitochondria to tissues; targeted destruction of damaged mitochondrial DNA; and so forth. Any group able to demonstrate significantly better outcomes in animal models than have been obtained from NAD+ upregulation should have no issues in raising funds for commercial development.
Restore a Youthful Human Gut Microbiome
Work on the human gut microbiome and the changes that take place with age has picked up considerably in past years. A number of groups have identified specific metabolites that are produced at lower levels by the aged microbiome, as well as changes in the balance of beneficial and harmful gut microbes that lead to greater chronic inflammation. In animal studies, transplantation of a young microbiome into old animals results in a lasting restoration of the microbiome in those older animals. In human medicine, fecal microbiota transplantation is well developed for use in a number of pathological conditions. It has not yet been applied to aging, but it should, or variants that dispense with the donor and just provide the appropriate mix of microbes directly. Further, it is not unreasonable to build probiotic-like treatments that deliver the right mix of microbes in sufficient volume to achieve the same effect. Given the diverse influences of the gut microbiome and the metabolites it produces, this may be a way to meaningfully reduce chronic inflammation, restore stem cell activity, and generally improve health in older people.
Reverse the Loss of Capillary Density with Age
Capillary density declines throughout the body with advancing age, reducing delivery of oxygen and nutrients, and thereby leading to dysfunction in cells and tissues, particularly in the energy hungry brain and muscles. The underlying causes of this manifestation of aging are not well understood, but the processes of angiogenesis in general, the regulatory mechanisms governing generation of blood vessels, are fairly well explored. There is an opportunity here to take what is known and apply it to this challenge. Approaches that restore lost capillary density may prove to be a useful means of reversing the loss in tissue function that occurs with age, but it requires a successful methodology to be demonstrated in at least animal models in order to understand just how useful. Loss of capillary density is directly implicated in neurodegeneration and heart failure, providing well-understood indications to target for any company working towards this form of repair biotechnology.
Activating Quiescent ILC2 Immune Cells in the Aging Mouse Brain Improves Cognitive Function
Immune cells play a wide variety of important roles in the normal function of tissues throughout the body. The more familiar tasks, such as chasing down pathogens and clearing up metabolic waste and other debris, are just one slice of a much broader spectrum. Many of the other activities undertaken by immune cells are poorly catalogued and understood, particularly in the brain, where resident immune cells appear critical to the fine details of neural function. As is often the case in cellular interactions, many of the distinct contributions of immune cells to tissue function take the form of secreted molecules (or extracellular vesicles) that act upon other cell types to change their behavior.
In today’s open access research, scientists identify a population of immune cells, ILC2 cells, largely concentrated in the choroid plexus in the aging brain, that could be helpful were they not largely quiescent. Given suitable signals to override their quiescence, these cells act to improve cognitive function. This is likely achieved via signal molecules secreted by ILC2 cells when active. The researchers identify IL-5 as an important signal, but it will no doubt be the work of years to more completely understand how benefits are produced in this case.
Activating Immune Cells Could Revitalize the Aging Brain
Group 2 innate lymphoid cells (ILC2s) reside in specific tissues of the body and help to repair them when they are damaged. Recently, for example, ILC2s in the spinal cord were shown to promote healing after spinal cord injury. Researchers examined the brains of both young and old mice and found that ILC2s accumulated with age in a structure called the choroid plexus. This structure produces cerebrospinal fluid and is close to the hippocampus, a region of the brain that plays a key role in learning and memory. Older mouse brains had up to five times as many ILC2 cells as younger brains. Crucially, the researchers also saw large numbers of ILC2s in the choroid plexus of elderly humans.
The ILC2s in old mouse brains were largely in an inactive, or quiescent, state, but the researchers were able to activate them by treating the animals with a cell signaling molecule called IL-33, causing the cells to proliferate and produce proteins that stimulate the formation and survival of neurons. Compared with ILC2s from younger animals, ILC2s from older mice were able to live longer and produce more ILC2 upon activation, the researchers found. Additionally, treating old mice with IL-33, or injecting them with ILC2 cells pre-activated in the lab, improved the animals’ performance in a series of cognitive tests designed to measure their learning and memory.
One of the proteins produced by activated ILC2s is the signaling molecule IL-5. The research team found that treating old mice with IL-5 increased the formation of new nerve cells in the hippocampus and reduced the amount of potentially damaging inflammation in the brain. Again, IL-5 treatment improved the cognitive performance of aged mice in a number of tests.
Activation of group 2 innate lymphoid cells alleviates aging-associated cognitive decline
In this study, we report the accumulation of tissue-resident ILC2 in the choroid plexus of the aged brain, with ILC2 comprising a major subset of lymphocytes in the choroid plexus of aged mice and humans. ILC2 in the aged brain are long-lived and capable of reversibly switching between cell cycle dormancy and proliferation. They are relatively resistant to cellular senescence and exhaustion under replication stress, leading to enhanced self-renewal capability. They are functionally quiescent at homeostasis but can be activated by exogenous IL-33 to produce large amounts of IL-5 and IL-13 as well as a variety of other effector molecules in vitro and in vivo.
When activated in vitro and transferred intracerebroventricularly, they revitalized the aged brains and enhanced cognitive function of aged mice. Administration of IL-5, a major ILC2 product, repressed aging-associated neuroinflammation and alleviated aging-associated cognitive decline. Together, these results suggest that aging may expand a unique population of brain-resident ILC2 with enhanced cellular fitness and potent neuroprotective capability. Targeting ILC2 in the aged brain may unlock therapies to combat aging-related neurodegenerative disorders.
Nicotinamide Mononucleotide Supplementation Restores Lost Fertility in Aged Female Mice
Studies of the various approaches to raising NAD+ levels in aged mitochondria are a good illustration of the importance of the loss of mitochondrial function in degenerative aging. Researchers have studied this effect in numerous tissues and organs, with most such work examining muscle or the brain, both energy-hungry tissues and thus more dependent on their mitochondria for normal function. Today’s open access paper is a study of mitochondrial function in a tissue that is less well studied in this context. The authors reporting that supplementation with nicotinamide mononucleotide (NMN) can restore lost fertility in old mice by improving mitochondrial function in oocytes.
