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Stalled Amyloid-β Production as a Contributing Cause of Alzheimer’s Disease
https://www.fightaging.org/archives/2025/02/stalled-amyloid-%ce%b2-production-as-a-contributing-cause-of-alzheimers-disease/
It took twenty years of work and enormous expenditure, but the most recent immunotherapies targeting amyloid-β are capable of clearing most of this form of amyloid from the brain. Unfortunately, this class of therapy produces very little gain for patients in the later stages of Alzheimer’s disease. This may be because the amyloid cascade hypothesis should be interpreted to mean that amyloid-β plays no great role in the pathology of the later stages of Alzheimer’s disease, it only sets the stage for neuroinflammation and tau aggregation, and it is those mechanisms that destroy the brain and kill patients. It remains to be seen as to whether these therapies can produce even modest gains in the early stages of the condition, acting in a more preventative mode to stop the development of later pathology.
The poor results for technically successful immunotherapies are spurring a greater interest in alternative mechanisms in the research community, continuing the trend started by frustration with the slow progress towards effective amyloid clearance. There are many programs, hypotheses, and mechanistic targets in search of support for the development of potential new therapies. They tend to keep a focus on the known molecular biochemistry surrounding amyloid-β, but bring new interpretations to the table. Today’s research materials are an example of the type, reintepreting the role of γ-secretase in the production of amyloid-β as a crucial part of disease progression. As with all of the other novel ideas, the only real way to determine the importance of this mechanism is to build therapies and try them in patients. The mouse models of Alzheimer’s disease have historically told us little about whether any given mechanism is actually important in our own species.
Study suggests stalled amyloid protein production drives Alzheimer’s disease
For several decades, researchers studying Alzheimer’s disease have been working to understand the ‘amyloid cascade hypothesis’, which proposes that a buildup of amyloid-β (Aβ) proteins kickstarts a cascade of events that leads to neurodegeneration and dementia. Despite advances in understanding the mutations that lead to Aβ aggregation, uncertainties about the assembly of neurotoxic Aβ proteins remain. Moreover, clinical trials of treatments targeting Aβ protein or its aggregates have only been modestly effective, prompting a re-evaluation of Aβ as the primary driver of the Alzheimer’s disease process.
Increasing focus is now being placed on the production of Aβ – a process called proteolysis, during which a precursor protein called amyloid precursor protein (APP) is trimmed by an enzyme called gamma-secretase (γ-secretase). Researchers have previously shown that mutations found in early-onset familial Alzheimer’s disease (FAD) prevent γ-secretase from trimming APP effectively, leading to a build-up of lengthy forms of APP/Aβ intermediates. During proteolysis, the γ-secretase enzyme binds together in a complex initially with APP and then with subsequent intermediate forms of the protein as it is trimmed. Researchers have now further assessed mutations in γ-secretase, showing that they increase the stability of enzyme-substrate complexes. This result makes sense alongside initial proteolysis analysis, which suggests the proteolytic process had stalled.
“We’ve shown that these mutations lead to stalled proteolysis and stabilize the enzyme with its substrate in an intermediate form. These findings are in keeping with our ‘stalled complex’ hypothesis, where it is these enzyme-substrate complexes that trigger neurodegeneration even in the absence of amyloid beta-protein production. We propose that γ-secretase activators that can rescue stalled proteolysis could complement treatments targeting other Alzheimer’s-associated pathways.”
Evaluating Drugs that Might be Repurposed to Boost Remyelination
https://www.fightaging.org/archives/2025/02/evaluating-drugs-that-might-be-repurposed-to-boost-remyelination/
Myelin structures form an insulating sheath coating the axons that connect neurons, and are essential for proper electrical function of an axon, the conduction of nerve impulses along the axon structure. Dramatic loss of myelin, as occurs in conditions such as multiple sclerosis, results in severe symptoms and eventual death. A lesser degree of loss of myelin occurs more broadly with age throughout the population, and is thought to provide some contribution to declining cognitive function and conditions such as mild cognitive impairment. In this second case, how exactly the mechanisms cause myelin loss are less well understood. One can look at the state of the oligodendrocyte population responsible for maintaining myelin and see changes in size or changes in activity, but connections to specific molecular biochemistry is ever a challenge.
