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Reason, the founder of Fight Aging! and Repair Biotechnologies, offers strategic consulting services to investors, entrepreneurs, and others interested in the longevity industry and its complexities. To find out more: https://www.fightaging.org/services/
Novel mTOR Inhibitors Viewed as a Safer Option by Conservative Investors
https://www.fightaging.org/archives/2024/04/novel-mtor-inhibitors-viewed-as-a-safer-option-by-conservative-investors/
The safest sort of investment into therapeutic development is one made in a part of a field that is well established, producing a small variant of an existing drug, using the well beaten path of small molecule development, targeting a mechanism that is very well understood, and that has extensive safety data associated with it. One could argue that mTOR inhibition is the canonical example of a low risk investment in the longevity field. Like most lower-risk exercises in medical development, the potential gain for patients is modest. mTOR inhibition can produce larger gains in mouse life span than exercise, but doesn’t beat calorie restriction.
Still, higher odds of a return on investment tends to far outweigh the size of potential patient benefits in the eyes of conservative investors. This is one of the reasons why progress in medicine is so very incremental. It is perhaps surprising that that the longevity industry exhibits a relatively small investment in mTOR inhibitor development in comparison to, say, the billions directed towards reprogramming approaches, given that the development of partial reprogramming therapies can hardly be described as a low-risk program at the present time.
Hevolution is a Saudi Arabian fund that has for a while now been discussing a 1 billion investment into research and development of longevity-enhancing therapies. There has been some question over how and when the Hevolution leadership will start to deploy meaningful amounts of capital in the longevity industry. To date, they have focused on funding academic research, collectively to a sizable amount. It appears that the fund is now making its first inroads into funding companies, and, judging from the company selected, is taking the conservative, safe approach.
Hevolution Foundation Announces 20 million Impact Investment to Advance Promising Aging Therapies, Leading a 50 million Series A Extension in Aeovian Pharmaceuticals
Hevolution Foundation announced its first life science impact investment of 20 million to help Aeovian Pharmaceuticals advance its innovative platform of selective mTORC1 inhibitors which could lead to several promising therapies for disease of aging. This investment – the leading contribution in a 50 million Series A financing extension for Aeovian – has the potential to address major unmet medical needs including TSC refractory epilepsy, neurological diseases, and prevalent diseases of aging.
After careful evaluation of over 200 opportunities, Hevolution selected Aeovian based on the company’s success in drug discovery, its expertise in development, the potential for commercialization, and its compelling platform for the discovery of selective mTORC1 inhibitors. Strategic collaborations focused on advancing the healthspan sector are integral to Hevolution’s investment approach. As the lead investor, Hevolution is joined in this investment by Apollo Health Ventures, Sofinnova Investments, venBio, Evotec, and b2venture. Hevolution’s Chief Investment Officer William Greene, M.D. will also join Aeovian’s Board of Directors, bringing over 25 years of leadership experience as a founder, biotechnology executive, investor, and clinician.
This investment underscores Hevolution’s commitment to increase the number of safe and effective treatments entering the market, compress the timeline of drug development, using the latest tools and technologies and increase accessibility to therapeutics that extend healthy lifespan. It follows Hevolution’s launch of the Breakthrough Innovation Alliance at the Global Healthspan Summit in November 2023. To date, Hevolution has committed more than 250 million in scientific funding to catalyze the healthspan ecosystem.
LyGenesis Commences Phase II Trial for Growth of Liver Organoids in Patient Lymph Nodes
https://www.fightaging.org/archives/2024/04/lygenesis-commences-phase-ii-trial-for-growth-of-liver-organoids-in-patient-lymph-nodes/
LyGenesis has been working towards liver organoid transplantation as a treatment for liver failure for some years now. Organs such as the liver, thymus, and a few others do not need to be in any specific place in the body to carry out many of their varied functions. Some of the vital work of the liver, for example, can be conducted in small organoids grown from liver cells transplanted into lymph nodes or other parts of the body that can act as stable bioreactors.
Even setting aside the possibility of growing functional liver organoids from patient cells or universal cell lines, it is worth noting that the old approach of harvesting donor livers could be used to create large numbers of organoids through the LyGenesis methology, and thereby help many more patients with liver disease than is presently possible through transplantation. In recent news, LyGenesis has now started a small clinical trial; we might hope that success for the company will spur the development of analogous approaches for other organs, such as the thymus.
‘Mini liver’ will grow in person’s own lymph node in bold new trial
More than 50,000 people in the United States die each year with liver disease. In the end stage of the disease, scar tissue that has accumulated prevents the organ from filtering toxic substances in the blood, and can lead to infection or liver cancer. A liver transplant can help, but there is a shortage of organs: about 1,000 people in the United States die every year waiting for a transplant. Thousands more aren’t eligible because they are too ill to undergo the procedure.