Mitochondria are the power plants of the cell, responsible for packaging the chemical energy store molecule ATP that is used to power cellular operations. For reasons that remain poorly understood, meaning that they are not well connected to the underlying molecular damage of aging, mitochondria become dysfunctional throughout the body with advancing age. Mitochondria are the descendants of ancient symbiotic bacteria, and they normally divide and fuse like bacteria, as well as passing component parts of their molecular machinery from one to another. In cells in old tissues, these dynamics change in ways that make mitochondria resistant to the quality control processes responsible for clearing out damaged structures in the cell. Cells become populated by problematic, poorly functioning mitochondria, and suffer accordingly.
A reduced amount of NAD+, a utility molecule important to a number of processes in mitochondria, is one proximate cause of these issues. The pace of synthesis and recycling of NAD+ falls off due to lowered levels of precursors and other necessary ingredients for the chemical reactions involved. This might be traced back to altered levels of gene expression due to epigenetic changes characteristic of aging, but this is still an exploration of proximate causes, and says little about what the underlying root causes might be in any detail.
To the extent that providing more NAD+ to cells restores mitochondrial function and thus cellular function to some degree, and this outcome is well demonstrated in mice, these benefits may be largely the result of enabling sufficient clearance of worn mitochondria to improve overall ATP production. This is better maintenance rather than better function per se; other lines of research also suggest that quality control is the critical item in mitochondrial function. When it comes to the means of raising NAD+ levels, delivery of NAD+ itself is not very efficient, and most current approaches are thus focused on delivering precursor molecules used in the synthesis or recycling of NAD+. Of these only nicotinamide riboside has even early clinical data to show some form of benefit in aged humans, but that will likely change over the next few years as more groups publish their work.
NAD+ Repletion Rescues Female Fertility during Reproductive Aging
The rate-limiting factor for successful pregnancy is oocyte quality, which significantly declines from late in the third decade of life in humans. Despite the enormous demand, there are no clinically viable strategies to either preserve or rejuvenate oocyte quality during aging, which is defined by the capacity of the oocyte to support meiotic maturation, fertilization, and subsequent embryonic development. A non-invasive, pharmacological treatment to maintain or restore oocyte quality during aging would alleviate a rate-limiting barrier to pregnancy with increasing age that has driven demand for assisted reproduction technologies (ARTs) such as in vitro fertilization (IVF), which is invasive, carries health risks, is expensive, and has a limited success rate.
Although somatic tissues undergo continual regeneration through turnover by a self-renewing population of resident precursor stem cells, oocytes in the ovary are laid down during in utero development in humans, where they form a finite pool that does not undergo self-renewal. Oocytes are therefore highly susceptible to age-related dysfunction. The molecular basis for the decline in oocyte quality with advancing age implicates genome instability, reduced mitochondrial bioenergetics, increased reactive oxygen species (ROS), and disturbances during meiotic chromosome segregation due to compromised function of the spindle assembly checkpoint (SAC) surveillance system. The molecular cause of chromosome mis-segregation in oocytes with advancing age is still unknown, and as a result, there are no pharmacological strategies to correct this problem. Understanding the molecular or metabolic basis of this defect could lead to therapies that could maintain or even rescue female fertility with advancing age.
The metabolite nicotinamide adenine dinucleotide (NAD+/NADH) is a prominent redox cofactor and enzyme substrate that is essential to energy metabolism, DNA repair, and epigenetic homeostasis. Levels of this essential cofactor decline with age in somatic tissues, and reversing this decline through treatment with metabolic precursors for NAD+ has gained attention as a treatment for maintaining late-life health. Here, we show that loss of oocyte quality with age accompanies declining levels of NAD+. Treatment with the NAD+ metabolic precursor nicotinamide mononucleotide (NMN) rejuvenates oocyte quality in aged animals, leading to restoration in fertility, and this can be recapitulated by transgenic overexpression of the NAD+-dependent deacylase SIRT2, though deletion of this enzyme does not impair oocyte quality. These benefits of NMN extend to the developing embryo, where supplementation reverses the adverse effect of maternal age on developmental milestones. These findings suggest that late-life restoration of NAD+ levels represents an opportunity to rescue female reproductive function in mammals.
A Gentler Approach to Transplanting Young Hematopoietic Stem Cells into Old Mice Modestly Extends Life Span
Stem cell populations become damaged and dysfunctional with age. Some of this is issues with the stem cells themselves, and some of this results from problem with the signaling environment and function of the stem cell niche. Which of these factors is more important likely varies by stem cell population. Among the best studied of stem cell types, the evidence suggests that muscle stem cells remain capable in old age, but become ever more quiescent, while hematopoietic stem cells become damaged and dysfunctional, unable to perform. Hematopoietic stem cells reside in the bone marrow and are responsible for generating blood and immune cells. Altered and reduced hematopoiesis is an important aspect of immune system decline with age, and thus providing functional replacement cells to older individuals may prove to be a useful form of rejuvenation therapy.
Unfortunately, the introduction of new hematopoietic stem cells at present requires removal of the existing population in order to make space in the stem cell niches of the bone marrow. The options for replacement are somewhat blunt and limited, deriving from the bone marrow transplant field. The standard approach is chemotherapy, which is quite unpleasant to experience, and further comes accompanied by a non-trivial risk of death or failure to adequately reconstitute the immune system following transplantation. That risk profile is considerably worse in older patients, and thus this sort of therapy is largely restricted to treatment of serious disease in the old, such as cancer.