As researchers note in today’s open access paper, there is no FDA-approved therapy to enhance remyelination. This isn’t for lack of trying in the usual small molecule development space, where much of the work is focused on trying to find existing drugs and targets that have some modest beneficial effect and few enough side-effects to make it worth the effort. One of the small molecules tested in the paper here was in clinical trials for multiple sclerosis, the antihistamine clemastine, but prevalent inflammatory side-effects caused that line of development to be halted. The other, LL-341070, is in clinical trials for the treatment of depression.
The primary thrust of the paper is an examination of the way in which mild deymelination spurs a response from oligodendrocytes to repair the problem, and the threshold at which that response is insufficient. Drugs that boost oligodendrocyte activity might in principle be able to make a dent in demyelination conditions by shifting this threshold. Interestingly, even drugs and doses that have too small an effect to matter for multiple sclerosis, and have thus been discarded by the development community, could be useful in the treatment of age-related demyelination more generally. Though they are unlikely to be rigorously tested for this use in the present regulatory environment!
Incomplete remyelination via therapeutically enhanced oligodendrogenesis is sufficient to recover visual cortical function
Demyelination is typically followed by a period of heightened new myelin formation known as remyelination, which can restore action potential propagation and prevent neurodegeneration. Remyelination is carried out primarily by newly formed oligodendrocytes differentiating from parenchymal and germinal zone derived oligodendrocyte precursor cells (OPCs) as well as – in some instances – by oligodendrocytes that survive the demyelinating injury. However, the endogenous remyelination response is often incomplete, resulting in chronic demyelination and limited functional recovery. Thus, understanding the drivers and limitations of endogenous remyelination and developing methods to enhance it are clinical imperatives for many demyelinating conditions. Despite substantial progress in identifying compounds that improve remyelination in recent years, there is still no FDA-approved remyelination therapy. Furthermore, independent of specific therapeutic strategies, we require a deeper understanding of fundamental aspects of therapeutic-induced remyelination, such as the dynamics and constraints of therapeutic action, and the magnitude and timing of remyelination required to recover neuronal function.
The afferent visual pathway is well-suited to investigate the relationship between myelin and neuronal function throughout de/remyelination. The circuits of primary visual cortex (V1) are sensitive to input spike precision and contain precise and reliable sensory-evoked activity, important for action potential transmission and visual coding. Moreover, perturbations in the timing of sensory-evoked activity in V1 have previously been observed in patients and animal models during de/remyelination. Here, we used longitudinal in vivo two-photon imaging of oligodendrocytes and high-density electrical recordings with single neuron resolution in V1 to study the dynamics of endogenous and therapeutic-induced neocortical remyelination and the relationship between remyelination and functional recovery. Demyelination was induced with cuprizone, and mice were treated with two remyelination drugs: a new thyroid hormone mimetic (thyromimetic), LL-341070, and a clinically validated therapeutic, clemastine.
Cuprizone treatment induced oligodendrocyte loss and a concomitant increase in visual response latency. This was followed by a rapid and robust endogenous remyelination response that was driven by recent oligodendrocyte loss. Endogenous remyelination was highly efficacious at mild demyelination levels, but when moderate or severe demyelination occurred quickly, endogenous remyelination failed to restore the oligodendrocyte population after seven weeks. Treatment with a high dose of LL-341070 substantially increased regenerative oligodendrogenesis during remyelination, acting more quickly and robustly than clemastine, and hastened neuron functional recovery. The therapeutic benefit of LL-341070 was loss-dependent, exclusively impacting remyelination after moderate or severe demyelination. Consequently, LL-341070 eliminated the endogenous remyelination deficit after seven weeks of remyelination, restoring oligodendrocyte numbers to original levels and myelin to levels comparable to those of age-matched healthy mice. However, full restoration of oligodendrocytes and myelin to these levels was not necessary to recover neuronal function.
