Fight Aging!

Researchers here note the discovery of a marker of dysfunctional hematopoietic cells in bone marrow. Hematopoietic stem cells and their immediate descendants are responsible for producing red blood cells and immune cells. The activities of hematopoietic cells are detrimentally affected by aging, as for every other cell population in the body, and some fraction of immune system aging derives from changes in the behavior and numbers of hematopoietic cells. If only some of these cells are very dysfunctional, however, then selectively clearing out the most problematic cells, or at least reducing their relative numbers as a fraction of all hematopoietic cells, should help to restore lost immune function.

Aging is a process accompanied by functional decline in tissues and organs with great social and medical consequences. Developing effective anti-aging strategies is of great significance. In this study, we demonstrated that transplantation of young hematopoietic stem cells (HSCs) into old mice can mitigate aging phenotypes, underscoring the crucial role of HSCs in the aging process.

Through comprehensive molecular and functional analyses, we identified a subset of HSCs in aged mice that exhibit "younger" molecular profiles and functions, marked by low levels of CD150 expression. Mechanistically, CD150low HSCs from old mice but not their CD150high counterparts can effectively differentiate into downstream lineage cells. Notably, transplantation of old CD150low HSCs attenuates aging phenotypes and prolongs lifespan of elderly mice compared to those transplanted with unselected or CD150high HSCs. Importantly, reducing the dysfunctional CD150high HSCs can alleviate aging phenotypes in old recipient mice.

Thus, our study demonstrates the presence of "younger" HSCs in old mice, and that aging-associated functional decline can be mitigated by reducing dysfunctional HSCs.

Link: https://doi.org/10.1038/s41422-024-01057-5

Why do traumatic brain injury survivors exhibit an increased risk of Alzheimer's disease? Researchers here observe a specific set of changes in the vasculature of the injured brain that appear to accelerate deposition of amyloid-β, an outcome supportive of the amyloid cascade hypothesis for the development of Alzheimer's disease. Despite the inability of amyloid-β clearance to much affect patient outcomes in the later stages of Alzheimer's disease, it remains the case that many lines of evidence support amyloid-β aggregation as the foundational pathology that initially causes Alzheimer's disease.

Traumatic brain injury (TBI) often leads to impaired regulation of cerebral blood flow, which may be caused by pathological changes of the vascular smooth muscle cells (VSMCs) in the arterial wall. Moreover, these cerebrovascular changes may contribute to the development of various neurodegenerative disorders such as Alzheimer's-like pathologies that include amyloid beta aggregation. Despite its importance, the pathophysiological mechanisms responsible for VSMC dysfunction after TBI have rarely been evaluated.

Here, we show that acute human TBI resulted in early pathological changes in leptomeningeal arteries, closely associated with a decrease in VSMC markers such as NOTCH3 and alpha smooth muscle actin (α-SMA). These changes coincided with increased aggregation of variable-length amyloid peptides including Aβ1-40/42, Aβ1-16, and β-secretase-derived fragment (βCTF) (C99) caused by altered processing of amyloid precursor protein (APP) in VSMCs. The aggregation of Aβ1-40/42 peptides were also observed in the leptomeningeal arteries of young TBI patients.

These pathological changes also included higher β-secretase (BACE1) in the leptomeningeal arteries, plausibly caused by hypoxia and oxidative stress as shown using human VSMCs in vitro. Importantly, BACE1 inhibition not only restored NOTCH3 signalling but also normalized ADAM10 levels in vitro. Furthermore, we found reduced ADAM10 activity and decreased NOTCH3, along with increased βCTF (C99) levels in mice subjected to an experimental model of TBI. This study provides evidence of early post-injury changes in VSMCs of leptomeningeal arteries that can contribute to vascular dysfunction and exacerbate secondary injury mechanisms following TBI.

Link: https://doi.org/10.1007/s00401-025-02848-9

Bimagrumab is a monoclonal antibody targeting αActRIIA and αActRIIB. These receptors are involved in the inhibition of muscle growth via the activity of myostatin; circulating myostatin binds to αActRIIB. Various means of preventing this from happening produce sizable muscle growth in a variety of animal species. Most of the examples involve mutation of the myostatin gene, but a few of the other approaches have made it into clinical trials, including antibodies to reduce circulating myostatin levels and gene therapies to increase circulating levels of follistatin, a protein that blocks the activity of myostatin. The point of all of this is to find a viable approach to produce muscle growth without the need for exercise, and turn back the loss of muscle mass and strength that occurs with age.