A better, more gentle approach is needed if replacement of hematopoietic stem cells is to become a widespread preventative treatment for older individuals, a way to postpone immunosenescence. In the past, I have suggested the application of suicide gene therapies to the selective destruction of cell populations, as presently being pioneered by Oisin Biotechnologies to target senescent and cancerous cells. Here, researchers apply a different approach, using signals that convince stem cells from the bone marrow to leave their niches and migrate into the bloodstream. This is already widely used as a way to collect cells from donors, and the data here provides compelling evidence for it to leave the niches empty enough to allow a meaningful number transplanted stem cells to engraft and set to work. That this approach modestly extends life in mice, when used to transplant young hematopoietic stem cells into older animals, is a good demonstration of the gentle nature of the technique in comparison to chemotherapy.
Mobilization-based transplantation of young-donor hematopoietic stem cells extends lifespan in mice
Stem cells are critical to tissue regeneration and homeostasis during aging and disease. As a hallmark of aging, stem cell dysfunction is critical to improving the quality of life for people with advanced age. Stem cell-based therapy holds considerable promise for treating aging-related diseases, with hematopoietic stem cells (HSCs) being the most widely used for stem cell therapies. It is becoming increasingly clear that age-related changes in the niche space can induce alterations in hematopoiesis, including myeloid lineage skewing. However, extrinsic stimulation of HSCs with cytokines is highly dependent on intrinsic determinants. To date, the “gold standard” measure of HSC functionality remains an in vivo repopulating assay to determine their ability to re-establish lineage cell production in recipients during hematopoietic stem cell transplantation (HSCT). Unfortunately, conventional HSCT procedures require harsh cytotoxic conditioning – irradiation and/or chemotherapy – that alters HSC niches in the bone marrow, permanently damaging bone architecture. These limitations have confounded efforts to assess health-associated benefits of HSC replacement and rejuvenation.
The majority of HSCs reside in specialized niches within the bone marrow, although some HSCs leave these niches and migrate into the blood, ~1-5% of total HSCs each day. Mobilization of HSCs into the peripheral blood can be achieved through administration of G-CSF, an effect that is dramatically increased when G-CSF is administered in combination with other mobilizers, such as AMD3100. This HSC mobilization strategy constitutes the basic mechanism underlying collection of peripheral blood donor stem cells in the clinic. Critically, this increased mobilization also creates temporarily empty niches in the bone marrow, opening a window of opportunity for donor cell engraftment. Here, we use a novel mobilization-based HSCT procedure to investigate the health-associated benefits of replacing HSCs from aged recipients with young-donor HSCs. Additionally, we take advantage of the niche-preserving properties of this mobilization-based HSCT to investigate the influence of aged niche signaling upon a low percentage of young-donor HSCs.
Using this approach, we are the first to report an increase in median lifespan (12%) and a decrease in overall mortality hazard (hazard ratio: 0.42) in aged mice following transplantation of young-donor HSCs. The increase in longevity was accompanied by reductions of frailty measures and increases in food intake and body weight of aged recipients. Young-donor HSCs not only preserved youthful function within the aged bone marrow stroma, but also at least partially ameliorated the dysfunctional hematopoietic phenotypes of aged recipients. This compelling evidence that mammalian health and lifespan can be extended through stem cell therapy adds a new category to the very limited list of successful anti-aging/life-extending interventions. Our findings have implications for further development of stem cell therapies for increasing health and lifespan.
Evidence for Bacterial DNA to Promote Tau Aggregation in Neurodegeneration
The field of Alzheimer’s disease research is in the midst of a slow-moving and consequential debate over the role of infection in the development of the condition. The fundamental question is this: in the absence of genetic variants that raise risk, why do only some people progress to full blown Alzheimer’s disease? The presence – in only some people – of sufficient degrees of persistent infection is one possible answer to that question. Candidates include herpesviruses, oral bacteria such as P. gingivalis, lyme disease spirochetes, and others.
Alzheimer’s is a condition characterized by amyloid-β aggregation in its early stages and tau aggregation in its later, more severe stages. The classic amyloid cascade view of the condition is that amyloid-β aggregation sets the stage for immune dysfunction and chronic inflammation leading to tau aggregation. The debate over whether or not persistent infection instead lies at the root of the condition has so far largely focused firstly on amyloid-β as an anti-microbial peptide, a part of the innate immune system that may be upregulated by infection, and secondly on the chronic inflammation that results from infection, as inflammation in the brain clearly strongly drives tau pathology.
Here, however, researchers offer evidence for the presence of bacterial DNA to accelerate the processes of tau aggregation through mechanisms independent of inflammation. Some forms of bacterial DNA may help to seed the aggregates of tau that can then spread independently. The challenge will be, as ever, to determine which of these various processes is the important one, which has the larger contribution. That is hard to accomplish without selectively blocking each disease process in isolation and observing the results.
Bacterial DNA promotes Tau aggregation
In addition to being one of the most devastating diseases of the 21st century, Alzheimer’s disease (AD) remains incurable. The cognitive symptoms and neurodegeneration appear to be mostly related to the extensive synaptic dysfunction and neuronal death observed in the brain. In turn, neuronal loss and synaptic damage appears to be mediated by the progressive misfolding, aggregation, and deposition of amyloid-β (Aβ) and tau proteins forming protein aggregates able to spread from cell-to-cell by a prion-like mechanism. Genetics alone cannot account for the complex process of protein misfolding, aggregation and subsequent neurodegeneration observed in AD, particularly because the large majority of the cases are not associated to genetic mutations. Thus, it is likely that diverse environmental factors and age-related abnormalities play an important role on the initiation of the pathological abnormalities. In this sense, various studies have shown that bacterial infection, as well as alterations in the intestinal microbiome may be implicated in the AD pathology.
Here, we report the first evidence for the capacity of extracellular DNA from certain bacterial species to substantially promote tau misfolding and aggregation. The promoting effect of DNA on tau aggregation was observed in a wide range of concentrations from 10 to 1000 ng. The use of these concentrations were informed by the range of cerebrospinal fluid DNA concentrations observed in patients with different diseases: 1-600 ng/mL. The sources of bacterial and fungal DNA were selected based on the literature and personal data that showed associations of certain microorganisms with AD. Among the bacteria previously cultivated directly from the brains of patients with AD, or those whose components (such as nucleic acids, lipopolysaccharides, enzymes) were identified in the cerebrospinal fluid, amyloid plaques, or brains of patients with AD, we used the DNA from B. burgdorferi, P. gingivalis, C. albicans, and E. coli.