LyGenesis has been trialling an approach that could help people in this situation – and make use of donated livers that would otherwise go to waste because a person on the transplant waiting list with a compatible health profile hasn’t materialized in time. The company’s strategy delivers the donor cells through a tube in the throat, injecting them into a lymph node near the liver. Lymph nodes, which also filter waste in the body and are an important part of the immune system, are ideal for growing mini livers, because they receive a large supply of blood and there are hundreds of them throughout the body, so if a few are used to generate mini livers, plenty of others can continue to function as lymph nodes.
The treatment has so far worked in mice, dogs, and pigs. To test the therapy in pigs, researchers restricted blood flow to the animals’ livers, causing the organs to fail, and injected donor cells into lymph nodes. Miniature livers formed within two months and had a cellular architecture resembling a healthy liver. Researchers even found cells that transport bile, a digestive fluid produced by the liver, in the mini livers of the pigs. In this case, they saw no build-up of bile acid, suggesting that the mini organs were processing the fluid.
The company aims to enroll 12 people into the phase II trial by mid-2025 and publish results the following year. The trial, which was approved by US regulators in 2020, will not only measure participant safety, survival time and quality of life post-treatment, but will also help to establish the ideal number of mini livers to stabilize someone’s health. The clinicians running the trial will inject liver cells in up to five of a person’s lymph nodes to determine whether the extra organs can boost the procedure’s success rate. LyGenesis has ambitions beyond mini livers, too. The company is now testing similar approaches to grow kidney and pancreas cells in the lymph nodes of animals.
Intermittent Methionione Restriction may be an Improvement on Continuous Methionine Restriction
https://www.fightaging.org/archives/2024/04/intermittent-methionione-restriction-may-be-an-improvement-on-continuous-methionine-restriction/
Regulatory systems that detect low levels of the essential amino acid methionine are one of the more important triggers for the metabolic response to fasting and calorie restriction. Methionine is not manufactured in mammalian cells, can only be obtained from the diet, but is nonetheless essential for protein synthesis. Thus reducing only methionine levels in the diet can capture a sizable fraction of the benefits of calorie restriction.
While it is possible for a self-experimenter armed with time, a suitable database of methionine content by food type, and considerable willpower to practice significant levels of methionine restriction, it arguably requires a great deal more effort than simply restricting calories. Medical diets structured to have low methionine levels exist, but are expensive. Methionine restriction is thus not widely practiced as a dietary choice by anyone other than those forced into it by rare medical conditions.
In today’s open access paper, researchers demonstrate that intermittent methionine restriction produces similar metabolic changes to continuous methionine restriction, while maintaining greater bone mineral density. This is interesting when considered in analogy to the past decade of work comparing the effects of intermittent fasting with calorie restriction. Some researchers theorize that the periods of refeeding between periods of restriction are beneficial, and that the optimal approach to nutrition is thus some arrangement of periodic fasting.
Intermittent Methionine Restriction Reduces Marrow Fat Accumulation and Preserves More Bone Mass than Continuous Methionine Restriction
Continuous methionine restriction (MR) is one of only a few dietary interventions known to dramatically extend mammalian healthspan. For example, continuously methionine-restricted rodents show less age-related pathology and are up to 45% longer-lived than controls. Intriguingly, MR is feasible for humans, and a number of studies have suggested that methionine-restricted individuals may receive similar healthspan benefits as rodents. However, long-term adherence to a continuously methionine-restricted diet is likely to be challenging (or even undesirable) for many individuals. To address this, we previously developed an intermittent version of MR (IMR) and demonstrated that it confers nearly identical metabolic health benefits to mice as the continuous intervention, despite having a relatively short interventional period (i.e., only three days per week). We also observed that female mice undergoing IMR show a more pronounced amelioration of diet-induced dysglycemia than continuously methionine-restricted counterparts, while male mice undergoing IMR retain more lean body mass as compared with continuously methionine-restricted controls. Prompted by such findings, we sought to determine other ways in which IMR might compare favorably with continuous MR.
While it is known that continuous MR has deleterious effects on bone in mice, including loss of both trabecular and cortical bone, we considered that mice undergoing IMR might retain more bone mass. Here, we report that, as compared with continuous MR, IMR results in a preservation of both trabecular and cortical bone, as well as a dramatic reduction in the accumulation of marrow fat. Consistent with such findings, mechanical testing revealed that the bones of intermittently methionine-restricted mice are significantly stronger than those of mice subjected to the continuous intervention. Finally, static histomorphometric analyses suggest that IMR likely results in more bone mass than that produced by continuous MR, primarily by increasing the number of osteoblasts. Together, our results demonstrate that the more practicable intermittent form of MR not only confers similar metabolic health benefits to the continuous intervention but does so without markedly deleterious effects on either the amount or strength of bone. These data provide further support for the use of IMR in humans.