Bimagrumab is currently in clinical trials aimed at obesity, as the present generation of GLP-1 receptor agonist drugs used for weight loss produce significant loss of muscle mass alongside loss of fat mass. Drugs that might counteract that undesirable loss of muscle mass are much sought after. In today's open access paper, researchers demonstrate that bimagrumab treatment is quite effective at increasing muscle mass and bone mineral density in mice. This increase in bone mineral density is also a feature of other approaches centered around myostatin, though not so often reported or the focus of research aimed at muscle tissue.

The Effect of Anti-Activin Receptor Type IIA and Type IIB Antibody on Muscle, Bone and Blood in Healthy and Osteosarcopenic Mice

Anti-Activin Receptor Type IIA and Type IIB antibody (αActRIIA/IIB ab) is a recently developed drug class that targets the activin receptor signalling pathway. Inhibition of receptor ligands (activins, myostatin, growth differentiation factor 11, etc.) can lead to skeletal muscle hypertrophy and bone formation. Despite the αActRIIA/IIB ab, bimagrumab, having progressed to clinical trials, two crucial questions about αActRIIA/IIB ab therapy remain: Does αActRIIA/IIB ab influence bone metabolism and bone strength similarly to its generic classmates (activin receptor-based ligand traps)? Therefore, the aim of the present study was to investigate the therapeutic potential of αActRIIA/IIB ab in a mouse model of concurrent sarcopenia and osteopenia and to investigate the effect on bonein more detail.

In C57BL/6JRj mice, combined sarcopenia and osteopenia were induced locally by injecting botulinum toxin A into the right hindlimb, resulting in acute muscle paresis. Immediately after immobilization, mice received twice-weekly intraperitoneal injections with αActRIIA/IIB ab (10 mg/kg) for 21 days, after which they were sacrificed. Muscle mass, skeletal muscle fibre size and Smad2 expression were analysed in the rectus femoris and gastrocnemius muscles. Bone mass and bone microstructure were analysed in the trabecular bone and cortical bone.

αActRIIA/IIB ab caused a large increase in muscle mass in both healthy (+21%) and immobilized (sarcopenic and osteopenic) (+12%) mice. Furthermore, αActRIIA/IIB ab increased trabecular bone (bone volume fraction) for both healthy (+65%) and immobilized (+44%) mice. For cortical bone, αActRIIA/IIB ab caused a small, but significant, increase in bone area (+6%) for immobilized mice, but not for healthy mice. These results suggest a potential in the treatment of concurrent osteopenia and sarcopenia.

The Golgi apparatus receives relatively little attention in the context of aging, but it suffers dysfunction like all structures in the cell. It is involved in directing newly manufactured proteins to their destination, whether inside the cell or to be secreted in extracellular vesicles. Researchers here show that extracellular vesicles harvested from a particular form of stem cell culture can act to improve Golgi apparatus function in aged tissues, and in doing so aid in improving bone density and bone regeneration in aged mice.

The production of stem cell aggregates (CA) is a regenerative technique that promotes normal stem cell function by encouraging high-density stem cells to secrete large amounts of extracellular matrix (ECM), which serves as an excellent cellular scaffold. Our previous studies have further revealed that CA-derived extracellular vesicles (CA-EVs) are featured with proteins that effectively promote tissue/organ regeneration.

In this study, we investigated the mechanisms underlying bone marrow mesenchymal stem cell (BMSCs) senescence in bone aging and explored whether CA-EVs can improve bone mass and regeneration with the advanced age. Surprisingly, we discovered that alterations of Golgi apparatus contributed to senescence of resident BMSCs and led to a reduction in the release of endogenous EVs, which has not been previously reported. We further found that locally transplanted CA lost its ability to promote bone regeneration in the aging microenvironment, which was also attributed to impaired structure and function of Golgi.