Our data indicate that DNA from various, unrelated gram-positive and gram-negative bacteria significantly accelerated Tau aggregation. One of the best promoters was DNA from E. coli species, which is interesting for several reasons. First, it was demonstrated that some strains of E. coli were detectable immunocytochemically in brain parenchyma and vessels in AD patients more frequently compared to control brains. Second, E. coli and P. gingivalis are known to share properties of facultative intracellular parasites and be localized within hippocampal neurons; the latter finding is significant, as the hippocampus is extensively damaged in AD. The intracellular localization of E. coli introduces unique possibilities regarding the interaction of bacterial DNA with tau proteins inside the neuron; e.g. DNA can be secreted via transportation to the outer membrane or released following prophage induction and directly access the host neuron’s cytosol, where tau is normally present. Of note, in brains of patients with AD, P. gingivalis is also localized intracellularly; therefore, as in the case of E. coli the same processes for the intracellular interaction of its DNA with tau are applicable for this microorganism.
Future studies should further investigate the possible role of DNA as an initial seeding factor for protein misfolding using cellular and in vivo models as well as the effect of DNA on inducing misfolding of other proteins, including those associated with neurodegeneration, autoimmune diseases, and cancer. Moreover, subsequent studies should explore the targeting of DNA as a therapeutic strategy to prevent tau aggregation.
The Epigenetic Profile of Werner Syndrome is Very Different from that of Aging
The research community has long used progeroid syndromes such as Hutchinson-Gilford progeria syndrome and Werner syndrome as tools in the investigation of aging. This category of conditions are colloquially thought of as accelerated aging, but are in fact only a little similar to aging. The various underling genetic causes of progeria result in accelerated accumulation of cellular damage of various sorts, different in each case, leading to tissue dysfunction and outcomes that resemble a range of normal age-related conditions. Aging is itself a process of damage accumulation, so it isn’t surprising to find some degree of similarity. The forms of cellular damage and their proportions are quite different, however, which makes it challenging to draw any specific lesson from progeroid syndromes and apply it to normal aging.
Werner syndrome (WRN) is a canonical member of a family of genetically determined disorders that include multiple phenotypes consistent with their characterizations as segmental progeroid syndromes. It is important to note, however, that these syndromes may include discordances with the usual phenotypic features of aging. For example, the ratio of epithelial to non-epithelial cancers in WRN is 1:1, whereas the ratio seen in usual aging is 10:1. Moreover, while WRN research has contributed to the widespread acceptance of genomic instability as one of the hallmarks of aging, features such as variegated translocation mosaicism and a preponderance of large deletions are particularly characteristic of WRN.
Epigenetic signatures of Werner syndrome occur early in life and are distinct from normal epigenetic aging processes. The vast majority (more than 90%) of differentially methylated CpGs and regions (DMRs) in WRN were not affected by aging, consistent with the view that WRN is not merely accelerated normal aging. A particularly striking finding was that DMRs were enriched in genes associated with transcription factor activity, leading us to hypothesize that WRN might best be conceptualized as a disease based upon aberrant controls of the expressions of a wide array of genetic loci, some of which are plausibly related to clinical phenotypes of WRN. Moreover, given that the methylation changes in the highest ranking DMR in the promoter region of the HOXA4 gene as well as in other DMRs preceded disease manifestation, it seems likely that these transcriptional aberrations began early in development. That finding reinforces the concept that how well one builds an organism makes a great deal of difference on how long it lasts and how well it functions!
The epigenome of an individual is most plastic during early development and is shaped by a plethora of stochastic, internal (i.e. genetic variation), and external factors (i.e. environmental exposures). The epigenetic changes associated with WRN and other segmental progerias are widespread but are all of small effect size. Both premature and normal aging phenotypes may manifest when the adverse factors exceed a critical threshold. Individuals with WRN may be endowed with an epigenome early in life which lowers their threshold for developing a number of specific aging phenotype.
An Interview with Hanadie Yousef of Juvena Therapeutics
The Life Extension Advocacy Foundation volunteers here interview Hanadie Yousef of Juvena Therapeutics. Her team is mining the secretions of pluripotent stem cells to find factors that can improve regeneration and stem cell activity in older individuals. Juvena represents one small slice of a broad trend in the regenerative medicine community, many teams building on the past decades of work on stem cell transplantation by seeking to understand and manipulate the cell signaling thought to produce benefits in patients undergoing these first generation therapies. In near all such stem cell therapies, the transplanted cells die rapidly rather than integrate into patient tissues, but benefits such as reductions in chronic inflammation and improved regeneration are nonetheless observed, albeit quite unreliably. Using the signals rather than cells as a basis for treatment should, in principle, turn out to be a more controllable, reliable approach.
Can you describe in more detail Juvena’s approach to developing protein therapeutics that promote tissue regeneration in the elderly?
We are utilizing the secretome of human embryonic stem cells. We know that human embryonic stem cells have the capability to develop every tissue in the body, an entire human being. I and my colleagues discovered, nearly a decade ago, that by isolating a sub-fraction of the proteins that they themselves secrete and produce in order to signal to stem cells to develop every tissue in the body, concentrating these proteins, and then adding them directly onto old muscle precursor cells isolated from humans over the age of 65, we could enhance their regenerative potential. When we injected this cocktail of proteins into injured old mice, we saw muscle regeneration returned to levels of younger animals, two-month old mice that are like people in their 20s, and this is a cocktail of human proteins.
The way that Juvena Therapeutics is taking this discovery into the clinic is by establishing a very efficient identification, high-throughput screening, and preclinical development pipeline, which has become ever more predictive and accelerated with the use of AI tools in order to identify what proteins in this original cocktail are actually driving the rejuvenation process, which ones are master regulators of signal transduction and key regulatory pathways involved in tissue differentiation and regeneration. By identifying those proteins and their sequences and exactly what they are compositionally, we can then test them individually and in combinations for their ability to promote human muscle precursor cell function and promote tissue regeneration in mouse models of human aging and human diseases.