What is Known of the Involvement of the Gut in the Development of Synucleinopathies
https://www.fightaging.org/archives/2025/02/what-is-known-of-the-involvement-of-the-gut-in-the-development-of-synucleinopathies/
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.
More on Reprogramming of Colon Cancer Cells into Normal Colon Cells
https://www.fightaging.org/archives/2025/02/more-on-reprogramming-of-colon-cancer-cells-into-normal-colon-cells/
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.
A Novel Rho-GTPase Focused Strategy to Reduce Cancer Metastasis
https://www.fightaging.org/archives/2025/02/a-novel-rho-gtpase-focused-strategy-to-reduce-cancer-metastasis/
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.
Continued Evolution of a NAD Centered View of Aging
https://www.fightaging.org/archives/2025/02/continued-evolution-of-a-nad-centered-view-of-aging/
There are researchers who consider declining levels of nicotinamide adenine dinucleotide (NAD) in mitochondria to be important in aging. The inability to produce sizable effects on longevity and age-related disease by upregulating NAD levels (or SIRT1 for that matter) argues against this view. Like very many other measures, NAD reduction is not all that important in and of itself, and fixing it in isolation isn’t all that useful. Still, a fair number of researchers continue to explore the biochemistry surrounding the role of NAD in mitochondrial function. As yet, ways to meaningfully influence the progression of aging have yet to emerge from this part of the space. Looking at the decades of work put into IGF-1 signaling with a similar lack of tangible results when it comes to the treatment of aging, we might expect this state of affairs to continue for research into NAD.
The very first attempt to have such a meaningful image for the regulation of aging and longevity resulted in the introduction of a concept named the “NAD World” in 2009. The NAD World is a systemic regulatory network that connects NAD+ metabolism, biological rhythm, and aging and longevity control in mammals. In the original NAD World concept, two critical components were proposed to drive the NAD World: The mammalian NAD+-dependent protein deacetylase SIRT1 and the key NAD+-biosynthetic enzyme NAMPT. While NAMPT generates a circadian oscillation of NAD+ production in multiple tissues, SIRT1 responds to NAD+ availability and regulates many fundamental cellular and physiological processes, including transcription, DNA repair, stress response, metabolism, circadian rhythm, and aging. Through these coordinated functions, SIRT1 and NAMPT control the system dynamics of the NAD World and determine the process of aging and eventually, lifespan. The most important prediction from the concept of the NAD World was that the driving force of aging is the systemic decline in NAD+ levels.
The concept of the NAD World was then reformulated as the NAD World 2.0 in 2016, based on significant progress in the field over seven years. In the NAD World 2.0, three key tissues have been identified: The hypothalamus as the control center of aging, skeletal muscle as a mediator, and adipose tissue as a modulator. The details of the NAD World 2.0 were described previously6. Among several predictions from the NAD World 2.0, the most critical one is that the secretion of extracellular NAMPT (eNAMPT) from adipose tissue is a key inter-tissue communication between the hypothalamus and adipose tissue in mammalian aging and longevity control. A related prediction is the importance of nicotinamide mononucleotide (NMN), a key NAD+ intermediate and the product of the NAMPT enzymatic reaction, in the maintenance of biological robustness. With these exciting developments, the further reformulated version of the concept, the NAD World 3.0, is now proposed, featuring multi-layered feedback loops mediated by NMN and eNAMPT for mammalian aging and longevity control.
Disrupted Lipid Metabolism in Alzheimer’s Disease
https://www.fightaging.org/archives/2025/02/disrupted-lipid-metabolism-in-alzheimers-disease/
The brain is a relatively fatty organ, and has its own complex lipid metabolism. A range of evidence suggests that detrimental shifts in this lipid metabolism accompany aging and neurodegenerative conditions. Some inroads have been made into linking specific lipid mechanisms to specific aspects of neurodegeneration, such as increased inflammatory activity on the part of microglia. Here, researchers review what is known of the role of lipids in the pathologies exhibited by patients with Alzheimer’s disease. As noted, there is much left to understand, and what is known today is just a small step into a large dark room.