Intriguingly, in-depth analysis suggested that CA-EVs exposed functional surface proteins to assemble the Golgi apparatus, such as Syntaxin 5 (STX5), which helped restore function of senescent BMSCs. Importantly, CA-EV replenishment promoted regeneration of bone defects and counteracted osteoporosis in aging mice. These findings provide the first evidence that Golgi-based vesicular disorders contribute to cell senescence and that CA-EVs effectively mitigate BMSC aging to retard age-related osteoporosis and safeguard aging bone regeneration.

Link: https://doi.org/10.1038/s41413-024-00386-w

Older patients exhibiting multimorbidity, meaning the presence of two or more diagnosed age-related conditions, are typically in relatively poor shape. Researchers here note that, in this population specifically, greater levels of exercise still correlate with reduced mortality over time. While human data can only show correlation and not causation, extensive animal studies of physical activity give us good reason to think that exercise does in fact act to improve health and that this isn't just a case of less healthy individuals being less able to exercise.

Our study represents one of the pioneering multinational efforts to investigate the longitudinal relationship between physical activity (PA) levels and mortality in individuals with multimorbidity. We found that higher levels of physical activity could significantly reduce mortality risk over an average 12-year follow-up period, even among those dealing with multiple chronic conditions. Our results show that, after adjusting for several potential confounding factors, individuals with multimorbidity who reported moderately low, moderately high and high levels of PA had a 36%, 47%, and 51% reduced mortality risk, respectively, compared to those with low levels of PA.

PA may reduce mortality through several mechanisms. First, engaging in regular PA boosts mitochondrial function, enhancing energy production and decreasing oxidative stress, thereby protecting cells from damage. PA also increases the expression of antioxidant enzymes, which help neutralize harmful free radicals. Second, PA regulates inflammation by lowering pro-inflammatory cytokine levels and raising anti-inflammatory interleukins. It also stimulates autophagy, the process by which cells remove damaged proteins and organelles, ensuring cellular health. Thirdly, PA enhances insulin sensitivity, aiding in blood glucose regulation and potentially slowing the accumulation of molecular damage. Together, these hormonal and molecular changes reduce the risk of chronic diseases and decrease overall mortality.

Link: https://doi.org/10.1002/jcsm.13695

Many drugs have their origin in a human gene variant or mutation that was discovered to be protective in some way. Typically such drugs are less effective than possessing the mutation, for all the usual reasons. A drug is only used for some years rather than the whole lifespan, doesn't give the 100% coverage of cells in a tissue that the mutation does, and usually only recreates a fraction of the effects of the mutation in any given cell. Thus mutations that lower circulating LDL-cholesterol in the bloodstream can produce as much as a 50% reduction in lifetime risk of cardiovascular mortality, but drugs that reduce LDL-cholesterol levels produce only a 10-20% reduction, depending on which studies one chooses to take as representative.

Nonetheless, the discovery of protective mutations and gene variants is a sizable concern continues to lead to drug development programs. Today's open access paper reviews the mechanisms by which a longevity-associated variant of BPIFB4 is thought to lower risk of mortality. It appears to act in two ways, firstly by improving vascular function in older people, and secondly by reducing inflammation. The effects on vascular function are complex, involving reduced stiffening of vessels due to smooth muscle dysfunction, increased formation of new vessels, and increased antioxidant activity to reduce oxidative stress. As is usually the case, it is unclear as to which of these mechanisms is most important in determining the observed outcome of reduced late life mortality; one could make a good case for most of them.

Protective role of the longevity-associated BPIFB4 gene on cardiac microvascular cells and cardiac aging

The longevity-associated variant (LAV) of BPIFB4 was discovered using a stringent threshold of statistical significance for genome-wide association studies (GWAS) in three independent cohorts of centenarians in Italy, Europe, and the US. The LAV-BPIFB4 haplotype was inversely correlated with frailty in elderly subjects, strengthening its relevance in influencing the health status and longevity of the elderly.

Further analyses showed that the LAV homozygous genotype was positively associated with high endothelial nitric oxide (eNOS) phosphorylation in mononuclear cells, which translates to augmented nitric oxide (NO) production and beneficial functions in the cardiovascular system. In keeping with the benefits to the vascular compartment, recombinant LAV-BPIFB4 protein supplementation enhanced the proangiogenic activity of young and senescent endothelial cells. Importantly, these advantages can be transferred through LAV-BPIFB4 gene therapy in older mice, whereas eNOS phosphorylation and vessel activity are restored to levels observed in young mice.