Why did you choose to focus on muscle cell regeneration?
Interesting fact about muscle: It’s the largest internal tissue organ in the body. One of the first hallmarks of aging is the fact that once we hit our 30s, everybody, for the rest of our lives, heads downhill. We’re losing muscle strength and mass every year, but it accelerates with every decade so that by the time we’re in your 60s, everyone has some form of muscle wasting, some people more severe than others, so severe enough, in fact, that it prevents their daily functions and daily living and can be so severe that they can be clinically diagnosed with the disease of sarcopenia. Because there is now an ICD-10 code for sarcopenia, which was only issued at the end of 2016, meaning it’s an age-related disease that has a clinical indication, we can actually make therapies to target it. There’s zero FDA approved therapies, so it’s a huge unmet need and a huge market.
Excitingly, one of the best experimental models that we have today to really understand how stem cells decline and function with age is the muscle system. Key discoveries made by my former co-thesis advisor, Irina Conboy, and other pioneers in the field, really paved the way for us to understand mechanistically how stem cells decline and function with age in muscle and develop methods to repair and rejuvenate them, so it’s a great first tissue to focus on. Juvena will use this as a way to then launch into other tissue types. Laser-like focus on muscle first; once we find the proteins that are secreted by human embryonic stem cells that can drive muscle regeneration, we’ll then apply our platform and our technology and our approach to identifying therapeutics, approaching candidates that can act as therapeutics to promote the brain and prevent things like dementia, really targeting regenerative diseases, as well as go after other tissue types, such as the heart, the skin, and other ones that are really affected with age and decline in function in part by loss of stem cell function.
Greater Height Correlates with a Lesser Risk of Dementia
Being taller is associated with a shorter life span, for reasons that are far from fully explored. The role of growth hormone in longevity is no doubt close to the roots of this correlation, but there are plenty of questions remaining, such as why lung disease plays a sizable role in greater mortality for taller people in later life. As illustrated by the research here, there is a bright side to being taller, which is that epidemiological studies show taller people to have a lesser incidence of dementia. Again, why exactly this is the case is far from fully explored. These and other natural variations between people are interesting, but we should expect them to vanish with the introduction of the first rejuvenation therapies in the near future, swamped by the benefits that might be achieved by directly addressing the causes of aging.
This study examined the relationship between body height and dementia and explored the impact of intelligence level, educational attainment, early life environment, and familial factors. A total of 666,333 men, 70,608 brothers, and 7388 twin brothers born 1939-1959 and examined at the conscript board were followed in Danish nationwide registers (1969-2016). Cox regression models were applied to analyze the association between body height and dementia. The findings of this current study provide substantial support to previous evidence of a link between body height and dementia. All previous studies had accounted for educational level and other socioeconomic indicators, yet none of these studies had adjusted for intelligence level earlier in life. Intelligence level has been suggested to be a stronger marker of brain and cognitive reserve than educational level. Intelligence level is furthermore correlated with body height and by itself associated with dementia.
In contrast to previous studies, we also investigated the impact of other potential early-life familial factors including genetics and socioeconomic resources in the family that may influence both body height and later risk of dementia. Body height has been shown to have a strong genetic component with around 80% of the variation in populations being explained by genetic differences between individuals. The genetic component of height has furthermore been found to be consistent across countries independent of living standards. The genetic and environmental variation influencing body height, but not risk of dementia, is smaller within brothers than between men in general, which may weaken the association between body height and dementia in the latter compared to the former group. Through this mechanism, the finding of a stronger association within brothers may be explained by less dilution of the effects of different harmful exposures early in life influencing both body growth and risk of dementia. These findings furthermore suggests that genetics has a minor role in the association of body height and dementia.
In conclusion, taller body height at the entry to adulthood, supposed to be a marker of early-life environment, is associated with lower risk of dementia diagnosis later in life. The association persisted when adjusted for educational level and intelligence test scores in young adulthood, suggesting that height is not just acting as an indicator of cognitive reserve.
A Comparison of Biological Age Measurement Approaches
Researchers here assess the performance of a range of approaches to measuring biological age, including a number of epigenetic clocks based on DNA methylation changes characteristic of aging. The ideal measurement of biological age is one that is quick and cheap to undertake, and that accurately reflects the underlying burden of damage and consequence that drives aging. Such a measure could be used to determine the effectiveness of potential rejuvenation therapies far more rapidly than is presently possible, and would thus accelerate development efforts. Unfortunately none of the existing approaches are quite ready for this, as it is far from clear as to whether they do actually measure the full range of damage and consequence in aging. Their effectiveness will have to be proven in conjunction with the development of each new class of rejuvenation therapies, starting with senolytics.
Everyone ages, but how aging affects health varies from person to person. This means that how old someone seems or feels does not always match the number of years they have been alive; in other words, someone’s “biological age” can often differ from their “chronological age”. Scientists are now looking at the physiological changes related to aging to better predict who is at the greatest risk of age-related health problems. Several measurements of biological age have been put forward to capture information about various age-related changes. For example, some measurements look at changes to DNA molecules, while others measure signs of frailty, or deterioration in cognitive or physical abilities. However, to date, most studies into measures of biological age have looked at them individually and less is known about how these physiological changes interact, which is likely to be important.
In a new study, researchers have looked at data on nine different measures of biological age in a group of 845 Swedish adults, aged between 50 and 90, that was collected several times over a follow-up period of about 20 years. The dataset also gave details of the individuals’ birth year, sex, height, weight, smoking status, and education. The year of death was also collected from national registers for all individual in the group who had since died. The nine measures were telomere length, four different epigenetic clocks, physiological age derived from a list of age-correlated biomarkers, chronological age, functional aging index, and frailty index. Researchers found that all nine biological age measures could be used to explain the risk of individuals in the group dying during the follow-up period. In other words, when comparing individuals with the same chronological age in the group under study, the person with a higher biological age measure was more likely to die earlier. The analysis also revealed that biological aging appears to accelerate as individuals approach 70 years old, and that there are noticeable differences in the aging process between men and women.