An Update on Reversal of Atherosclerosis at Repair Biotechnologies
https://www.fightaging.org/archives/2024/04/an-update-on-reversal-of-atherosclerosis-at-repair-biotechnologies/
As some of you know, Repair Biotechnologies is the company I co-founded with Bill Cherman back in 2018. We’ve been working on an approach to reverse atherosclerosis for much of that time, and matters have progressed through the stage of great data in mice to present preparations for a pre-IND meeting with the FDA. While excess cholesterol has long been understood to be important to the development of atherosclerosis, it turns out that circulating cholesterol bound to LDL particles is less important than the amount of localized excess cholesterol in the liver and blood vessel walls.
Any localized excess of cholesterol can overwhelm the ability of cells to reduce uptake or store cholesterol in either the cell membrane or in esterified droplets. The resulting free cholesterol inside cells is toxic. The gene therapies developed by the Repair Biotechnologies scientists put in place novel protein machinery that can selectively and safely break down this excess free cholesterol without harming the cholesterol necessary to cell function. This can, for example, protect macrophages from becoming foam cells when exposed to excessive cholesterol. It can also put a halt to dysfunction in liver cells affected by the excess cholesterol present in a fatty liver.
Repair Biotechnologies’ gene therapy rapidly reverses atherosclerosis in mice
Gene therapy company Repair Biotechnologies has revealed promising preclinical results that demonstrate its technology rapidly reverses the progression of atherosclerosis in mouse models. The company says the development holds potential for treating both atherosclerosis and a rare genetic condition called familial hypercholesterolemia, in humans.
Atherosclerosis is a condition characterized by the buildup of plaque in arteries, eventually blocking blood flow, and contributing significantly to heart disease, stroke, and death. In experiments, scientists at Repair Biotechnologies treated atherosclerotic mouse models with the lipid nanoparticle (LNP)-messenger RNA (mRNA) therapy over a six-week period, with promising results.
Both groups of mice, one representing a general population model for atherosclerosis, and another modeling familial hypercholesterolemia, exhibited significant reductions in plaque buildup. Specifically, the atherosclerotic mice showed a 19% drop in plaque lipids and a 23% increase in plaque collagen, indicating stabilization of vulnerable plaque. The mice with familial hypercholesterolemia experienced a 17% reduction in plaque obstruction in the aortic root, alongside improved cardiovascular health demonstrated by increased treadmill capacity.
Based in Syracuse, New York, Repair Bio is developing LNP-mRNA therapies targeting a range of health conditions. Unlike traditional therapies that focus on reducing LDL-cholesterol levels in the bloodstream, the company’s therapy targets intracellular free cholesterol, which is toxic to cells and contributes to the development of numerous conditions. Repair Bio’s approach leverages its cholesterol degrading platform technology to safely break down excess free cholesterol within cells.
“Unfortunately statins and PCSK9 inhibitors that reduce LDL-cholesterol in the blood exhibit little ability to reduce the size of established atherosclerotic lesions,” said Mourad Topors, CSO at Repair Bio. “Our studies in severely atherosclerotic mice demonstrate that LDL-cholesterol is the wrong target if the goal is the outright regression of plaque and dramatic reduction in risk of cardiovascular events. Instead, clearance of intracellular free cholesterol can potentially achieve these goals.”
TLR2 Important in the Dysfunction of Hair Follicles
https://www.fightaging.org/archives/2024/04/tlr2-important-in-the-dysfunction-of-hair-follicles/
Dysfunction in hair follicles and loss of the capacity for hair growth is a perhaps surprisingly complex aspect of aging and disease. For all the the basic mechanisms of hair growth are well-investigated, the hair follicle is a complex structure, and hair growth involves the collaboration of many cell types, activities, and signaling that shifts over time as the follicle progresses through the stages of growth. It has proven to be hard to pin down any one specific mechanism as vital, and it may turn out to be the case that no one specific mechanism is the key to preventing loss of hair with advancing age and other circumstances.
Nonetheless, researchers continue to search for that one specific mechanism that may reverse age-related loss of hair follicle function and hair growth. In today’s open access paper, researchers argue for innate immune involvement to be important, mediated by toll-like receptor 2 (TLR2). Level and activity of TLR2 both decline with age, while delivery of a suitable native ligand that interacts with TLR2 produces improved regeneration of hair follicles and hair regrowth following injury in mice. Whether this approach will also work to reverse hair thinning and hair follicle dysfunction in old, uninjured animals remains to be seen.
TLR2 regulates hair follicle cycle and regeneration via BMP signaling
Hair follicles (HFs) represent one of the best examples of mini-organs with the ability to regenerate throughout life, which, in turn, relies on the proliferation and differentiation of HF stem cells (HFSCs) within hair bulge. The cyclic renewal of HFs is orchestrated by the interplay between inhibitory and stimulatory signals. Despite the immune privileged status of HFs, they have a unique microbiome and immune system, including resident macrophages and other immune cells. Components of the HF immune system have been implicated in regulating the HF cycle and its regeneration. Given their exposure to pathogens, HFs are equipped with innate immune receptors, particularly Toll-like receptors (TLRs), which detect and respond to pathogens by stimulating the secretion of defensins.