Alongside the eNOS downstream substrate, the SDF-1/CXCR4 axis is a crucial effector of the cardiovascular protective and immunomodulatory activity of LAV-BPIFB4. In this regard, LAV-BPIFB4 activates SDF-1/CXCR4 signaling to remodel the immune system and resolve inflammation through various mechanisms involving protective macrophage polarization toward the pro-resolving M2 phenotype, favorable redistribution of circulating monocyte cell subsets, and reduction in T-cell activation.

The body changes with age, and many of those changes are fairly similar from person to person in their relationship with disease and mortality. Thus any sufficiently large set of data on body structure or biochemistry can be used to produce a clock algorithm that reflects mortality risk and the burden of age-related damage and dysfunction. Typically the result is framed as a measure of age, and called biological age, though there are some who think that researchers should be more careful in how they talk about what exactly is being measured by a clock.

Biological age (BA) is a potentially useful construct that attempts to reflect the cumulative physiologic effect of lifestyle habits, genetic predisposition, and superimposed disease processes beyond simply the number of years lived. Attempts at deriving an effective BA date back at least half a century, but with only limited success. Much of the current geroscience focus to date for attempting to derive an effective BA has centered on various "frailomics" at the cellular and subcellular levels, including genomics and epigenomics (e.g., telomere length and epigenetic clock), proteomics, and metabolomics, as well as various other laboratory and clinical measures.

Imaging biomarkers have generally received less attention for estimating BA, but arguably may better reflect the cumulative macroscopic effects of aging at the tissue and organ levels. In particular, abdominal computed tomography (CT) represents an appealing candidate for a more personalized investigation. Thus we derived and tested a CT-based biological age model for predicting longevity that quantifies skeletal muscle, abdominal fat, aortic calcification, bone density, and solid abdominal organs.

We applies this tool to abdominal CT scans from 123,281 adults (mean age, 53.6 years; 47% women). The final weighted CT biomarker selection was based on the index of prediction accuracy. The CT model significantly outperforms standard demographic data for predicting longevity (index of prediction accuracy, IPA = 29.2 vs. 21.7). Age- and sex-corrected survival hazard ratio for the highest-vs-lowest risk quartile was 8.73 for the CT biological age model, and increased to 24.79 after excluding cancer diagnoses within 5 years of CT. Muscle density, aortic plaque burden, visceral fat density, and bone density contributed the most.

Link: https://doi.org/10.1038/s41467-025-56741-w

The various aging clocks only become truly useful to the degree that there is enough existing data on their performance to understand whether or not one can trust their outputs for a given novel intervention targeting aging. A way to rapidly assess effects on biological age will steer the development of therapies towards the most effective approaches much more rapidly than is presently the case. Even through the clocks have issues, the largest of which being that the research community cannot link clock components to specific mechanisms of aging via a clear chain of cause and effect, using them broadly in as many human trials as possible is a good idea, including lifestyle interventions and supplements thought to have only modest effects. In this study, for example, researchers found that a few of these interventions slowed the increase of biological age over time in older people by something like 10%, on average.

While observational studies and small pilot trials suggest that vitamin D, omega-3, and exercise may slow biological aging, larger clinical trials testing these treatments individually or in combination are lacking. Here, we report the results of a post hoc analysis among 777 participants aged 70 years and older of the DO-HEALTH trial on the effect of vitamin D (2,000 IU per day) and/or omega-3 (1 g per day) and/or a home exercise program on four next-generation DNA methylation (DNAm) measures of biological aging (PhenoAge, GrimAge, GrimAge2 and DunedinPACE) over 3 years.

Omega-3 alone slowed the DNAm clocks PhenoAge, GrimAge2 and DunedinPACE, and all three treatments had additive benefits on PhenoAge. Overall, from baseline to year 3, standardized effects ranged from 0.16 to 0.32 units (2.9-3.8 months). In summary, our trial indicates a small protective effect of omega-3 treatment on slowing biological aging over 3 years across several clocks, with an additive protective effect of omega-3, vitamin D and exercise based on PhenoAge.