Lastly, when combining all nine biological age measures, some of them worked better than others. Measurements of methylation groups added to DNA (known as DNA methylation age) and frailty (the frailty index) led to improved predictions for an individual’s risk of death. Ultimately, if future studies confirm these results for measures from single individuals, DNA methylation and the frailty index may be used to help identify people who may benefit the most from interventions to prevent age-related health conditions.
An Interview with Lewis Gruber of SIWA Therapeutics
SIWA Therapeutics is one of the few senolytics biotech companies founded prior to the past few years, invigorated with new funding now that the clearance of senescent cells as a basis for rejuvenation is an area of intense interest for the research and development community. The company is also, I believe, running the only senolytics program based the use of monoclonal antibodies. This is a way to encourage the immune system to destroy cells bearing specific surface markers, in this case a form of advanced glycation endproduct that is found on cancerous, senescent, and otherwise dysfunctional cells.
Many of our readers are familiar with CAR-T immunotherapy, which has enjoyed some success, but it’s not without considerable challenges. How does your approach differ?
We are using a simpler approach of just manufacturing a monoclonal antibody. Of course, we do that in Chinese Hamster Ovary (CHO) cells and purify and produce a monoclonal antibody product so that we don’t have to modify patient cells or any other cells in order to apply our treatment. It’s just a straight typical monoclonal antibody product, the same sort of immunotherapy that’s used in a variety of cancer therapies. In this case, we’ve found a marker that’s on cancer cells and senescent cells because of the way the markers are produced, and therefore the monoclonal antibody can enable removal of those cancer cells.
Can you summarize a bit more how that antibody SIWA 318H works?
It binds to proteins on the surface of oxidatively damaged cells that may be senescent or cancerous, or just very dysfunctional. By doing so, it provokes an immune response, initially an innate immune response with the natural killer cells. The bottom line is, the immune response not only destroys and removes the cells to which the antibody binds, but immune cells also secrete factors that promote regeneration. So, while we’re removing cells that are not going to function properly, we’re promoting their replacement with new cells from adult stem cell populations. The interesting thing about the markers is that they are a product of glycolysis, and high levels of glycolysis were associated even back before World War Two by Otto Warburg. They were shown on cancer cells. Cancer cells and senescent cells have their peculiarities, and they are high producers of this particular marker; therefore, we can hone in on those two types of cells.
Is it a coincidence that the marker is present on both senescent and cancerous cells? Or is there a reason for that?
Both types of cells conducted an elevated level of glycolysis and there are various explanations in the scientific literature. Both are highly metabolically active. Some people think of senescent cells as almost dead, but, in fact, they are among the most metabolically active of cells, and cancer cells are as well because of high proliferation. Both types of cells have a high need for ATP. One explanation in the literature is that they both resort to glycolysis to get additional ATP. The senescent cells put all of their efforts into the senescence associated secretory phenotype, so they’re producing a lot of cytokines and other molecules, so they need to use glycolysis, but they’re not using it to divide. A simplified way of looking at it is that senescent cells grow, and they need energy for growth; they basically get to the size that a cell would normally be when it divides, and then they just don’t divide. When you look under the microscope, you see large, flattened cells that are senescent cells, because they’ve grown but they just didn’t divide. Cancer cells, of course, will go ahead and do the division and you’ll have two daughter cells. The bottom line is that they both have to grow to that large size.
Does this mean a vaccine might be developed for senescent cells or even cancer?
Yes, and we are working on what we have. We’ve done preliminary studies in mice, and now we’re looking at expanding it into other species, even beyond humans, but we do have a candidate vaccine already in the works. As with any drug, you do want to be careful about certain conditions, pregnancy or other conditions where you don’t want to disrupt any things happening. For example, senescent cells have been found in fetuses. The one common thing, strangely enough, with senescent cells is every situation in which they’re beneficial, they’re removed. After they form the different structures in the fetus, they’re eliminated. The same thing is true in wound healing, which is often given as an example of a beneficial effect. Initially, senescence promotes proliferation of repairing cells, but if that’s allowed to go on too long, the wound tends to produce scar tissue, fibrosis, and the bottom line is that in the natural healing process, senescent cells appear for a time and then are removed. Although you do have to be somewhat careful, you don’t want to interfere with the initial stage of wound healing or with fetal development, otherwise, it’s a good rule of thumb that removing a senescent cell or a cancer cell is not a bad thing.
An Approach that Prevents Earlier than Expected Cell Death in Alzheimer’s Disease
Researchers here provide evidence for significant levels of cell death to occur in the brain earlier than expected in the development of Alzheimer’s disease, during the stage of mild cognitive impairment thought to be driven by the aggregation of amyloid-β. The researchers identify some portions of a mechanism by which amyloid-β might be triggering this cell death, and propose a novel class of therapeutic approaches that will interfere in this link. Given the artificial nature of animal models in Alzheimer’s research, and the comparatively sparse nature of human data, it is good to adopt a cautious wait and see approach in response to this sort of news. It is similar in character to numerous other lines of research in the Alzheimer’s field that ultimately didn’t translate from mice to humans.
The exact cause of Alzheimer’s disease is unknown, but pathological changes in the brain, including neuron loss and an accumulation of protein aggregates called beta-amyloid plaques, are a diagnostic hallmark of Alzheimer’s disease. Mild cognitive impairment (MCI) describes the slight but measurable changes in cognitive function that are often a precursor to Alzheimer’s disease. However, despite the importance of MCI, very little is known about the changes that occur in the brain during the progression from MCI to Alzheimer’s.