TLRs play a key role in recognizing and responding to either pathogen-associated molecular patterns or damage-associated molecular patterns, mediating the cytokine response. However, the role of TLRs extends beyond this function, as they have been shown to directly promote tissue regeneration and homeostasis in multiple tissues, particularly in stem and progenitor cells.
Multiple reports connect altered HFs’ immunity to hair loss, including a breakdown of immune privilege in alopecia areata. Likewise, androgen, which is tightly linked to TLR activation, was shown to influence the innate immunity of HFs in androgenic alopecia. The decline of innate immunity processes due to aging or conditions like obesity is widely recognized and these conditions are causatively associated with hair thinning and loss. Alopecia patients often have higher body weight index and weight compared to healthy individuals. Increased body weight index is linked to more significant hair loss severity in adults and a higher prevalence of hair disorders in children and adolescents. Mouse models support these findings, showing that activation of innate immunity through pathogen signals might lead to alopecia and that high-fat diets inducing obesity cause hair thinning through HFSC depletion.
Transcriptome analysis of aging hair follicles uncovered changes in immune pathways, including TLRs. Our findings demonstrate that the maintenance of hair follicle homeostasis and the regeneration capacity after damage depend on TLR2 in hair follicle stem cells (HFSCs). In healthy hair follicles, TLR2 is expressed in a hair cycle-dependent manner and governs HFSCs activation by countering inhibitory BMP signaling. Hair follicles in aging and obesity exhibit a decrease in both TLR2 and its endogenous ligand carboxyethylpyrrole (CEP), a metabolite of polyunsaturated fatty acids. Administration of CEP stimulates hair regeneration through a TLR2-dependent mechanism. These results establish a novel connection between TLR2-mediated innate immunity and HFSC activation, which is pivotal to hair follicle health and the prevention of hair loss and provide new avenues for therapeutic intervention.
Dysfunction of the Glymphatic System Correlates with Faster Progression of Alzheimer’s Disease
https://www.fightaging.org/archives/2024/04/dysfunction-of-the-glymphatic-system-correlates-with-faster-progression-of-alzheimers-disease/
The glymphatic system is one of the pathways for drainage of cerebrospinal fluid from the brain to the body. This drainage is necessary to remove metabolic waste from the brain, and there is good evidence for reduced outflow of cerebrospinal fluid to lead to the development of neurodegenerative conditions. The work here adds to this body of evidence, showing that impaired flow of cerebrospinal fluid through the glymphatic system correlates with later severity of Alzheimer’s disease.
The glymphatic system is an essential fluid-clearance system in the brain. The highly organized cerebrospinal fluid (CSF) transport system subserves the influx of CSF into the brain parenchyma along the arterial perivascular spaces and subsequent transfer to the brain interstitial space. Impaired brain clearance mechanisms may be an essential factor contributing to the deposition of pathological proteins in Alzheimer’s disease (AD). The novel fluid transport system provides a promising target for the prevention or treatment of AD.
Recently, a measure of perivascular clearance activity in the human brain using diffusion MRI called diffusion tensor image analysis along the perivascular space (DTI-ALPS) has been proposed. The reliability of the ALPS index as a measure of glymphatic activity was supported in a recent study that found a significant correlation between the ALPS index and glymphatic clearance function. In the field of AD, previous studies have observed a decreased ALPS index in AD patients compared to controls. The ALPS index is also associated with cognitive performance in AD and is negatively associated with amyloid and tau deposition on positron emission tomography (PET) images.
In the present study, we used the ALPS index to investigate the cross-sectional and longitudinal associations between glymphatic activity and clinical and pathological features of AD, including diagnosis, cognitive scores, and CSF and neuroimaging biomarkers. Taking advantage of the large-scale and longitudinal measurements of the ALPS index and AD hallmarks in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort, we further investigated the sequential relationship between glymphatic dysfunction, as measured by the ALPS index, and markers of AD pathology in the development of AD.
ALPS index was significantly lower in AD dementia than in mild cognitive impairment (MCI) or controls. Lower ALPS index was significantly associated with faster changes in amyloid positron emission tomography (PET) burden and AD signature region of interest volume, higher risk of amyloid-positive transition and clinical progression, and faster rates of amyloid- and neurodegeneration-related cognitive decline. Furthermore, the associations of the ALPS index with cognitive decline were fully mediated by amyloid PET and brain atrophy. Thus glymphatic failure may precede amyloid pathology, and predicts amyloid deposition, neurodegeneration, and clinical progression in AD.