Link: https://doi.org/10.1038/s43587-024-00793-y

Today's open access paper is a good introduction to what makes the Rho-GTPase family an important area of study in molecular biochemistry: it is relevant to efforts to suppress cancer metastasis. If metastasis could be eliminated, the majority of cancer mortality would evaporate, even if no further advances occurred in the field. Surgical techniques would be sufficient to remove most tumors even at later stages. Cancer would become a localized problem in the body, much less of a threat.

Unfortunately, while the biochemistry of metastasis is quite well understood, satisfactory efforts to interfere have yet to emerge. As is so often the case in cell biology, the runaway mechanisms involved in the migration and attachment of cancer cells are also essential to normal tissue function. One can't just break the mechanism for benefit, as that generates serious side-effects, too serious for even cancer patients. So, as illustrated by this paper, one has to approach the target mechanism in a better, more indirectly.

An allosteric inhibitor of RhoGAP class-IX myosins suppresses the metastatic features of cancer cells

Tumour cells disseminate by migration, either collectively as sheets and clusters, or individually, where single cells transition through a mesenchymal- and/or amoeboid type of migration to escape from the primary tumour and invade target organs to establish new connective attachments, followed by unrestrained growth and proliferation. Single and collective cell migration, both share common pathways of receptor-mediated stimulation that are tightly regulated via signalling cascades involving members of the Ras homologous (Rho) family of small guanosine triphosphatases (GTPases), including Rho, Rac, and Cdc42.

Aberrant RhoGTPase signalling is considered a dominant driving force of metastasis and cancer progression. Particularly, oncogenic mutations in RhoGTPases and their regulators, excessive receptor signalling, and altered effector activity patterns, are factors that stimulate cells to gain pro-migratory capabilities and acquire highly invasive, proliferative phenotypes that promote dissemination and metastasis formation. Thus, targeted interference of Rho-associated signalling cues has become a viable and increasingly investigated strategy for suppressing cancer metastasis. Lack of target selectivity, side effects, and development of resistances have yet prevented positive responses to treatments and therapeutic breakthroughs.

A promising, yet elusively explored approach to target the metastatic properties of cancer cells, particularly those related to enhanced migration and invasiveness, is to gain control over the activity of GTPase-activating proteins (GAPs), the negative regulators of RhoGTPases. Drugs that are capable of enhancing and/or locally controlling RhoGAP activity provide a means to suppress the adhesive and migratory properties of cancer cells, and thus metastasis.

Here, we report the identification and characterization of adhibin, a synthetic allosteric inhibitor of RhoGAP class-IX myosins that abrogates ATPase and motor function, suppressing RhoGTPase-mediated modes of cancer cell metastasis. In human and murine adenocarcinoma and melanoma cell models, including three-dimensional spheroid cultures, we reveal anti-migratory and anti-adhesive properties of adhibin, affecting actin-dynamics and actomyosin-based cell-contractility. Adhibin blocks membrane protrusion formation, disturbs remodelling of cell-matrix adhesions, affects contractile ring formation, and disrupts epithelial junction stability; processes severely impairing single/collective cell migration and cytokinesis.

That immune cells in an inflammatory environment produce a much greater amount of oxidizing molecules is one of the reasons why increased levels of chronic inflammation and oxidative stress tend to be linked in older individuals. Researchers here review this mechanism in the context of Alzheimer's disease, as a way in which inflammation can drive detrimental epigenetic changes in cell populations in the brain, as those changes are in a part a reaction to an environment of greater oxidative stress.

It is widely accepted that chronic neuroinflammation plays a role in the development of Alzheimer's disease (AD), although the specific mechanisms remain elusive. Chronic low-grade inflammation is a characteristic of ageing and systemic inflammation is associated with AD onset, and we have presented a multitude of studies that suggest an effector role for immune cells in AD pathology. The extent to which peripheral immune cells, such as neutrophils, can enter the brain remains unclear and is difficult to measure temporally, however signs of oxidative stress are evident and clearly contribute to the aetiology of AD. Sources of oxidative stress are abundant in AD and include dysfunctional mitochondria, neurons, and endothelial cells, but immune cells are emerging as an abundant and potentially modifiable source.