Researchers have now found that neuronal death occurs much earlier than originally thought, with higher levels of necrosis seen in patients with MCI than in patients with full-blown Alzheimer’s disease. The researchers also observed a significant decrease in the levels of a protein known as YAP in Alzheimer’s disease model mice and human patients with MCI. YAP positively affects the activity of a second protein called TEAD, a deficiency of which leads to neuronal necrosis. Microscopic examination revealed that the missing YAP was sequestered within beta-amyloid plaques, which have also been linked to neuronal toxicity.
By directly injecting a gene therapy vector expressing YAP analog into the cerebrospinal fluid of mice that were genetically engineered to provide a model of Alzheimer’s, the researchers were able to prevent early-stage neuron loss, restore cognitive function, and prevent the development of beta-amyloid plaques. “Confirming that neuronal necrosis was dependent on YAP was really the pivotal moment for us, but observing the almost transformative effects of YAP supplementation was hugely exciting. By showing that neuronal necrosis is YAP-dependent and begins prior to the onset of most symptoms, we predict that novel Alzheimer’s disease therapies will be developed to prevent the initiation of Alzheimer’s disease.”
A Short Review of the Development of Senolytic Therapies to Reverse Aspects of Aging
This short open access review paper covers some of the high points of the past decade of development of senolytic therapies capable of selectively destroying senescent cells in old tissues, as well as some of the earlier, much more sparse work on cellular senescence, prior to the general acceptance of an important role for senescent cells in aging. Senescent cells are constantly created and destroyed in the body. They are beneficial when present in the short term, acting to coordinate wound healing and in suppression of potentially cancerous cells, for example. Near all are destroyed soon after their creation, via programmed cell death or the activity of the immune system. A lingering population of senescent cells grows in number with age, however, as the processes of clearance falter and the tissue environment becomes more damaged. The mix of signals that these cells generate, the senescence-associated secretory phenotype, causes chronic inflammation and disruption of tissue structure and function, contributing to the progression of age-related disease and mortality.
Aging is defined as a progressive decrease in physiological function accompanied by a steady increase in mortality. The antagonistic pleiotropy theory proposes that aging is largely due to the natural selection of genes and pathways that increase fitness and decrease mortality early in life but contribute to deleterious effects and pathologies later in life. Cellular senescence is one such mechanism, which results in a permanent cell cycle arrest that has been described as a mechanism to limit cancer cell growth. However, recent studies have also suggested a dark side of senescence in which a build-up of senescent cells with age leads to increased inflammation due to a senescence-associated secretory phenotype (SASP). This phenotype that includes many cytokines promotes tumorigenesis and can exhaust the pool of immune cells in the body.
In a 2006 primate study, it was observed that senescent cells, as estimated by ATM activation do accumulate and can reach over 15% of the total cell population in aged individuals. In contrast to the vast majority of in vitro studies, this was one of the first studies showing a clear association between aging and the accumulation of senescent cells in vivo. Although this established a strong correlation, efforts were underway to establish causation between the accumulation of senescent cells and aging in vivo. In 2011, the researchers showed that removing p16Ink4a positive senescent cells delayed age-related disorders and increased healthspan in a BubR1 progeroid accelerated model of aging mice. Later studies confirmed the beneficial effects of senescent cell removal in wild type mice that showed increased median lifespan, delayed tumorigenesis, and attenuated age-related multi-organ deterioration. Removal of senescent cells in mice has also been shown to attenuate markers of age-associated neurodegenerative diseases such as tau hyperphosphorylation and neurofibrillary tangle deposition.
Substantial evidence in the last decade connecting senescent cell accumulation, age-related ailments, and roles in lifespan and healthspan fueled the search for therapeutic compounds that could selectively target senescent cells. A transcriptomic analysis between senescent cells and proliferating cells showed increased expression of pro-survival/anti-apoptotic genes such as Bcl-xL, a member of the Bcl-2 family of proteins that regulates programmed cell death by blocking caspase activation. This provided evidence to support the observation that senescent cells accumulate with age by being resistant to a variety of stresses that would normally induce apoptosis. Consistent with this idea, siRNAs to reduce Bcl-xL expression selectively reduced survival and viability in senescent cells while not affecting proliferating cells. Quercetin and dasatinib were obtained as hits from a drug screen based on these observations.
These compounds form one of the first discovered members of the senolytic class of drugs that selectively induce apoptosis in senescent cells. Four years after their initial identification as candidate senolytics, a dasatinib and quercetin combination was reported to decrease the senescent cell burden in humans as part of a Phase-1 clinical trial in diabetic kidney disease patients. This 2019 study was the first peer-reviewed study to demonstrate the efficacy of senolytics to decrease senescent cell burden in humans. This was carried out after an initial pilot study in early 2019 in 14 idiopathic pulmonary fibrosis (IPF) patients was completed to evaluate the feasibility of implementing a senolytic treatment. What now remains to be determined is whether future clinical trials will demonstrate any positive medical outcomes resulting from decreased senescent cell burden in diabetes and other age-associated ailments.
EnClear Therapies Raises 10 Million to Develop a Means to Filter Molecular Waste from Cerebrospinal Fluid
Leucadia Therapeutics and EnClear Therapies are both testing the hypothesis that clearance of molecular waste from cerebrospinal fluid is a viable form of prevention and treatment for many neurodegenerative conditions, though they couldn’t be more different in their areas of focus and specific implementations. Most of the common neurodegenerative conditions are characterized by rising levels of various forms of harmful molecular waste in the brain, misfolded proteins, and the like. Cerebrospinal fluid circulates in the brain and drains into the body through a variety of pathways, carrying away this waste. Unfortunately, these channels of drainage atrophy or ossify with age, and this loss contributes to the pathological levels of harmful metabolic byproducts that are present in the aging brain. Leucadia seeks to restore drainage through the cribriform plate pathway, while EnClear seeks to filter out the molecular waste present in cerebrospinal fluid though an approach similar to blood filtration, except carried out via a spinal tap.