BHLHE40 and BHLHE41 Deletion May Make Macrophages and Microglia More Efficient
https://www.fightaging.org/archives/2024/04/bhlhe40-and-bhlhe41-deletion-may-make-macrophages-and-microglia-more-efficient/
Macrophages in the body and microglia in the brain are similar forms of innate immune cell, responsible for clearing metabolic waste, among other duties. A number of age-related conditions involve the growing incapacity of macrophages or microglia, their transition to inflammatory states, and inability to clear debris and waste as they should. Atherosclerosis, for example, is arguably a condition caused by macrophage dysfunction, in which macrophages fail to clear excess cholesterol from blood vessel walls. Neurodegenerative conditions such as Alzheimer’s disease, on the other hand, are characterized by the presence of activated, senescent, and overly inflammatory microglia. Can these cells be made more resilient to the aged tissue environment, made less inflammatory, made better at the task of waste clearance? Perhaps, as the work here indicates.
Genetic and experimental evidence suggests that Alzheimer’s disease (AD) risk alleles and genes may influence disease susceptibility by altering the transcriptional and cellular responses of macrophages, including microglia, to damage of lipid-rich tissues like the brain. Recently, single cell RNA sequencing studies identified similar transcriptional activation states in subpopulations of macrophages in aging and degenerating brains and in other diseased lipid-rich tissues. We collectively refer to these subpopulations of microglia and peripheral macrophages as disease-associated and lipid-associated cells, here DLAMs for brevity.
Using macrophage RNA-seq data from healthy and diseased human and mouse lipid-rich tissues, we reconstructed gene regulatory networks and identified 11 strong candidate transcriptional regulators of the DLAM response across species. Loss or reduction of two of these transcription factors, BHLHE40 and BHLHE41, in iPSC-derived microglia and human THP-1 macrophages as well as loss of Bhlhe40/41 in mouse microglia, resulted in increased expression of DLAM genes involved in cholesterol clearance and lysosomal processing, increased cholesterol efflux and storage, and increased lysosomal mass and degradative capacity. These findings provide targets for therapeutic modulation of macrophage/microglial function in AD and other disorders affecting lipid-rich tissues.
Cholesterol-Consuming Gut Microbes Lower Heart Disease Risk
https://www.fightaging.org/archives/2024/04/cholesterol-consuming-gut-microbes-lower-heart-disease-risk/
Variations in the relative proportions of microbial species making up the gut microbiome apparently contribute to variations in LDL-cholesterol in the bloodstream. Lower LDL-cholesterol sustained over a lifetime produces a slower development of atherosclerotic plaque, and lower risk of consequent cardiovascular disease. While it seems likely there is no one optimal gut microbiome, there are certainly specific improvements that can be achieved for most older individuals. Fortunately, producing lasting changes in the balance of microbial populations making up the gut microbiome is an achievable goal. Fecal microbiota transplantation works well, for example. This is a little explored but potentially quite useful area of medical development.
Researchers analyzed metabolites and microbial genomes from more than 1,400 participants in the Framingham Heart Study, a decades-long project focused on risk factors for cardiovascular disease. The team discovered that bacteria called Oscillibacter take up and metabolize cholesterol from their surroundings, and that people carrying higher levels of the microbe in their gut had lower levels of cholesterol. The results suggest that interventions that manipulate the microbiome in specific ways could one day help decrease cholesterol in people.
The researchers found that species in the Oscillibacter genus were surprisingly abundant in the gut, representing on average 1 in every 100 bacteria. The researchers then wanted to figure out the biochemical pathway the microbes use to break down cholesterol. To do this, they first needed to grow the organism in the lab. Fortunately, the lab has spent years collecting bacteria from stool samples to create a unique library that also included Oscillibacter.
After successfully growing the bacteria, the team used mass spectrometry to identify the most likely byproducts of cholesterol metabolism in the bacteria. This allowed them to determine the pathways the bacteria uses to lower cholesterol levels. They found that the bacteria converted cholesterol into intermediate products that can then be broken down by other bacteria and excreted from the body. Next, the team used machine-learning models to identify the candidate enzymes responsible for this biochemical conversion, and then detected those enzymes and cholesterol breakdown products specifically in certain Oscillibacter in the lab.
The team found another gut bacterial species, Eubacterium coprostanoligenes, that also contributes to decreased cholesterol levels. This species carries a gene that the scientists had previously shown is involved in cholesterol metabolism. In the new work, the team discovered that Eubacterium might have a synergistic effect with Oscillibacter on cholesterol levels, which suggests that new experiments that study combinations of bacterial species could help shed light on how different microbial communities interact to affect human health.
Mitochondrial Hydrogen Peroxide Does Not Damage Nuclear DNA
https://www.fightaging.org/archives/2024/04/mitochondrial-hydrogen-peroxide-does-not-damage-nuclear-dna/
Researchers here report on an interesting in vitro demonstration, in which they show that hydrogen peroxide (H2O2) generated in mitochondria does not cause nuclear DNA damage. Oxidizing molecules generated as a byproduct of mitochondrial generation of the chemical energy store molecule adenosine triphosphate (ATP) are thought to be important in aging. Oxidative stress is a feature of aging and age-related changes to mitochondrial structure, dynamics, and function. Oxidative damage to nuclear DNA is also a feature of this cell-wide oxidative stress, and it is commonly thought that mitochondria are the source of this stress and thus this damage. But perhaps they are not.