Microglia are specialised immune cells of myeloid lineage that reside chiefly in the central nervous system and comprise up to 15% of all cell types found in the brain. Their main function is surveillance and maintenance of the central nervous system through clearance of dead and dying cells, as well as plaques. Microglia express NOX, an enzyme that produces superoxide and results in the formation of a range of oxidant species. Immune cell-derived oxidants differ greatly in their specificity and reactivities and produce a range of radical and non-radical species that can influence a variety of cellular and molecular processes, but can also cause tissue injury.

Oxidative stress can alter neuronal health both by directly damaging the DNA and causing cell death but also in more subtle ways, through the manipulation of key cellular enzymes and cofactors that have the potential to modify the epigenetic regulation of the genes associated with Alzheimer's disease onset and progression. Further studies are required to explore the impact of immune-derived oxidants on DNA methylation profiles in the ageing brain with the aim of uncovering targeted immunomodulatory, epigenetic, or mitochondrial therapeutic agents in the treatment of AD. As the world's population ages, it will become increasingly important to find reliable biomarkers of oxidative stress in middle-aged humans, before the onset of age-related disease such as AD, with the ultimate goal of prolonging the health span of individuals as they age.

Link: https://doi.org/10.1080/13510002.2024.2428152

Engineering the growth of new adult teeth has been a work in progress for some years now. As noted here, researchers have moved on from small mammals such as rats and are attempting regrowth of teeth in pigs. The process involves implanting a artificial tooth bud into the jaw, made of a suitable mix of cells seeded into a scaffold material. In this case, the researchers used decellularized tooth bud extracellular matrix as the scaffold, ensuring the correct chemical cues are present. The challenge in all of this lies in controlling the shape and structure of the resulting tooth; a tooth bud implanted in the jaw in this way does not naturally result in a correctly shaped tooth, so something is still missing from the recipe.

The use of dental implants to replace lost or damaged teeth has become increasingly widespread due to their reported high survival and success rates. In reality, the long-term survival of dental implants remains a health concern, based on their short-term predicted survival of ~15 years, significant potential for jawbone resorption, and risk of peri-implantitis. The ability to create functional bioengineered teeth, composed of living tissues with properties similar to those of natural teeth, would be a significant improvement over currently used synthetic titanium implants.

To address this possibility, our research has focused on creating biological tooth substitutes. The study presented here validates a potentially clinically relevant bioengineered tooth replacement therapy for eventual use in humans. We created bioengineered tooth buds by seeding decellularized tooth bud (dTB) extracellular matrix (ECM) scaffolds with human dental pulp cells, porcine tooth bud-derived dental epithelial cells, and human umbilical vein endothelial cells. The resulting bioengineered tooth bud constructs were implanted in the mandibles of adult Yucatan minipigs and grown for 2 or 4 months. We observed the formation of tooth-like tissues, including tooth-supporting periodontal ligament tissues, in cell-seeded dTB ECM constructs.

Link: https://doi.org/10.1093/stcltm/szae076

Cells are state machines, more or less, their behavior largely driven by the specific pattern of gene expression they adopt. With age other factors can enter play, such as the presence of molecular waste (lipofuscin and so forth) that is very hard for cells to break down or eject, and changes in the exterior environment that produce corresponding reactions within the cell, including cross-linking of the extracellular matrix, inflammatory signaling, and the like. Even so, the potential offered by any means of reliably controlling gene expression is the ability to selectively reset the behavior of cells, to override their unfortunate reactions to the aged environment, and to restore behaviors that result in improved tissue function. Control of cell behavior implies a sizable degree of control over disease, dysfunction, aging.

Much of the cell reprogramming space is focused on treatment of aging, reversing at least some of the characteristic age-related changes in gene expression that alter cell function for the worse. Much of that work centers around application of the Yamanaka factors that are involved in transforming adult germline cells into embryonic stem cells in early embryogenesis. But this is just one form of reprogramming. There are many others. Why not, for example, reprogram a cancerous cell to stop being a cancerous cell? That is the topic of today's research materials, narrowly focused on colon cancer as a first application of a platform for discovering ways to revert specific cancerous changes in specific tissues. This line of work is now under development at a new biotech company, Biorevert.