Lipid homeostasis is crucial for the physiological function of organisms. In the central nervous system (CNS), altered lipid homeostasis and disrupted lipid metabolism signaling pathways are often seen in aging and neurodegeneration. A plethora of genome-wide association studies (GWAS) have identified variants in genes involved in lipid-modifying processes such as transportation, synthesis, and conversion, suggesting altered lipid metabolism may serve as key drivers of late onset Alzhemer’s disease (LOAD). However, the chemical diversity and functional heterogeneity of lipids have long posed challenges in characterizing lipid alterations and understanding their biological implications in Alzheimer’s disease (AD).
In this review, we provided an overview of recent advancements in lipidomics techniques and their applications in AD research. Current findings strongly support the involvement of specific lipid classes, including sphingolipids, cholesterol, and phospholipids, in AD pathology. This is further underscored by numerous studies elucidating the molecular mechanisms by which lipids influence multiple pathological aspects of AD. These insights lay a solid foundation for the identification of diagnostic lipid biomarkers and the development of lipid-related therapies.
The crosstalk of lipids and AD pathologies such as amyloid-β, tau, and neuroinflammation plays a significant role in modulating neurodegeneration. As essential intracellular bioactive molecules and key components of cell membranes, lipids also influence cellular functions by participating in oxidative stress responses and mediating synaptic activities among other mechanisms. Further understanding of these connections will provide guidance for leveraging lipidomics information during targeted therapy of these disease mechanisms. Moreover, integrating lipidomics into the evaluation of the diagnostic and treatment efficacy will broaden our options for developing personalized treatment strategies and identifying new biomarkers for AD. Ongoing research aimed at uncovering novel mechanisms of lipid involvement in AD is poised to provide valuable insights that will guide future data-driven clinical investigations.
Selenoprotein Antioxidants Decline with Age in Hematopoietic Stem Cells
https://www.fightaging.org/archives/2025/02/selenoprotein-antioxidants-decline-with-age-in-hematopoietic-stem-cells/
Researchers here provide some initial evidence for declining expression of a network of natural antioxidant molecules known as selenoproteins to contribute to the aging of hematopoietic stem cells, responsible for generating red blood cells and immune cells. Note that the researchers impaired selenoprotein expression and observed impaired function, which is nowhere near as convincing as restoring lost expression to observe improved function. There are any number of ways to break cell function and produce results that look similar to aging, even though the specific breakage isn’t all that relevant to normal aging. The next step for this line of research is to find a way to restore selenoprotein expression in aged mice, and look for improvement in hematopoiesis.
Human cells have 25 different selenoproteins. These antioxidant enzymes help convert dangerous reactive oxygen species (ROS), such as lipid peroxides, into a safer form. Buildup of lipid peroxides can affect critical cells called hematopoietic stem cells (HSCs), a phenomenon observed in aging diseases. “We observed that aged HSCs frequently display impaired selenoprotein synthesis, but it was unclear how this could contribute to cell aging and if it could be reversed. We hypothesized that selenoproteins are a critical part of the antioxidant system that fights age-related changes in HSCs.”
To investigate this, the team used a mouse model with tRNAsec knocked out, leading to disrupted selenoprotein production. They then examined how this affected different cell types, finding that the knockout negatively impacted HSCs and immune cells with B cell lineage (types of white blood cells) but had few effects on myeloid cells (a different family of immune cells). These observations, along with increased expression levels of aging-related genes in these cell types, were consistent with what is frequently seen in age-related diseases. Further investigation indicated that the effects were driven by lipid peroxidation. Additionally, experiments with cells from the mouse model revealed that the disruption in selenoprotein synthesis could support B progenitors switching to the myeloid cell family.