Reactive Oxygen Species (ROS) derived from mitochondrial respiration are frequently cited as a major source of chromosomal DNA mutations that contribute to cancer development and aging. However, experimental evidence showing that ROS released by mitochondria can directly damage nuclear DNA is largely lacking. In this study, we investigated the effects of H2O2 released by mitochondria or produced at the nucleosomes using a titratable chemogenetic approach. This enabled us to precisely investigate to what extent DNA damage occurs downstream of near- and supraphysiological amounts of localized H2O2.
Nuclear H2O2 gives rise to DNA damage and mutations and a subsequent p53 dependent cell cycle arrest. Mitochondrial H2O2 release shows none of these effects, even at levels that are orders of magnitude higher than what mitochondria normally produce. We conclude that H2O2 released from mitochondria is unlikely to directly damage nuclear genomic DNA, limiting its contribution to oncogenic transformation and aging.
Age-Related Changes in the Immune Response to Bone Injury
https://www.fightaging.org/archives/2024/04/age-related-changes-in-the-immune-response-to-bone-injury/
The aged immune system becomes consistently biased towards inflammation, existing in a state of constant low-grade unresolved inflammatory signaling. This changes cell behavior for the worse, and is disruptive to processes that require transient inflammation and participation of immune cells, such as regeneration following injury, or clearance of infectious pathogens. Here researchers discuss some of the details relating to the participation of the immune system in regeneration following bone injury. It is interesting to note the sizable differences between sexes, in addition to those introduced by aging.
Inflammation is thought to be dysregulated with age leading to impaired bone fracture healing. However, broad analyses of inflammatory processes during homeostatic bone aging and during repair are lacking. Here, we assessed changes in inflammatory cell and cytokine profiles in circulation and in bone tissue to identify age- and sex-dependent differences during homeostasis and repair. During homeostatic aging, male mice demonstrated accumulation of CD4+ helper T cells and CD8+ cytotoxic T cells within bone while both pro-inflammatory “M1” and anti-inflammatory “M2” macrophage numbers decreased. Female mice saw no age-associated changes in immune-cell population in homeostatic bone.
Concentrations of IL-1β, IL-9, IFNγ, and CCL3/MIP-1α increased with age in both male and female mice, whereas concentrations of IL-2, TNFα, TNFR1, IL-4, and IL-10 increased only in female mice – thus we termed these “age-accumulated” cytokines. There were no notable changes in immune cell populations nor cytokines within circulation during aging. Sex-dependent analysis demonstrated slight changes in immune cell and cytokine levels within bone and circulation, which were lost upon fracture injury. Fracture in young male mice caused a sharp decrease in number of M1 macrophages; however, this was not seen in aged male mice nor in female mice of any age.
Injury itself induced a decrease in the number of CD8+ T cells within the local tissue of aged male and of female mice but not of young mice. Cytokine analysis of fractured mice revealed that age-accumulated cytokines quickly dissipated after fracture injury, and did not re-accumulate in newly regenerated tissue. Conversely, CXCL1/KC-GRO, CXCL2/MIP-2, IL-6, and CCL2/MCP-1 acted as “fracture response” cytokines: increasing sharply after fracture, eventually returning to baseline. Collectively, we classify measured cytokines into three groups: (1) age-accumulated cytokines, (2) female-specific age-accumulated cytokines, and (3) fracture response cytokines. These inflammatory molecules represent potential points of intervention to improve fracture healing outcome.
A Look at the Research Yet to be Accomplished for Cellular Senescence
https://www.fightaging.org/archives/2024/04/a-look-at-the-research-yet-to-be-accomplished-for-cellular-senescence/
While early senolytic therapies to clear senescent cells do well in mice, clearing a third to a half of the lingering senescent cells in some tissues and rapidly reversing many aspects of aging, to go much further than this will require a greater understanding of cellular senescence. Unfortunately, it is becoming clear that what we call senescence varies considerably from cell type to cell type, and there is much yet to be discovered regarding targets for therapy, ways to assess the burden of senescence, and more.
Despite significant advances in the characterization of senescent cells (SnCs), many questions about the biology of these cells remain open. Firstly, it is necessary to understand which markers are necessary and sufficient to define that a cell is in a “full” or “deep” senescent state. Similarly, the dynamics and adaptability of SnCs still need to be better understood, including how plastic those cells are for the expression of senescent cell anti-apoptotic pathways (SCAPs), the structure of intracellular compartments, or senescence-associated secretory phenotype (SASP) composition, the pathways governing these transitions, and how intense these phenotypic variations must be to influence the non-autonomous role played by SnCs. Understanding these aspects may also allow us to infer whether differences within SnCs of cell populations occur due to different states in different SnCs or the plasticity of individual SnCs. Finally, it is also imperative to comprehend the heterogeneity and the cause-and-effect between subcellular features and the outcome of SnCs. New evidence regarding the above questions can also contribute to understanding questions such as how long an SnC lives and whether death is the only possible outcome.