A Molecular Switch that Reverses Cancerous Transformation at the Critical Moment of Transition​

A research team has succeeded in developing a fundamental technology to capture the critical transition phenomenon at the moment when normal cells change into cancer cells and analyze it to discover a molecular switch that can revert cancer cells back into normal cells. A critical transition is a phenomenon in which a sudden change in state occurs at a specific point in time. The research team discovered that normal cells can enter an unstable critical transition state where normal cells and cancer cells coexist just before they change into cancer cells during tumorigenesis, the production or development of tumors, and analyzed this critical transition state using a systems biology method to develop a cancer reversal molecular switch identification technology that can reverse the cancerization process. They then applied this to colon cancer cells and confirmed through molecular cell experiments that cancer cells can recover the characteristics of normal cells.

This is an original technology that automatically infers a computer model of the genetic network that controls the critical transition of cancer development from single-cell RNA sequencing data, and systematically finds molecular switches for cancer reversion by simulation analysis. Among the common target genes of the discovered transcription factor combinations, researchers identified cancer reversing molecular switches that were predicted to suppress cancer cell proliferation and restore the characteristics of normal colon cells. When inhibitors for the molecular switches were provided to organoids derived from colon cancer patients, it was confirmed that cancer cell proliferation was suppressed and the expression of key genes related to cancer development was inhibited, and a group of genes related to normal colon epithelium was activated and transformed into a state similar to normal colon cells.

Attractor Landscape Analysis Reveals a Reversion Switch in the Transition of Colorectal Tumorigenesis

Cell fate changes often involve abrupt transition, called "critical transition," at key points, superimposed on a background of more gradual changes. In particular, it has been well known that tumorigenesis incurs such critical transition. So, questions arise as to what the core molecular regulatory network underlying the critical transition is and whether we can reverse it by controlling a master regulator of the core network.

A number of intriguing studies have been followed to the present reporting the possibility of reverting cancer cell states to phenotypically healthy cell states under various experimental settings. However, these approaches often relied on trial-and-error experiments or comparative analyses mostly that focus on static network properties, limiting their ability to capture dynamic transitions.

Here a systems framework, REVERT, is presented with which can reconstruct the core molecular regulatory network model and a reversion switch based on single-cell transcriptome data over the transition process is identified. The usefulness of REVERT is demonstrated by applying it to single-cell transcriptome of patient-derived matched organoids of colon cancer and normal colon. REVERT is a generic framework that can be applied to investigate various cell fate transition phenomena.

Atrial fibrillation is a dysfunction arising in the aging heart that is associated with later cardiovascular disease; in this context it might be taken as an advance warning of the consequences of a growing burden of cell and tissue damage. As for many age-related conditions, there is a correlation with the chronic inflammation of aging. Lasting, unresolved inflammatory signaling changes the behavior of cells for the worse and is disruptive to tissue structure and function. Here, researchers identify the starting point of one specific pathway by which which inflammation disrupts the regulation of heart rhythm.

Chronic inflammation is a common denominator in many conditions associated with atrial fibrillation (AF). However, the exact mechanisms linking inflammation to arrhythmia have remained elusive. Interleukin-1 beta (IL-1β) - a molecule of the immune system involved in regulating inflammation - can directly influence the heart's electrical activity, creating a predisposition to AF. "The present work marks a key scientific milestone in the field of knowledge. Many review papers had already suggested that IL-1β could play a vital role in atrial fibrillation. We were able to demonstrate that this actually happens."

The research team began by analyzing the immunological profiles of 92 patients, including 30 healthy controls and 62 individuals diagnosed with AF. To delve deeper, the researchers used mice to investigate the effects of IL-1β. By administering controlled doses of IL-1β over 15 days, they simulated prolonged systemic inflammation. During observation, the rodents developed cardiac alterations that made them more susceptible to AF. Additionally, the team employed genetically modified mice lacking IL-1β receptors in macrophages - immune cells found throughout the body, including the heart. These animals did not develop AF, demonstrating that IL-1β triggers the condition by activating its receptors on macrophages.

The study also opens new avenues for treatment. Medications that inhibit IL-1β or caspase-1 - the enzyme that activates IL-1β production - are promising candidates to prevent AF in at-risk patients, particularly those with chronic inflammatory conditions.