An Update on Engineered Heart Muscle Tissue Applied as Patches to an Injured Heart
https://www.fightaging.org/archives/2025/02/an-update-on-engineered-heart-muscle-tissue-applied-as-patches-to-an-injured-heart/
The heart is one of the least regenerative organs in the mammalian body, and the scarring that follows injuries such as that sustained during a heart attack impairs function. Transplantation of cardiomyocyte cells to produce regeneration of scarred heart tissue has been a work in progress for going on twenty years now. It is possible to produce patient-matched cardiomyocytes from induced pluripotent stem cells, but such cells exhibit minimal survival and perform poorly when transplanted. The development of artificial tissues using nanoscale scaffolds, enabling the production of thin patches of heart muscle made up of cardiomyocytes, has improved matters. More cells survive following transplantation, and functional improvements are observed in animal models of heart injury. The latest concerns have revolved around whether heart electrical function remains disrupted by the introduction of new cells, causing arrhythmia or worse, but as noted here even that problem seems to be yielding to the latest state of the art.
Cardiomyocytes can be implanted to remuscularize the failing heart. Challenges include sufficient cardiomyocyte retention for a sustainable therapeutic impact without intolerable side effects, such as arrhythmia and tumour growth. We investigated the hypothesis that epicardial engineered heart muscle (EHM) allografts from induced pluripotent stem cell-derived cardiomyocytes and stromal cells structurally and functionally remuscularize the chronically failing heart without limiting side effects in rhesus macaques.
After confirmation of in vitro and in vivo (nude rat model) equivalence of the newly developed rhesus macaque EHM model with a previously established Good Manufacturing Practice-compatible human EHM formulation, long-term retention (up to 6 months) and dose-dependent enhancement of the target heart wall by EHM grafts constructed from 40 to 200 million cardiomyocytes/stromal cells were demonstrated in macaques with and without myocardial infarction-induced heart failure. In the heart failure model, evidence for EHM allograft-enhanced target heart wall contractility and ejection fraction, which are measures for local and global heart support, was obtained. Histopathological and gadolinium-based perfusion magnetic resonance imaging analyses confirmed cell retention and functional vascularization. Arrhythmia and tumour growth were not observed.
The obtained feasibility, safety and efficacy data provided the pivotal underpinnings for the approval of a first-in-human clinical trial on tissue-engineered heart repair. Our clinical data confirmed remuscularization by EHM implantation in a patient with advanced heart failure.
Mortality Effects of Healthy versus Unhealthy Plant Based Diets
https://www.fightaging.org/archives/2025/02/mortality-effects-of-healthy-versus-unhealthy-plant-based-diets/
In this meta-analysis, researchers review epidemiological studies that employed a simple classification system to assess both how healthy a diet is and how vegan it is, the plant-based diet index. It is perfectly possible to eat an unhealthy vegan diet: just consume a lot of sugar and processed grains. The result is much as one might expect, in that those adhering to a more vegan diet exhibit lower mortality provided that the diet is healthy. There is some debate regarding which of the possible mechanisms are important in producing this outcome, such as levels of inflammation, a modestly lower overall calorie and protein intake, and so forth.
The adherence to plant-based diets has been shown to positively impact longevity by reducing the incidence and severity of lifestyle-related diseases. Previous studies on the association of plant-based dietary pattern, as evaluated by plant-based dietary index (PDI), healthy plant-based dietary index (hPDI) and unhealthy plant-based dietary index (uPDI), with mortality risk have reported inconsistent results. We performed the present meta-analysis to summarize evidence on this association and to quantify the potential dose-response relationship based on all available cohort studies.
A total of 11 eligible cohort studies (13 datasets) were eventually included in this meta-analysis. Participants in the highest quintile of both the PDI and hPDI had a significantly decreased risk of all-cause mortality (pooled hazard ratio for PDI = 0.85; pooled hazard ratio for hPDI = 0.86) compared to participants in the lowest quintile. In contrast, the highest uPDI was associated with an increased risk of mortality (pooled hazard ratio for uPDI = 1.20). In conclusion, greater adherence to PDI or hPDI dietary pattern was associated with a lower risk of mortality, whereas uPDI dietary pattern was positively associated with mortality risk.