A better understanding of essential features of SnCs can also contribute to translational issues in which cellular senescence appears to be relevant. Questions like the role of SASP in acute responses and chronic conditions and the most relevant SASP molecules for pathophysiological responses may allow the mitigation of detrimental impacts or the increase of beneficial effects played by SnCs. It is also mandatory to uncover novel avenues for senotherapies, such as senolytics (for instance, by targeting the heterogeneity of this phenotype), senopreventives (by elucidating mechanisms allowing senescence entry), and senomorphics (by affecting the detrimental effects of SASP selectively). Nevertheless, several barriers need to be overcome to allow the clinical application of basic concepts in cellular senescence, such as the lack of specific therapies to reduce detrimental but not beneficial effects played by SnCs, the best time to affect senescence in pathophysiological responses, and how to assess the effectiveness of senotherapies.
In conclusion, although several clinical trials targeting SnCs are ongoing, various questions about the biology of SnCs remain open, resulting in a gap between molecular and cellular data. Concerning the need, initiatives such as SenNet aiming to create openly accessible atlases of SnCs should contribute enormously to the area. Advances in understanding the subcellular structure, the heterogeneity, and the dynamics of SnCs require the integration of molecular and cellular techniques with data analysis packages to evaluate high throughput evidence from microscopy and flow cytometry. It is also necessary to develop new equipment or protocols for long-term live cell tracking or high-resolution microscopy beyond new molecular reporters, allowing the chronic study of live cells. Combining evidence from these diverse sources can transform the field, enhancing our comprehension of how SnCs acts on human health and extending beyond the advancement of more effective and specific senotherapies.
SENS Research Foundation and Lifespan.io to Merge
https://www.fightaging.org/archives/2024/04/sens-research-foundation-and-lifespan-io-to-merge/
Merging the non-profits SENS Research Foundation and Lifespan.io is one of those ideas that makes a lot of sense in hindsight. SENS Research Foundation is research focused and very much interested in expanding into patient advocacy, as it depends on philanthropic funding. Lifespan.io is a patient advocacy organization that is very much interested into expanding into helping to advance the science of aging and clinical trials for therapies of aging. They complement one another, and may well produce greater gains as one organization than as two.
Lifespan.io, renowned for its unwavering advocacy for longevity and responsible journalism, is joining hands with SENS Research Foundation, a trailblazer in longevity-focused research and a pioneer of the damage-repair approach to combating aging. Together, these organizations bring a formidable quarter-century of combined expertise to the table. Their collaborative efforts have propelled the field forward and been instrumental in garnering recognition for longevity research as a vital and transformative industry.
This merger represents a deliberate alignment of research and advocacy efforts, uniting them toward the immediate goal of expediting advancements in extending healthy human lifespan instead of waiting for the distant future. With an aim of bolstering the industry at large, they will offer a platform for information creation and dissemination to foster global impact. By pooling together resources, expertise, and networks, the newly formed entity is positioned to significantly influence the progress of rejuvenation biotechnologies while enhancing public awareness and involvement.
Upon completion of the regulatory process, the merger is slated to be finalized by the end of 2024. Lisa Fabiny-Kiser as Chief Executive Officer, and Stephanie Dainow as Chief Business Officer are poised to be Co-Founders of this new entity, joined by an equally representative Board of Directors. By leveraging their combined strengths and a redoubled focus on impactful and translatable research, the merged organization will serve a key sense-making and unifying role for the longevity industry, accelerating the development, translation, and equitable distribution of therapies to increase healthy human lifespan.
Enabling Microglia to Better Clear Amyloid by Interfering in the LILRB4-APOE Interaction
https://www.fightaging.org/archives/2024/04/enabling-microglia-to-better-clear-amyloid-by-interfering-in-the-lilrb4-apoe-interaction/
Researchers here describe a mechanism that reduces the ability of microglia to ingest and clear misfolded amyloid-β, the protein aggregates associated with Alzheimer’s disease. Interestingly, this involves APOE, and thus might be affected by the different APOE variants connected to Alzheimer’s disease risk. The researchers demonstrate that interfering in the interaction between APOE and the LILRB4 receptor present on microglia can restore microglia-mediated clearance of amyloid-β.
Toxic clumps of brain proteins are features of many neurodegenerative conditions, including Alzheimer’s disease (AD), Parkinson’s disease, amyotrophic lateral sclerosis, and Huntington’s disease. Microglia surround plaques to create a barrier that controls the damaging protein’s spread. They also can engulf and destroy the plaque proteins, but in Alzheimer’s disease they usually do not. The source of their passivity could result from a protein called APOE that is a component of amyloid plaques. The APOE proteins in the plaque bind to a receptor – LILRB4 – on the microglia surrounding the plaques, inactivating them.