EnClear Therapies, a life sciences company developing device-based therapies for the treatment of neurodegenerative disease, today announced a 10 million Series A financing. “We are thrilled to have a strong syndicate committed to our team and platform technology, enabling EnClear to move our therapeutic system to our first-in-human clinical trial in Amyotrophic Lateral Sclerosis, as well as expand our platform into new applications and strategic partnerships. Our differentiated technology has the potential to transform not only the treatment of this devastating disease, but also many other conditions related to the central nervous system.”
“The founders of EnClear are focused on producing a technology that could revolutionize the field by allowing fast diagnosis, delivery of any drug directly into the cerebrospinal fluid, and the development of new CNS-focused therapeutics. I am excited to help EnClear grow their business to help the millions of patients living with CNS diseases. We believe that EnClear’s technology has the potential to fundamentally change the way neurodegenerative diseases are treated and ultimately improve patients’ lives.”
Reduced Generation of New Oligodendrocytes May Contribute to Declining Memory with Age
A number of the aspects of cognitive decline are connected to loss of stem cell activity with age, and thus reduced numbers of new somatic cells created to carry out functions in the brain. This is certainly the case for memory, but most such research is focused on neurogenesis, the process by which new neurons are created and integrated into neural circuits. Researchers here point to a different contributing population and mechanism, a reduced creation of oligodendrocytes and thus a reduced supply of myelin, the protein that sheaths nerves and is essential for their function. It is well known that myelin sheathing deteriorates with age, and this lack of oligodendrocyte cells may be an important proximate cause of that deterioration.
While the vast majority of myelin sheaths in the brain are laid down early in life, new studies reveal that a fresh supply of the fatty axonal conductor is required to establish and maintain memories in the adult brain. One reported that newly minted, myelin-producing oligodendrocytes act to cement unpleasant memories in mice. The other reported that the birth of new oligodendrocytes plummets with age – a slowdown that could underlie age-related memory loss. In both, a drug that fosters the growth of new oligodendrocytes improved memory. The studies add to growing evidence that active myelination plays a crucial role in memory function, and mesh with recent studies implicating myelination malfunctions in neurodegenerative disease.
Part and parcel of most functional axons, myelin sheaths speed up the conductance of neuronal signals in the brain. While much of the myelin in the brain is as old as the axons themselves, a fraction of myelin continues to be produced by a small pool of new oligodendrocytes that develop throughout life, in response to new experiences and learning. This experience-dependent myelination is thought to bestow structural plasticity on the brain. Such myelination has been implicated in motor learning, and drugs that interfere with oligodendrocyte function reportedly cause memory deficits in mice.
If new oligodendrocytes are important in memory, might a slowdown in their production underlie age-related memory loss? Researchers started by tracking myelin production in mice with age. Using transgenic mice in which newly formed oligodendrocytes and myelin sheaths can be inducibly labeled, the researchers spotted numerous myelin-producing newbies in four- to six-month-old mice in the corpus callosum, but by 13 months of age, new oligodendrocytes were few and far between. As the spigot of fresh myelin started to pinch, age-related memory deficits emerged. Compared with 4-month-old mice, 13-month-olds took longer to learn the location of a submerged platform in the Morris water maze test of spatial memory. The hippocampus is crucial for storage of spatial memory, and the researchers found far fewer newly minted, myelin-producing oligodendrocytes in the CA1 region of the hippocampus in 13-month-old than in younger adult mice. Expression of myelin basic protein (MBP) – the building block of myelin sheaths – was also lower in the hippocampi of older mice.
Wielding a menagerie of mouse models, the researchers went on to reveal that blocking differentiation of oligodendrocytes led to memory loss in 4-month-old mice, while revving up the maturation of new oligodendrocytes prevented memory deficits in older mice, and even upped the density of synaptic puncta in the hippocampus.
Correction of Mitochondrial Dysfunction as an Approach to Treat Heart Failure
Mitochondria are the power plants of the cell, and when their activity falters, cell and tissue function suffers as a consequence. Unfortunately mitochondrial dysfunction is a feature of aging, and is connected to the progression and severity of numerous age-related conditions. The research here examines age-related mitochondrial decline in the context of heart failure. As is appropriate for this new era of intervention in the aging process, the focus is on what might be done about this. At the very least, the evidence suggests that even early approaches that can only somewhat restore mitochondrial function in the old, such as NAD+ upregulation or mitochondrially targeted antioxidants, might produce benefits in heart failure patients. Better methodologies capable of greater restoration of mitochondrial function are very much required, however.
The burden of heart failure (HF) in terms of health care expenditures, hospitalizations, and mortality is substantial and growing. The failing heart has been described as “energy-deprived” and mitochondrial dysfunction is a driving force associated with this energy supply-demand imbalance. Existing HF therapies provide symptomatic and longevity benefit by reducing cardiac workload through heart rate reduction and reduction of preload and afterload but do not address the underlying causes of abnormal myocardial energetic nor directly target mitochondrial abnormalities.
Numerous studies in animal models of HF as well as myocardial tissue from explanted failed human hearts have shown that the failing heart manifests abnormalities of mitochondrial structure, dynamics, and function that lead to a marked increase in the formation of damaging reactive oxygen species (ROS) and a marked reduction in on demand adenosine triphosphate (ATP) synthesis. Correcting mitochondrial dysfunction to enhance the energy supply of the failing heart to meet the desired energy needs offers considerable potential to improve cardiac function, reduce symptoms, and improve exercise tolerance in HF, and ultimately offer improved quality of life and survival for patients, and reduce the overall economic burden of this condition.
Elamipretide (SS-31) is a water-soluble, aromatic-cationic mitochondria-targeting tetrapeptide that readily penetrates and transiently localizes to the inner mitochondrial membrane and associates with cardiolipin to restore mitochondrial bioenergetics. Studies in dogs with coronary microembolization-induced chronic HF showed that 3 months of treatment with daily subcutaneous injections of elamipretide improved left ventricle (LV) systolic function and prevented progressive LV dilation without affecting heart rate, blood pressure, or systemic vascular resistance. Elamipretide also elicited a normalization of mitochondrial function evidenced by improved respiration, normalization of membrane potential, reduced ROS formation, and improved maximum rate of ATP synthesis.