Exposure to Cold as an Approach to Modestly Slow Aging
https://www.fightaging.org/archives/2025/02/exposure-to-cold-as-an-approach-to-modestly-slow-aging/
Mild stresses are observed to slow aging in short-lived species, sometimes dramatically. Low nutrient intake, heat, cold, toxins, and anything else that makes cells react by upregulating maintenance processes tends to produce sweeping improvements in metabolism, reduced inflammation, and a range of other benefits. This results in extended healthy life span. Unfortunately, long-lived species such as our own do not exhibit anywhere near the same degree of extended life, even while the cellular biochemistry of the response to mild stress looks very similar. The underlying reasons for this difference have yet to be established.
Although the longevity benefits of low temperatures were documented over a century ago, the precise mechanisms by which cold influences lifespan and healthspan are not fully understood. The prevailing hypothesis suggests that cold-induced longevity is mainly attributed to a slowdown in the rate of biochemical reactions and metabolic processes, leading to reduced energy expenditure and a decelerated pace of physiological activities. Recent research, however, has uncovered more intricate mechanisms through which cold exposure can extend lifespan and improve health.
Cold exposure has been shown to impact several key physiological processes related to aging. One of the major mechanisms is its ability to reduce chronic inflammation, a condition often referred to as “inflammaging”. Chronic, low-grade inflammation is a hallmark of aging and is associated with the development of various age-related diseases, including cardiovascular diseases, diabetes, and neurodegenerative disorders. It has been reported that cold exposure can mitigate inflammation by modulating immune responses and reducing the production of pro-inflammatory cytokines in healthy individuals as well as patients with inflammatory diseases. These cytokines are typically elevated in chronic inflammation and are associated with various age-related diseases. By lowering their production, cold exposure may help decrease systemic inflammation.
Another significant aspect of aging is oxidative stress, which results from the accumulation of reactive oxygen species (ROS) that causes damage to cellular components and contributes to cellular aging and various diseases. The free radical theory of aging posits that oxidative stress is a major driver of the aging process. Cold exposure has been shown to reduce oxidative stress and enhance the body’s antioxidant defenses, thereby reducing inflammation and protecting cells from damage.
Metabolic regulation is also profoundly affected by cold exposure by increasing energy expenditure and altering metabolic pathways. Activating brown adipose tissue (BAT) through cold exposure increases energy expenditure and improves metabolic health. This process enhances insulin sensitivity, promotes lipid metabolism, and helps to regulate glucose metabolism, thereby mitigating inflammatory responses associated with metabolic dysfunction. These metabolic pathways play a crucial role in maintaining overall health and longevity. Additionally, recent studies have also revealed that cold exposure can activate proteasomes through PA28γ/PSME3 pathway, enhancing protein degradation and reducing disease-related protein aggregation.
Despite the promising short-term benefits of cold exposure, the long-term effects remain unclear. Epidemiological studies present a paradox: while short-term cold exposure seems to offer health benefits, populations living in high-altitude cold environments face an increased health risks, including higher mortality rates and a greater incidence of cardiovascular diseases. This complexity underscores the need for further research to fully understand the relationship between cold exposure and aging.
Age-Related Epigenetic Changes Impair Memory Function
https://www.fightaging.org/archives/2025/02/age-related-epigenetic-changes-impair-memory-function/
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.
Identifying a Specific Inflammatory Signal as a Contribution to Atrial Fibrillation
https://www.fightaging.org/archives/2025/02/identifying-a-specific-inflammatory-signal-as-a-contribution-to-atrial-fibrillation/
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.
Continued Efforts to Grow Engineered Teeth in a Large Mammal
https://www.fightaging.org/archives/2025/02/continued-efforts-to-grow-engineered-teeth-in-a-large-mammal/
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.
Epigenetic Changes Driven by Oxidative Stress in the Aging Brain
https://www.fightaging.org/archives/2025/02/epigenetic-changes-driven-by-oxidative-stress-in-the-aging-brain/
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.