Link: https://www.eurekalert.org/news-releases/1072499

Here find a discussion of the relevance of age-related changes in the epigenetic regulation of gene expression to memory function. The behavior of a cell is determined by the structure of nuclear DNA, which regions are accessible to the transcription machinery responsible for producing RNA molecules, and thus which RNAs and proteins are produced. That structure is shaped by epigenetic mechanisms such as the addition of methyl groups to specific sites on the genome and the addition of acetyl groups to the histone proteins that DNA is spooled around.

Memory formation is associated with constant modifications of neuronal networks and synaptic plasticity gene expression in response to different environmental stimuli and experiences. Dysregulation of synaptic plasticity gene expression affects memory during aging and neurodegenerative diseases. Covalent modifications such as methylation on DNA and acetylation on histones regulate the transcription of synaptic plasticity genes. Changes in these epigenetic marks correlated with alteration of synaptic plasticity gene expression and memory formation during aging.

These epigenetic modifications, in turn, are regulated by physiology and metabolism. Steroid hormone estrogen and metabolites such as S-adenosyl methionine and acetyl CoA directly impact DNA and histones' methylation and acetylation levels. Thus, the decline of estrogen levels or imbalance of these metabolites affects gene expression and underlying brain functions.

In the present review, we discussed the importance of DNA methylation and histone acetylation on chromatin modifications, regulation of synaptic plasticity gene expression and memory consolidation, and modulation of these epigenetic marks by epigenetic modifiers such as phytochemicals and vitamins. Further, understanding the molecular mechanisms that modulate these epigenetic modifications will help develop recovery approaches.

Link: https://doi.org/10.3389/fragi.2024.1480932

The protein α-synuclein can misfold in ways that encourage other α-synuclein molecules to also misfold in the same way. These misfolded proteins spread slowly from cell to cell through the nervous system, clumping together to form aggregates surrounded by a toxic biochemistry that stresses and kills neurons. This gives rise to the age-related neurodegenerative conditions known as synucleinopathies, characterized by the formation of Lewy bodies, aggregates of α-synuclein that form inside neurons. Parkinson's disease is the synucleinopathy that receives the most attention; motor neurons are the most vulnerable to disease pathology, and motor function is affected as these vital cells die, giving rise to the most evident symptoms of the condition.

An association between gastrointestinal dysfunction and Parkinson's disease was noted long before the advent of modern biotechnology. Now, given the means to study the biochemistry and microbial populations of the gastrointestinal tract in fine detail, researchers have found that in many cases misfolded α-synuclein appears to originate in the intestines and then spread to the brain. Associations exist between specific differences in the gut microbiome and Parkinson's disease. It remains to be seen as to what will emerge from all of this work; the best way forward may be to develop efficient ways to clear misfolded α-synuclein, and in that case the mechanisms of origin and spread will become irrelevant.

Lewy body diseases and the gut

Gastrointestinal (GI) involvement in Lewy body diseases (LBDs) has been observed since the initial descriptions of patients by James Parkinson. Recent experimental and human observational studies raise the possibility that pathogenic alpha-synuclein (⍺-syn) might develop in the GI tract and subsequently spread to susceptible brain regions. The cellular and mechanistic origins of ⍺-syn propagation in disease are under intense investigation. Experimental LBD models have implicated important contributions from the intrinsic gut microbiome, the intestinal immune system, and environmental toxicants, acting as triggers and modifiers to GI pathologies.

Here, we review the primary clinical observations that link GI dysfunctions to LBDs. We first provide an overview of GI anatomy and the cellular repertoire relevant for disease, with a focus on luminal-sensing cells of the intestinal epithelium including enteroendocrine cells that express ⍺-syn and make direct contact with nerves. We describe interactions within the GI tract with resident microbes and exogenous toxicants, and how these may directly contribute to ⍺-syn pathology along with related metabolic and immunological responses. Finally, critical knowledge gaps in the field are highlighted, focusing on pivotal questions that remain some 200 years after the first descriptions of GI tract dysfunction in LBDs.

We predict that a better understanding of how pathophysiologies in the gut influence disease risk and progression will accelerate discoveries that will lead to a deeper overall mechanistic understanding of disease and potential therapeutic strategies targeting the gut-brain axis to delay, arrest, or prevent disease progression.