For reasons that are still unknown, the researchers found that, in mice and people with Alzheimer’s disease, microglia that surround plaques produce and position LILRB4 on their cell surface, which inhibits their ability to control damaging plaque formation upon binding to APOE. Researchers treated mice that had amyloid beta plaques in the brain with a homemade antibody that blocked APOE from binding to LILRB4. The researchers found that activated microglia were able to engulf and clear the amyloid beta plaques.
After amyloid beta plaques form in the brain, another brain protein – tau – becomes tangled inside neurons. In this second stage of the disease, neurons die and cognitive symptoms arise. High levels of LILRB4 and APOE have been observed in AD patients in this later stage. It is possible that blocking the proteins from interacting and activating microglia could alter later stages of the disease. In future studies, the researchers will test the antibody in mice with tau tangles.
Long-Lived RNA that is Never Replaced in Neurons
https://www.fightaging.org/archives/2024/04/long-lived-rna-that-is-never-replaced-in-neurons/
The question of whether there are long-lived molecules in long-lived neurons in the brain is an interesting one. Are there specific molecules in the brain that never get replaced across a lifetime, and thus might be vulnerable to damage in the form of modifications that disrupt function? This remains a somewhat hypothetical concern, in the sense that there is no direct demonstration that this is a significant source of dysfunction in late life. Researchers have found evidence for long-lived nuclear pore proteins, however, and here another group presents evidence for long-lived RNA molecules.
Most cells in the human body are regularly renewed, thereby retaining their vitality. However, there are exceptions: the heart, the pancreas, and the brain consist of cells that do not renew throughout the whole lifespan, and yet still have to remain in full working order. Now researchers were able to demonstrate for the first time that certain types of ribonucleic acid (RNA) that protect genetic material exist just as long as the neurons themselves.
“This is surprising, as unlike DNA, which as a rule never changes, most RNA molecules are extremely short-lived and are constantly being exchanged. We succeeded in marking the RNAs with fluorescent molecules and tracking their lifespan in mice brain cells. We were even able to identify the marked long-lived RNAs in two year old animals, and not just in their neurons, but also in somatic adult neural stem cells in the brain.”
In addition, the researchers discovered that the long-lived RNAs, that they referred to as LL-RNA for short, tend to be located in the cells’ nuclei, closely connected to chromatin, a complex of DNA and proteins that forms chromosomes. This indicates that LL-RNA play a key role in regulating chromatin. In order to confirm this hypothesis, the team reduced the concentration of LL-RNA in an in-vitro experiment with adult neural stem cell models, with the result that the integrity of the chromatin was strongly impaired.
Delivery of TGF-β1 Following Heart Attack Reduces Reperfusion Injury
https://www.fightaging.org/archives/2024/04/delivery-of-tgf-%ce%b21-following-heart-attack-reduces-reperfusion-injury/
A heart attack is triggered by rupture of an atherosclerotic plaque and downstream blockage of an important vessel feeding oxygenated blood to heart tissue. Much of the permanent harm resulting from a heart attack occurs when blood flow is restored to ischemic tissue, however. A cascade of maladaptive reactions, inflammation, and cell death occurs, leading to scarring and loss of function in the heart muscle. This damage to the heart can be reduced to some degree by anti-inflammatory signaling applied soon after the heart attack takes place, as researchers here demonstrate.
Despite major improvements using primary percutaneous intervention (PPCI) to treat patients with acute ST-elevation myocardial infarction (STEMI), progression to heart failure after infarction represents a major clinical problem. Despite state-of-the-art medical care, 22% of patients with STEMI treated with PPCI develop heart failure symptoms within 1 year. Detrimental progression is substantively determined by the original infarct size and time to reperfusion. An acute exuberant proinflammatory response can further enhance local cardiac injury. Over time, this can lead to adverse ventricular remodeling and gradual loss of cardiac function that can result in heart failure. For patients with STEMI, particularly those with large infarcts, additional intervention in the acute phase is needed to reduce ischemia-reperfusion injury and protect myocardial tissue, thereby reducing the risk of progression to heart failure.
Transforming growth factor (TGF)-β1 is a potent anti-inflammatory cytokine released in response to tissue injury. The aim of this study was to investigate the protective effects of TGF-β1 after myocardial infarction. In patients with STEMI, there was a significant correlation between higher circulating TGF-β1 levels at 24 hours after myocardial infarction and a reduction in infarct size after 3 months, suggesting a protective role of early increase in circulating TGF-β1. A mouse model of cardiac ischemia reperfusion was used to demonstrate multiple benefits of exogenous TGF-β1 delivered in the acute phase. It led to a significantly smaller infarct size (30% reduction), reduced inflammatory infiltrate (28% reduction), lower intracardiac expression of inflammatory cytokines IL-1β and CCL2 (more than a 50% reduction) at 24 hours, and reduced scar size at 4 weeks (21% reduction) after reperfusion.
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